Obesity

C

Comorbidities

Obesity <-> Gastroesophageal Reflux Disease

Obesity <-> Heart Failure

Obesity <-> Obstructive Sleep Apnea

Obesity <-> Polycystic Ovary Syndrome

◈

Mechanistic Hypotheses

1

Amplification of polygenic obesity risk in adverse contexts via shared energy-imbalance convergence

pgs_context_amplification EMERGING

Evidence balance 2 support

Polygenic-score-by-context (PGS×C) interactions reported for obesity in the UK Biobank appear to reflect amplification rather than context-specific causal variants: the same susceptibility loci (e.g. FTO, MC4R, and other appetite/CNS-acting variants) exert systematically larger effects in disease-promoting contexts. This entry proposes that the amplification arises because polygenic liability and adverse exposures — obesogenic diet, physical inactivity, alcohol intake and socioeconomic deprivation — converge on the shared Energy Imbalance node, so their joint effect on the liability-threshold scale is super-additive rather than additive. Nagpal & Gibson (Nat Genet 2026, PMID:42443528) show amplifying context pairs for BMI-defined obesity (e.g. glucose with omega-3 fatty acids, and walking pace with beer intake) and note that the major contexts differ between BMI- and waist-to-hip-ratio definitions, consistent with BMI polymorphisms acting on central appetite regulation versus WHR variants acting on peripheral metabolic traits.

EMERGING hypothesis motivated by population-scale PGS×context analyses (primary source PMID:42443528; general amplification mechanism corroborated by PMID:37228747). The convergence claim (polygenic liability + adverse exposures → Energy Imbalance) is a mechanistic interpretation and is not itself established as causal — see the reverse-causation knowledge gap under discussions.

Show evidence (2 references)

PMID:42443528 SUPPORT Computational

"The predominant mechanism for PGS×C is the amplification of genetic effects in adverse contexts, such as low polyunsaturated fatty acids or social determinants of ill health"

Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and 75 contexts, amplification of genetic effects in adverse contexts is identified as the predominant mechanism of PGS×context interaction — the mechanism applied in this hypothesis.

PMID:37228747 SUPPORT Computational

"GxSex is pervasive but acts primarily through systematic sex differences in the magnitude of many genetic effects"

Corroborates amplification — systematic differences in the magnitude of polygenic effects rather than in the identity of causal variants — as the primary mode of gene-by-context interaction.

?

Discussions and Knowledge Gaps

2

Are the obesity PGS×context interactions driven by adverse exposures causally amplifying genetic risk, or are some "contexts" (e.g. fasting insulin, leptin, reduced physical activity) actually downstream consequences of adiposity (reverse causation)?

KNOWLEDGE GAP OPEN obesity_pgsxc_reverse_causation

Attached to

pathophysiology#Energy Imbalance biochemical#Leptin biochemical#Fasting Insulin environmental#Sedentary Lifestyle

Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are largely unable to establish the causality of specific contexts. For obesity this is acute for the biochemical "contexts": leptin and fasting insulin rise as a consequence of increased fat mass and are modelled in this entry as readouts of adipose dysfunction rather than upstream drivers, and reduced physical activity or slower walking pace may be consequences of established obesity rather than causes. Distinguishing genuine amplification of genetic effects from reverse causation determines whether the modelled lifestyle interventions would actually reduce risk.

Proposed experiments

Mendelian randomization of exposure-to-obesity direction across PGS strata

obesity_pgsxc_mr_direction

Use bidirectional / multivariable Mendelian randomization to test whether each candidate context (physical activity, alcohol, fasting insulin, leptin) causally affects adiposity versus being a consequence of it, and whether the causal effect estimate scales with polygenic liability as the amplification model predicts.

Decision criterion

A context is retained as a causal amplifier if MR supports exposure-to-disease directionality and the exposure-attributable risk difference increases across increasing PGS strata; it is flagged as a reverse-causation suspect otherwise.

Prospective incident-obesity analysis restricted to pre-onset exposure windows

obesity_pgsxc_prospective_temporal

Restrict exposures to measurements taken well before obesity onset and repeat the PGS×context liability-threshold modelling on incident cases only, to reduce the chance that exposure values (particularly activity and metabolic biomarkers) reflect established adiposity rather than antecedent risk.

Decision criterion

Amplification is supported if the PGS×context deviation from additivity persists when only pre-onset exposure windows and incident cases are used.

Does baseline fecal Akkermansia muciniphila abundance decide who benefits from A. muciniphila supplementation, and if so, is the mechanism headroom for improvement or something about the resident community?

KNOWLEDGE GAP OPEN akkermansia_baseline_abundance_responder

Attached to

treatments#Pasteurized Akkermansia muciniphila MucT Supplementation pathophysiology#Depletion of Mucosal Symbiont Akkermansia muciniphila

Two independent trials of different preparations point the same way. In the weight-maintenance trial (PMID:42120725) participants stratified below the median fecal A. muciniphila level after weight loss regained less weight and improved more in insulin sensitivity, blood pressure and fecal energy content than those above it, with no such split in the placebo arm; that analysis was exploratory and post hoc. In a separate trial of live AKK-WST01 in overweight/obese type 2 diabetes (PMID:39879980), benefit and colonization were likewise confined to the low-baseline group. If this holds prospectively it makes baseline abundance a pre-treatment stratifier rather than an incidental covariate, and it would change how a maintenance trial is powered and who is enrolled. The competing readings are not distinguished by the current data: greater room for improvement in depleted individuals, versus a resident community in high-abundance individuals that resists an added preparation. Note the mechanism cannot simply be colonization for the pasteurized product, which is non-viable.

Proposed experiments

Prospectively stratified maintenance trial by baseline fecal A. muciniphila

akkermansia_baseline_stratified_rct

Randomize weight-loss-maintenance participants to pasteurized MucT or placebo within strata defined prospectively by quantitative fecal A. muciniphila measured before randomization, powered on the stratum-by-treatment interaction rather than on the marginal effect, with fecal energy excretion measured against total daily fecal output.

Decision criterion

Baseline abundance is a genuine response modifier if the stratum-by-treatment interaction on weight regain is significant in a prospectively powered design; it is an artifact of the post hoc median split otherwise.

Show evidence (2 references)

PMID:42120725 SUPPORT PRIMARY RESULT Human Clinical

"Initial Akkermansia spp. abundance was associated with cardiometabolic response to MucT."

States the baseline-abundance dependence that this gap is about.

PMID:39879980 SUPPORT PRIMARY RESULT Human Clinical

"AKK-WST01 supplementation showed high colonization efficiency and significant reductions in body weight, fat mass, and HbA1c, which were not found in the placebo group."

Independent trial of a live preparation showing the same restriction of benefit to participants with low baseline abundance.

⚙

Pathophysiology

9

Energy Imbalance

Chronic positive energy balance from excess caloric intake relative to expenditure leads to fat accumulation. Multiple regulatory systems (leptin, ghrelin, insulin) fail to restore balance.

Energy Homeostasis GO:0097009

Show evidence (2 references)

PMID:17212793 SUPPORT

"Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation."

Describes the role of leptin and ghrelin as key hormones regulating energy balance in obesity.

PMID:17212793 SUPPORT

"In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant."

Explains the paradox of elevated leptin levels in obesity with concurrent leptin resistance, contributing to failed energy balance restoration.

Adipose Tissue Dysfunction

Expanded adipose tissue becomes dysfunctional with increased inflammation, altered adipokine secretion, and impaired metabolic function. Adipocyte hypertrophy leads to hypoxia and macrophage infiltration.

Adipocyte CL:0000136 Adipose Tissue Macrophage CL:0000863

Adipokine Secretion GO:0070163

Show evidence (3 references)

PMID:39456156 SUPPORT

"Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called "adipose tissue plasticity"."

Describes the dynamic remodeling of adipose tissue in response to obesity, including changes in cellular composition and metabolic function.

PMID:14679177 SUPPORT

"Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells."

Provides histological evidence of macrophage infiltration into dysfunctional adipose tissue in obesity.

PMID:14679177 SUPPORT

"These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance."

Establishes the causal role of adipose tissue macrophages in obesity-related metabolic dysfunction.

Chronic Low-Grade Inflammation

Systemic inflammation from adipose tissue contributes to insulin resistance, cardiovascular disease, and other complications. Elevated CRP, IL-6, and TNF-alpha levels.

Inflammatory Response GO:0006954

Show evidence (3 references)

PMID:14679177 SUPPORT

"Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance."

Establishes both correlative and causative links between chronic inflammation and insulin resistance in obesity.

PMID:14679177 SUPPORT

"We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue."

Proposes that obesity-induced insulin resistance represents a chronic inflammatory disease originating in adipose tissue.

PMID:27503945 SUPPORT

"Particularly chronic inflammation in adipose tissue seems to play an important role in the development of obesity-related insulin resistance."

Highlights the central role of chronic adipose tissue inflammation in obesity-related insulin resistance.

Hypothalamic Dysregulation

Central appetite regulation becomes impaired with leptin resistance and altered reward signaling, perpetuating overeating despite adequate energy stores. Hypothalamic neuroinflammation involves microglial and astrocyte activation that impairs melanocortin signaling. The genes bound to this node are the ones whose disruption is known to produce this state: leptin and its hypothalamic receptor LepRb set the afferent arm, and the melanocortin-4 receptor pathway downstream of it is the arm whose disruption produces hyperphagia. In common obesity these genes act as susceptibility rather than as sufficient causes; the monogenic diseases in which they are sufficient are curated separately (see notes).

Hypothalamus Cell CL:2000030 Microglial Cell CL:0000129

LEP hgnc:6553 LEPR hgnc:6554 POMC hgnc:9201 MC4R hgnc:6932

Feeding Behavior GO:0007631

Show evidence (4 references)

PMID:38490517 SUPPORT

"Leptin acts through its receptor LepRb, expressed mainly in the hypothalamus, and induces a negative energy balance by potent inhibition of feeding and activation of energy expenditure."

Describes the central hypothalamic mechanism by which leptin normally regulates energy balance.

PMID:38490517 SUPPORT

"However, the majority of patients with obesity presents elevated leptin production, suggesting that in this setting leptin is ineffective in the regulation of energy balance."

Explains leptin resistance in obesity where elevated leptin fails to regulate energy balance through hypothalamic circuits.

PMID:35528826 SUPPORT Human Clinical

"Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity."

Supports binding POMC and MC4R to this node: the melanocortin-4 receptor pathway is the hypothalamic circuit whose failure produces hyperphagia, and biallelic defects in it are the clearest demonstration of that circuit's role in human appetite regulation.

+ 1 more reference

Adipocyte Mitochondrial Dysfunction

Obesity causes mitochondrial fragmentation in white adipocytes through RalA-mediated activation of the fission protein DRP1 (DNM1L). This leads to reduced oxidative capacity and contributes to weight gain and insulin resistance. Mitochondrial dynamics shift toward excessive fission.

Adipocyte CL:0000136

Mitochondrial Fission GO:0000266 Fatty Acid Oxidation GO:0019395

Show evidence (3 references)

PMID:38286821 SUPPORT

"Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA."

Demonstrates that obesity causes mitochondrial fragmentation through RalA in white adipocytes.

PMID:38286821 SUPPORT

"Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation."

Describes the molecular mechanism by which RalA promotes mitochondrial fission through DRP1 dephosphorylation.

PMID:38286821 SUPPORT

"Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance."

Provides human evidence linking DNM1L expression to obesity and insulin resistance.

Depletion of Mucosal Symbiont Akkermansia muciniphila

Akkermansia muciniphila is a mucin-degrading symbiont of the colonic mucus layer that uses host-derived mucus as its primary carbon and nitrogen source, placing it directly at the host-microbe interface. Its relative abundance is reduced in obesity, type 2 diabetes and metabolic syndrome and correlates inversely with body weight in rodents and humans. Loss of this population removes a signal that supports mucus-layer thickness and epithelial barrier integrity, and is the state that A. muciniphila-directed interventions are designed to compensate for.

mucus-layer maintenance at the colonic epithelium GO:0030277 ↓ DECREASED

Downstream

Intestinal Barrier Dysfunction and Metabolic Endotoxemia Fewer mucus-resident Akkermansia is associated with a thinner mucus layer and a more permeable epithelium in rodent models of diet-induced obesity.

Show evidence (3 references)

PMID:23671105 SUPPORT PRIMARY RESULT Model Organism

"This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice."

Direct measurement showing the symbiont is depleted in obese and diabetic animals.

PMID:31263284 SUPPORT INDIRECT BACKGROUND Human Clinical

"In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension"

States the human cohort evidence for depletion in obesity. The quoted sentence is this trial report's summary of prior human studies rather than its own measurement, hence quote_role BACKGROUND; the correlation is also cross-sectional, so it bears on the depletion claim only indirectly.

PMID:32167023 SUPPORT BACKGROUND Human Clinical

"The abundance of A. muciniphila is severely reduced in several pathological conditions (i.e., obesity, type 2 diabetes, inflammatory bowel diseases, and appendicitis)."

Restates the human disease-state depletion across conditions. Quoted from the introduction of a mouse study, so the paper is MODEL_ORGANISM work but the sentence reports the human clinical picture.

Intestinal Barrier Dysfunction and Metabolic Endotoxemia

Thinning of the colonic mucus layer and loss of epithelial barrier integrity allow bacterial lipopolysaccharide to reach the systemic circulation, producing the low-grade endotoxemia that couples the gut to adipose inflammation and insulin resistance. A. muciniphila supports barrier function at least partly through its abundant outer-membrane protein Amuc_1100, a Toll-like receptor 2 ligand that survives pasteurization.

lipopolysaccharide-mediated signaling pathway GO:0031663 ↑ INCREASED

Downstream

Chronic Low-Grade Inflammation Circulating lipopolysaccharide engages innate immune receptors and sustains the systemic inflammatory tone already established in expanded adipose tissue.

Show evidence (2 references)

PMID:23671105 SUPPORT INDIRECT Model Organism

"we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance"

The barrier/endotoxemia step is inferred from the therapeutic result: restoring the symbiont reverses metabolic endotoxemia and adipose inflammation in mice. Graded INDIRECT because the claim follows from the response to treatment rather than from a measurement of the untreated mechanism.

PMID:27892954 SUPPORT PRIMARY RESULT Model Organism

"We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium."

Identifies the molecular route from the symbiont to barrier function, and the thermostability that makes a pasteurized preparation plausible.

Efficient Intestinal Energy Harvest

The share of ingested energy that is absorbed rather than excreted in feces is a determinant of energy balance that sits upstream of adipose expansion. In diet-induced obese mice, pasteurized A. muciniphila lowers food energy efficiency and raises fecal energy excretion, apparently through reduced carbohydrate absorption and faster intestinal epithelial turnover, implying that the untreated state retains a correspondingly larger fraction of ingested energy.

intestinal absorption GO:0050892 ↑ INCREASED

Downstream

Energy Imbalance Energy retained rather than excreted adds to the positive balance that drives fat accumulation.

Show evidence (2 references)

PMID:32167023 SUPPORT INDIRECT Model Organism

"we observed that treatment with pasteurized A. muciniphila increased energy excretion in the feces"

The absorption step is inferred from its modification: treatment shifts energy from absorption to excretion, so the untreated state absorbs more.

PMID:32167023 SUPPORT PRIMARY RESULT Model Organism

"we demonstrated that this effect was not due to the modulation of intestinal lipid absorption or chylomicron synthesis but likely involved a reduction of carbohydrates absorption and enhanced intestinal epithelial turnover"

Localizes the effect to carbohydrate absorption and epithelial turnover rather than to lipid handling.

Post-Weight-Loss Weight Regain

After energy restriction the body defends its previous mass through a coordinated set of responses: resting energy expenditure falls disproportionately to fat-free mass, anorexigenic signals fall while orexigenic signals rise, and shrinking adipocytes generate extracellular-matrix stress and immune activation in subcutaneous adipose tissue. Adipose tissue additionally retains a transcriptional and epigenetic memory of the prior obese state that primes it for accelerated regain. This node, rather than weight loss itself, is what maintenance therapy targets.

defense of pre-diet body mass GO:0097009

Downstream

Increased Body Mass Index Regain restores the adiposity phenotype that the weight-loss phase reduced.

Show evidence (2 references)

PMID:30655624 SUPPORT REVIEW SYNTHESIS Human Clinical

"we show that weight loss-induced variations in cellular stress, extracellular matrix remodelling, inflammatory responses, adipokine secretion and lipolysis seem to be associated with the amount of weight that is regained after successful weight loss"

Synthesis of the human adipose-tissue responses associated with how much weight is regained. It is a review's synthesis of work it did not perform, hence quote_role REVIEW_SYNTHESIS.

PMID:39558077 SUPPORT PRIMARY RESULT Model Organism

"Mice carrying this obesogenic memory show accelerated rebound weight gain"

Shows the adipose memory is not merely correlative: animals carrying it regain weight faster. The corresponding human data in the same study are transcriptional rather than an observed regain rate.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

7

Cardiovascular 1

Hypertension FREQUENT HP:0000822

Show evidence (1 reference)

PMID:19320986 SUPPORT Human Clinical

"Statistically significant associations with obesity were found with the incidence of type II diabetes, all cancers except esophageal and prostate cancer, all cardiovascular diseases, asthma, gallbladder disease, osteoarthritis and chronic back pain."

Systematic review and meta-analysis linking obesity to incident cardiovascular disease, supporting hypertension as an obesity-related complication.

Metabolism 2

Insulin Resistance VERY_FREQUENT HP:0000855

Show evidence (2 references)

PMID:14679177 SUPPORT

"Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues."

Defines insulin resistance as a key metabolic phenotype in obesity.

PMID:27503945 SUPPORT

"Insulin resistance may link accumulation of adipose tissue in obesity to metabolic diseases, although the underlying mechanisms are not completely understood."

Links adipose tissue accumulation in obesity to insulin resistance and metabolic disease.

Dyslipidemia FREQUENT Hyperlipidemia HP:0003077

Nervous System 1

Obstructive Sleep Apnea FREQUENT HP:0010535

Constitutional 2

Joint Pain FREQUENT Arthralgia HP:0002829

Weight-bearing joint stress

Show evidence (1 reference)

PMID:19320986 SUPPORT Human Clinical

"The meta-analysis determined statistically significant associations for overweight with the incidence of type II diabetes, all cancers except esophageal (female), pancreatic and prostate cancer, all cardiovascular diseases (except congestive heart failure), asthma, gallbladder disease,..."

Meta-analysis linking excess weight to incident osteoarthritis and chronic back pain, supporting joint pain as an obesity-related musculoskeletal complication.

Fatigue FREQUENT HP:0012378

Growth 1

Increased Body Mass Index VERY_FREQUENT Obesity HP:0001513

BMI greater than or equal to 30 kg/m2

🧬

Genetic Associations

5

FTO (Risk Factor)

Gene: FTO hgnc:24678 gene page relationship_type: RISK_FACTOR variant_origin: GERMLINE

Show evidence (1 reference)

PMID:17434869 SUPPORT Human Clinical

"The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele."

Large genome-wide association study establishing the common FTO variant as a robust risk factor for higher BMI and obesity.

MC4R (Risk Factor)

Gene: MC4R hgnc:6932 gene page relationship_type: RISK_FACTOR variant_origin: GERMLINE

Show evidence (1 reference)

PMID:29031731 SUPPORT BACKGROUND Human Clinical

"While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R."

Quantifies the contribution of heterozygous MC4R variants to severe obesity. Graded BACKGROUND because the sentence is the framing of a setmelanotide trial rather than that trial's own result.

LEP (Causative)

Gene: LEP hgnc:6553 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:9202122 SUPPORT Human Clinical

"The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans."

First human evidence that a homozygous LEP frameshift mutation causes severe early-onset obesity via leptin deficiency.

LEPR (Causative)

Gene: LEPR hgnc:6554 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:17229951 SUPPORT PRIMARY RESULT Human Clinical

"The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%."

Establishes how much of severe early-onset obesity biallelic LEPR deficiency accounts for in a systematically screened cohort.

POMC (Causative)

Gene: POMC hgnc:9201 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:35528826 SUPPORT Human Clinical

"Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity."

Supports POMC as a causative gene acting through the melanocortin-4 receptor pathway in severe early-onset obesity.

💊

Medical Actions

8

Lifestyle Modification

Action: Lifestyle Therapy NCIT:C15900

Platform: Behavioral / lifestyle

Dietary changes and increased physical activity as foundation of treatment.

Mechanism Target:

INHIBITS Energy Imbalance — Reducing energy intake and raising expenditure acts directly on the energy balance node. The link is definitional rather than empirical, so it carries no evidence of its own; the treatment's efficacy evidence is on the treatment itself.

Show evidence (1 reference)

PMID:25182101 SUPPORT Human Clinical

"Significant weight loss was observed with any low-carbohydrate or low-fat diet."

Meta-analysis of randomized trials showing dietary lifestyle modification produces significant weight loss in overweight and obese adults.

GLP-1 Receptor Agonists

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: semaglutide CHEBI:167574 liraglutide CHEBI:71193

Platform: Peptide

Semaglutide, liraglutide provide substantial weight loss through central appetite suppression and metabolic effects.

Mechanism Target:

MODULATES Hypothalamic Dysregulation — GLP-1 receptor agonism acts on central appetite and food-reward circuits, restoring the satiety signalling that leptin resistance has blunted.

Show evidence (1 reference)

PMID:28266779 SUPPORT PRIMARY RESULT Human Clinical

"Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods."

Mechanism-of-action crossover trial measuring the appetite and food-reward changes this node describes.

INHIBITS Energy Imbalance — The appetite effect converts into a measured reduction in ad libitum energy intake, which is what moves the energy balance node.

Show evidence (1 reference)

PMID:28266779 SUPPORT PRIMARY RESULT Human Clinical

"ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide"

Directly measures energy intake, the quantity the Energy Imbalance node is about.

INHIBITS Post-Weight-Loss Weight Regain — Suppression of regain is contingent on continued dosing: in the STEP 1 off-treatment extension participants regained two-thirds of their lost weight within a year of stopping, and cardiometabolic gains reverted with it. The drug holds the regain node down rather than resolving it.

Show evidence (1 reference)

PMID:35441470 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables"

That regain resumes on withdrawal establishes that the treatment had been acting on this node. Graded INDIRECT because the suppression is inferred from what happens when the drug is stopped.

Show evidence (2 references)

PMID:33567185 SUPPORT Human Clinical

"In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight."

STEP 1 randomized trial demonstrating substantial, sustained weight loss with the GLP-1 receptor agonist semaglutide in obesity.

PMID:41782434 SUPPORT Other

"Strong recommendations were made for bupropion-naltrexone, semaglutide, tirzepatide, and setmelanotide, with moderate-certainty evidence."

The joint TOS/OMA/OAC pharmacological-management guidance makes a strong recommendation for semaglutide (a GLP-1 receptor agonist) for adults with obesity.

GLP-1/GIP Dual Agonists

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: tirzepatide CHEBI:194186

Platform: Peptide

Tirzepatide offers enhanced weight loss of 15-25% through dual incretin receptor activation.

Mechanism Target:

INHIBITS Energy Imbalance — Dual GIP/GLP-1 receptor agonism reduces energy intake and produces sustained weight reduction. No tirzepatide-specific energy-intake measurement is cited here, so the link carries no evidence of its own.

INHIBITS Post-Weight-Loss Weight Regain — SURMOUNT-4 is a randomized withdrawal design and so measures this node directly: after a 36-week lead-in, participants switched to placebo regained weight while those continuing treatment did not.

Show evidence (1 reference)

PMID:38078870 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction."

A randomized withdrawal trial whose endpoint is weight-loss maintenance, which is this node.

Show evidence (2 references)

PMID:35658024 SUPPORT Human Clinical

"In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight."

SURMOUNT-1 randomized trial showing the GLP-1/GIP dual agonist tirzepatide produces substantial, sustained weight loss in obesity.

PMID:41782434 SUPPORT Other

"Strong recommendations were made for bupropion-naltrexone, semaglutide, tirzepatide, and setmelanotide, with moderate-certainty evidence."

The joint TOS/OMA/OAC pharmacological-management guidance makes a strong recommendation for tirzepatide (a GLP-1/GIP dual agonist) for adults with obesity.

Bariatric Surgery

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Roux-en-Y gastric bypass, sleeve gastrectomy for severe obesity.

Mechanism Target:

MODULATES Hypothalamic Dysregulation — Rerouting the gut alters the entero-hypothalamic endocrine axis: postprandial PYY and GLP-1 rise after Roux-en-Y gastric bypass but not after gastric banding producing equivalent weight loss, so the effect is anatomical rather than a consequence of having lost weight.

Show evidence (1 reference)

PMID:16371744 SUPPORT PRIMARY RESULT Human Clinical

"Compared with lean and obese controls, patients following Roux-en-Y gastric bypass (RYGB) had increased postprandial plasma PYY and GLP-1 favoring enhanced satiety."

Measures the gut-hormone change that acts on central satiety signalling.

INHIBITS Energy Imbalance — Restriction plus the anorectic hormone profile lowers energy intake. Carried as a description rather than evidence because the cited trials measure weight and risk factors, not energy intake.

Show evidence (1 reference)

PMID:15616203 SUPPORT Human Clinical

"As compared with conventional therapy, bariatric surgery appears to be a viable option for the treatment of severe obesity, resulting in long-term weight loss, improved lifestyle, and, except for hypercholesterolemia, amelioration in risk factors that were elevated at baseline."

Swedish Obese Subjects study showing bariatric surgery produces durable weight loss and risk-factor improvement in severe obesity.

Behavioral Therapy

Action: behavioral counseling Ontology label: Behavioral Counseling NCIT:C181743

Platform: Behavioral / lifestyle

Cognitive behavioral therapy for eating behaviors.

Show evidence (1 reference)

PMID:38285378 SUPPORT REVIEW SYNTHESIS Human Clinical

"Our results indicated that CBT and BT are effective interventions for weight loss, and that successful weight loss requires more aggressive interventions such as BT or CBT than MC and UC."

Network meta-analysis of randomized trials placing CBT and behavioral therapy above usual and minimal care for weight loss. REVIEW_SYNTHESIS because the pooled estimate synthesizes trials the authors did not run.

Orlistat

Action: Pharmacotherapy NCIT:C15986

Agent: orlistat CHEBI:94686

Platform: Small molecule

Lipase inhibitor reducing fat absorption.

Mechanism Target:

INHIBITS Efficient Intestinal Energy Harvest — Gastrointestinal lipase inhibition blocks hydrolysis of dietary triglyceride, so ingested fat leaves in the stool instead of being absorbed. Orlistat and pasteurized A. muciniphila MucT both act on this node by unrelated routes: one blocks a digestive enzyme, the other is reported to reduce carbohydrate absorption and raise epithelial turnover.

Show evidence (1 reference)

PMID:39783852 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"MR-O and Conv-O similarly increased fecal fat percentage from 3.8% to 13.5%, confirming pharmacodynamic equivalence."

Human pharmacodynamic measurement of the shift from absorption to fecal excretion that defines this node.

INHIBITS Post-Weight-Loss Weight Regain — The European Multicentre trial's second year is a maintenance phase, in which continuing orlistat halved the regain seen after switching to placebo.

Show evidence (1 reference)

PMID:9683204 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo"

Second-year maintenance result, measuring regain directly.

Show evidence (1 reference)

PMID:9683204 SUPPORT Human Clinical

"Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period."

European Multicentre Orlistat randomized trial demonstrating the lipase inhibitor orlistat produces clinically significant weight loss in obese patients.

Naltrexone-Bupropion

Action: Pharmacotherapy NCIT:C15986

Agent: naltrexone CHEBI:7465 bupropion CHEBI:3219

Platform: Small molecule

Fixed-dose sustained-release naltrexone plus bupropion, developed to act on two complementary central pathways: bupropion stimulates hypothalamic POMC neurons, and naltrexone blocks the opioid-mediated autoinhibitory feedback that otherwise limits that stimulation. Approved for chronic weight management and strongly recommended in the joint TOS/OMA/OAC guidance already cited elsewhere in this entry.

Mechanism Target:

MODULATES Hypothalamic Dysregulation — Both components act on central circuits regulating body weight rather than on peripheral energy handling, which is what places this treatment on the hypothalamic node.

Show evidence (1 reference)

PMID:20673995 SUPPORT INDIRECT BACKGROUND Other

"Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight."

States the central mechanism the combination was designed around. It is the trial's framing of prior pharmacology rather than a result of the trial, so it is graded BACKGROUND and OTHER, and bears on the node only indirectly.

Show evidence (2 references)

PMID:20673995 SUPPORT PRIMARY RESULT Human Clinical

"84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion"

COR-I co-primary endpoint, the proportion achieving at least 5% weight loss.

PMID:41782434 SUPPORT Other

"Strong recommendations were made for bupropion-naltrexone, semaglutide, tirzepatide, and setmelanotide, with moderate-certainty evidence."

The joint TOS/OMA/OAC guidance makes a strong recommendation for bupropion-naltrexone for adults with obesity.

Pasteurized Akkermansia muciniphila MucT Supplementation

Action: pasteurized Akkermansia muciniphila MucT supplementation Ontology label: Nutritional Support NCIT:C15433

Platform: Other

Daily oral capsules of pasteurized Akkermansia muciniphila MucT (heat-treated 30 minutes at 70 C; 3 x 10^10 inactivated cells per capsule) taken during the weight maintenance phase that follows a low-energy diet. Heat inactivation removes the oxygen sensitivity and manufacturing constraints of the live organism while preserving the thermostable outer-membrane protein Amuc_1100, and in rodents it increased rather than abolished the metabolic benefit. The indication tested is maintenance of weight already lost, not weight loss itself.

Mechanism Target:

INHIBITS Post-Weight-Loss Weight Regain — The registered primary outcome. Over 24 weeks of ad libitum healthy diet after an 8-week low-energy diet, the supplemented group regained less weight than placebo and ended with greater net weight loss from baseline.

Show evidence (1 reference)

PMID:42120725 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Here we show that MucT led to lower body weight regain versus placebo at the end of the weight maintenance period (MucT: 1.2 ± 0.7 kg, placebo: 3.2 ± 0.4 kg, P = 0.012)."

Primary outcome of the randomized trial, stating the effect on the targeted mechanism.

INHIBITS Efficient Intestinal Energy Harvest — Proposed mechanism: a shift of ingested energy from absorption to fecal excretion. Established in diet-induced obese mice; in the human trial the increase in fecal energy content did not reach significance, and only the within-group inverse association with weight change supported it.

Show evidence (1 reference)

PMID:32167023 SUPPORT PRIMARY RESULT Model Organism

"We confirmed that daily oral administration of pasteurized A. muciniphila alleviated diet-induced obesity and decreased food energy efficiency."

Shows the treatment acts on how efficiently ingested energy is retained.

RESTORES Intestinal Barrier Dysfunction and Metabolic Endotoxemia — Proposed mechanism: the thermostable outer-membrane protein Amuc_1100 signals through TLR2 and improves gut barrier function, which is the route by which a non-viable preparation can act on host metabolism without colonizing.

Show evidence (1 reference)

PMID:27892954 SUPPORT PRIMARY RESULT Model Organism

"We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium."

Establishes the barrier-directed mechanism and that it survives pasteurization.

Show evidence (4 references)

PMID:42120725 SUPPORT PRIMARY RESULT Human Clinical

"Additionally, the MucT group had a greater net weight loss from baseline to end of maintenance than the placebo group (3.1 ± 0.7 kg, P = 0.009)."

Net weight loss from baseline to the end of maintenance, the secondary anthropometric outcome.

PMID:42120725 SUPPORT PRIMARY RESULT Human Clinical

"No serious adverse events related to the treatment were observed."

Safety outcome of the 24-week maintenance trial.

PMID:31263284 SUPPORT PRIMARY RESULT Human Clinical

"Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity"

The earlier proof-of-concept human trial in metabolic syndrome, which found the metabolic signal without a significant weight effect on an unchanged ad libitum diet.

+ 1 more reference

🌍

Environmental Factors

5

High-Calorie Diet

Especially ultra-processed foods

Show evidence (1 reference)

PMID:31105044 SUPPORT Human Clinical

"participants gaining 0.9 ± 0.3 kg (p = 0.009) during the ultra-processed diet and losing 0.9 ± 0.3 kg (p = 0.007) during the unprocessed diet"

Inpatient randomized crossover trial with diets matched for presented calories, energy density, macronutrients, sugar, sodium and fibre -- so the 508 kcal/day excess intake and the weight change are attributable to processing itself rather than to nutrient composition. This is the strongest available design for the annotation claim.

Mechanism Target:

TRIGGERS Energy Imbalance — Ultra-processed diets drive excess energy intake and weight gain even when calories presented, energy density and macronutrients are matched.

Show evidence (1 reference)

PMID:31105044 SUPPORT DIRECT Human Clinical

"participants gaining 0.9 ± 0.3 kg (p = 0.009) during the ultra-processed diet and losing 0.9 ± 0.3 kg (p = 0.007) during the unprocessed diet"

Inpatient randomised crossover trial in which the excess intake and weight gain are attributable to food processing itself rather than nutrient composition. This is direct experimental support for the energy-imbalance node.

Sedentary Lifestyle

Sedentary behaviour is associated with becoming overweight or obese (OR 1.33 highest vs lowest category), though its association with body weight itself is small and inconsistent

Show evidence (2 references)

PMID:29189928 SUPPORT Human Clinical

"Meta-analysis of data from prospective cohort studies showed small, inconsistent and non-significant associations between sedentary behavior and body weight"

PARTIAL, and the note was rewritten, because this is less settled than it is usually assumed to be. The same meta-analysis did find a significant odds ratio of 1.33 for becoming overweight or obese in the highest versus lowest sedentary category, and a small waist-circumference effect -- but not an association with body weight, and it does not evidence the reduced-energy-expenditure mechanism the note previously asserted.

PMID:29189928 SUPPORT Human Clinical

"The odds ratio of becoming overweight or obese was 1.33 (95% CI 1.11-1.60; p = 0.001) in the highest compared with lowest categories of sedentary behavior"

Quotes the odds ratio the rewritten note states, so the note is self-supporting rather than relying on a figure the reader must go to the abstract to find. Paired deliberately with the PARTIAL item above: this is the positive signal, that one is the null result it sits inside.

Obesogenic Environment

Food availability, marketing, built environment

Show evidence (1 reference)

PMID:35290815 SUPPORT Human Clinical

"the number of and distance to unhealthy food outlets increased the likelihood of fast-food consumption and higher BMI for children of any SES"

Systematic review restricted to causal-inference studies. PARTIAL on two counts: the BMI effect is established for children of any socioeconomic status but among adults only for selected groups (females, black and Hispanic residents of low and medium density areas), and the marketing component of this annotation is not covered.

Mechanism Target:

PREDISPOSES Increased Body Mass Index — Density of and proximity to unhealthy food outlets raises fast-food consumption and body mass index.

Show evidence (1 reference)

PMID:35290815 SUPPORT INDIRECT Human Clinical

"the number of and distance to unhealthy food outlets increased the likelihood of fast-food consumption and higher BMI for children of any SES"

Systematic review restricted to causal-inference studies. The environment acts through consumption and the energy-imbalance node rather than on body mass directly, and the BMI effect is established for children of any socioeconomic status but among adults only for selected groups.

Sleep Deprivation

Alters appetite hormones

Show evidence (1 reference)

PMID:15602591 SUPPORT Human Clinical

"In Western societies, where chronic sleep restriction is common and food is widely available, changes in appetite regulatory hormones with sleep curtailment may contribute to obesity."

Population cohort study showing short sleep duration reduces leptin and elevates ghrelin, linking sleep deprivation to increased BMI and obesity risk.

Psychological Stress

Emotional eating

Show evidence (1 reference)

PMID:19926299 SUPPORT Other

"Stress and emotional brain networks foster eating behaviors that can lead to obesity"

States the emotional-eating route this annotation names, and gives the mechanism: stressors bias cognition toward emotional activity and degraded executive function, favouring habitual over deliberate food choice. OTHER because the quoted sentence is a review's mechanistic synthesis rather than a measurement.

🔬

Biochemical Markers

4

Leptin (Elevated)

Context: Leptin resistance present despite high levels

Adiponectin (Decreased)

Context: Reduced with adipose dysfunction

C-Reactive Protein (Elevated)

Context: Chronic inflammation marker

Fasting Insulin (Elevated)

Context: Compensatory hyperinsulinemia

🔬

Diagnosis

1

Body mass index (Diagnostic)

In clinical practice adult obesity is identified by body mass index, measured weight in kilograms divided by measured height in metres squared, against the WHO classification: a BMI of 30 kg/m2 or more defines obesity, graded I to III, and 25.0-29.9 kg/m2 defines overweight (pre-obesity). BMI estimates body fatness and does not capture its distribution, for which waist circumference is added.

body mass index measurement NCIT:C219071

body mass index LOINC:39156-5

Reference Ranges

Body mass index (BMI) [Ratio] (WHO BMI classification (WHO 1997), adults over 18 years, as tabulated in the 2015 European Guidelines for Obesity Management in Adults)

Healthy weight (18.5–25.0 kg/m2) Pre-obese state (overweight) (25.0–30.0 kg/m2) Obesity grade I (30.0–35.0 kg/m2) Obesity grade II (35.0–40.0 kg/m2) Obesity grade III (≥ 40.0 kg/m2)

Pre-obese state (overweight): Overweight, not obesity.

Source phrasing, from Table 1 "BMI categories (WHO 1997)" of the 2015 European guidelines: "Healthy weight | 18.5–24.9", "Pre-obese state | 25.0–29.9", "Obesity grade I | 30.0–34.9", "Obesity grade II | 35.0–39.9", "Obesity grade III | >40". Half-open bands, so "25.0–29.9" is recorded as [25, 30) and so on. The table writes grade III as ">40", which leaves exactly 40.0 in no category; the half-open band places it in grade III. The same table's underweight row (printed "<1.8.5" in the cached text, evidently 18.5) is a cut-off for underweight, not for obesity, and is not recorded; the healthy-weight band therefore starts at 18.5. The guideline text adds that lower BMI cut-off points apply to some ethnic groups. The WHO expert consultation on Asian populations (PMID:14726171) retained the WHO cut-off points as the international classification and proposed additional public health action points at 23.0, 27.5, 32.5 and 37.5 kg/m2 without redefining the categories for Asian populations, so no separate Asian range is recorded. The 2000 WHO technical report that set out the classification (PMID:11234459) is PubMed-indexed, but its abstract does not state the cut-off values.

Show evidence (6 references)

PMID:26641646 SUPPORT REVIEW SYNTHESIS Other

"In adults (age over 18 years) obesity is defined by a BMI 30 kg/m2 and overweight (also termed pre-obesity) by a BMI between 25 and 29.9 kg/m2."

States the adult obesity and overweight cut-offs. The cached text lacks a comparison sign before 30 kg/m2; the guideline's Table 1 gives obesity as BMI 30.0 and above.

PMID:26641646 SUPPORT REVIEW SYNTHESIS Other

"Pre-obese state | 25.0–29.9"

The WHO pre-obese (overweight) category as tabulated in the guideline.

PMID:26641646 SUPPORT REVIEW SYNTHESIS Other

"Obesity grade I | 30.0–34.9"

The WHO obesity grade I category.

+ 3 more references

LOINC:39156-5 is the method-less BMI code. The bands are the adult WHO classification only (the cited guideline applies it from age 18); no paediatric BMI cut-off is recorded here. The phenotype Increased Body Mass Index on this entry carries the same 30 kg/m2 threshold as free text.

Show evidence (3 references)

PMID:11234459 SUPPORT REVIEW SYNTHESIS Other

"In particular, the Consultation considered the system for classifying overweight and obesity based on the body mass index, and concluded that a coherent system is now available and should be adopted internationally."

The WHO consultation that adopted the BMI-based classification of overweight and obesity bound on this row.

PMID:26641646 SUPPORT REVIEW SYNTHESIS Other

"In clinical practice, the body fatness is usually estimated by BMI. BMI is calculated as measured body weight (kg) divided by measured height squared (m2)."

BMI as the clinical measurement of body fatness and its definition.

PMID:26641646 SUPPORT REVIEW SYNTHESIS Other

"Lower BMI cut-off points apply for some ethnic groups (e.g. Southeast Asians)"

The guideline's caveat that the WHO cut-offs are not universal.

📊

Related Datasets

4

Gut microbiome in obesity after weight-loss intervention bioproject:PRJNA290729

Whole metagenome shotgun sequencing characterizing gut microbial community of obese patients following weight-loss intervention. Tracks microbiome changes with weight loss.

human gut metagenome WGS

fecal sample UBERON:0001988

Conditions: obese pre-intervention obese post-weight loss

PMID:26934690

PLOS ONE 2016 - weight loss microbiome dynamics

Gut microbiome in pediatric NAFLD and obesity bioproject:PRJNA328258

Shotgun metagenomics examining taxonomic and functional differences between microbiomes of youth with obesity with and without non-alcoholic fatty liver disease (NAFLD).

human gut metagenome WGS n=36

fecal sample UBERON:0001988

Conditions: obese with NAFLD obese without NAFLD healthy controls

PMID:35344283

Hepatology Communications 2022

Gut microbiome of metabolically healthy obese individuals bioproject:PRJNA881023

Metagenomic characterization of gut microbiome in metabolically healthy obese (MHO) patients and correlations with metabolic and inflammatory profiles. 120 obese individuals without metabolic comorbidities.

human gut metagenome WGS n=120

fecal sample UBERON:0001988

Conditions: metabolically healthy obese

Scientific Reports 2024 - MHO microbiome signatures

Clostridia diversity and obesity association bioproject:PRJNA417579

High-resolution analysis of intra-species diversity in gut microbiome focusing on Clostridia class associations with obesity. 16S rRNA, dnaK, and gyrB gene sequencing.

human gut metagenome

fecal sample UBERON:0001988

Conditions: obese individuals lean controls

mSystems 2024 - Clostridia negatively associated with obesity

🔬

Clinical Trials

1

NCT05417360 NOT_APPLICABLE COMPLETED

Double-blind, placebo-controlled randomized trial at Maastricht University (n = 90 enrolled, 84 randomized, 80 completed). Participants first lost at least 8% of body weight on an 8-week low-energy diet, then took daily pasteurized A. muciniphila MucT or matched placebo for 24 weeks of ad libitum healthy diet. The primary outcome was change in body weight during the maintenance period.

Target Phenotypes: Obesity HP:0001513 Insulin Resistance HP:0000855

Show evidence (2 references)

clinicaltrials:NCT05417360 SUPPORT Other

"investigators hypothesize that pasteurized A. muciniphila will be superior to placebo intervention in maintaining body weight after a phase of weight loss (low caloric diet) in adult participants with overweight or obesity."

Registered hypothesis and population of the trial reported in PMID:42120725.

PMID:42120725 SUPPORT PRIMARY RESULT Human Clinical

"adults with overweight/obesity (n = 90) underwent an 8-week low-energy diet for ≥8% weight loss, followed by a 24-week healthy ad libitum diet with daily supplementation of pasteurized A. muciniphila MucT or placebo"

Design and population of the trial as reported in the primary publication.

{ }

Source YAML

click to show

name: Obesity
creation_date: '2025-12-18T17:01:35Z'
description: >-
  Obesity is a chronic metabolic disease characterized by excessive body fat
  accumulation resulting from sustained positive energy balance, in which
  regulatory systems involving leptin, ghrelin, and insulin fail to restore
  homeostasis. Expanded, dysfunctional adipose tissue develops chronic
  low-grade inflammation and altered adipokine secretion, while hypothalamic
  dysregulation and leptin resistance perpetuate excess intake. Genetic
  susceptibility (FTO, MC4R, LEP, LEPR) interacts with environmental and
  behavioral factors, and the resulting state drives insulin resistance,
  dyslipidemia, hypertension, and other cardiometabolic complications.
category: Complex
parents:
- Metabolic Disease
notes: >-
  This entry is the complex, common form of obesity and is bound to the MONDO
  class for it. The gene-defined monogenic diseases that MONDO files beneath that
  class, under MONDO:0019182 inherited obesity, are curated elsewhere and are not
  duplicated here as subtypes: LEP-related congenital leptin deficiency as
  Congenital_Leptin_Deficiency, and the LEPR, POMC, PCSK1, MC4R and SIM1 diseases
  as subtypes of Obesity_Due_to_MC4R_Pathway_Disruption, which models the shared
  leptin-melanocortin mechanism they converge on. MONDO:0014309 obesity due to
  CEP19 deficiency has no subtype row here either: CEP19 is curated as a
  Bardet-Biedl syndrome disease gene in Bardet-Biedl_Syndrome, following
  Orphanet's gene list for that syndrome. Syndromic obesity is likewise curated in
  the entries for the syndromes themselves, including Prader-Willi_Syndrome and
  Bardet-Biedl_Syndrome.

  The genes in the `genetic` section below are the ones this entry's own
  pathograph accounts for. FTO is the common-variant susceptibility locus and is
  not bound to a mechanism node because no node here models its mechanism.
disease_term:
  preferred_term: obesity disorder
  term:
    id: MONDO:0011122
    label: obesity disorder
pathophysiology:
- name: Energy Imbalance
  description: >
    Chronic positive energy balance from excess caloric intake relative
    to expenditure leads to fat accumulation. Multiple regulatory systems
    (leptin, ghrelin, insulin) fail to restore balance.
  biological_processes:
  - preferred_term: Energy Homeostasis
    term:
      id: GO:0097009
      label: energy homeostasis
  evidence:
  - reference: PMID:17212793
    reference_title: "The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review."
    supports: SUPPORT
    snippet: "Leptin is a mediator of long-term regulation of energy balance, suppressing food intake and thereby inducing weight loss. Ghrelin on the other hand is a fast-acting hormone, seemingly playing a role in meal initiation."
    explanation: Describes the role of leptin and ghrelin as key hormones regulating energy balance in obesity.
  - reference: PMID:17212793
    reference_title: "The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review."
    supports: SUPPORT
    snippet: "In obese subjects the circulating level of the anorexigenic hormone leptin is increased, whereas surprisingly, the level of the orexigenic hormone ghrelin is decreased. It is now established that obese patients are leptin-resistant."
    explanation: Explains the paradox of elevated leptin levels in obesity with concurrent leptin resistance, contributing to failed energy balance restoration.
- name: Adipose Tissue Dysfunction
  description: >
    Expanded adipose tissue becomes dysfunctional with increased inflammation,
    altered adipokine secretion, and impaired metabolic function. Adipocyte
    hypertrophy leads to hypoxia and macrophage infiltration.
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  - preferred_term: Adipose Tissue Macrophage
    term:
      id: CL:0000863
      label: M1 macrophage
  biological_processes:
  - preferred_term: Adipokine Secretion
    term:
      id: GO:0070163
      label: regulation of adiponectin secretion
  evidence:
  - reference: PMID:39456156
    reference_title: "Adipose Tissue Plasticity: A Comprehensive Definition and Multidimensional Insight."
    supports: SUPPORT
    snippet: "Under various physiological or pathological conditions, adipose tissue shifts cellular composition, lipid storage, and organelle dynamics to respond to the stress; this remodeling is called \"adipose tissue plasticity\"."
    explanation: Describes the dynamic remodeling of adipose tissue in response to obesity, including changes in cellular composition and metabolic function.
  - reference: PMID:14679177
    reference_title: "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance."
    supports: SUPPORT
    snippet: "Histologically, there is evidence of significant infiltration of macrophages, but not neutrophils and lymphocytes, into WAT of obese mice, with signs of adipocyte lipolysis and formation of multinucleate giant cells."
    explanation: Provides histological evidence of macrophage infiltration into dysfunctional adipose tissue in obesity.
  - reference: PMID:14679177
    reference_title: "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance."
    supports: SUPPORT
    snippet: "These data suggest that macrophages in WAT play an active role in morbid obesity and that macrophage-related inflammatory activities may contribute to the pathogenesis of obesity-induced insulin resistance."
    explanation: Establishes the causal role of adipose tissue macrophages in obesity-related metabolic dysfunction.
- name: Chronic Low-Grade Inflammation
  description: >
    Systemic inflammation from adipose tissue contributes to insulin
    resistance, cardiovascular disease, and other complications. Elevated
    CRP, IL-6, and TNF-alpha levels.
  biological_processes:
  - preferred_term: Inflammatory Response
    term:
      id: GO:0006954
      label: inflammatory response
  evidence:
  - reference: PMID:14679177
    reference_title: "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance."
    supports: SUPPORT
    snippet: "Increasing evidence from human population studies and animal research has established correlative as well as causative links between chronic inflammation and insulin resistance."
    explanation: Establishes both correlative and causative links between chronic inflammation and insulin resistance in obesity.
  - reference: PMID:14679177
    reference_title: "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance."
    supports: SUPPORT
    snippet: "We propose that obesity-related insulin resistance is, at least in part, a chronic inflammatory disease initiated in adipose tissue."
    explanation: Proposes that obesity-induced insulin resistance represents a chronic inflammatory disease originating in adipose tissue.
  - reference: PMID:27503945
    reference_title: "Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance?"
    supports: SUPPORT
    snippet: "Particularly chronic inflammation in adipose tissue seems to play an important role in the development of obesity-related insulin resistance."
    explanation: Highlights the central role of chronic adipose tissue inflammation in obesity-related insulin resistance.
- name: Hypothalamic Dysregulation
  description: >
    Central appetite regulation becomes impaired with leptin resistance
    and altered reward signaling, perpetuating overeating despite adequate
    energy stores. Hypothalamic neuroinflammation involves microglial and
    astrocyte activation that impairs melanocortin signaling. The genes bound to
    this node are the ones whose disruption is known to produce this state: leptin
    and its hypothalamic receptor LepRb set the afferent arm, and the
    melanocortin-4 receptor pathway downstream of it is the arm whose disruption
    produces hyperphagia. In common obesity these genes act as susceptibility
    rather than as sufficient causes; the monogenic diseases in which they are
    sufficient are curated separately (see notes).
  genes:
  - preferred_term: LEP
    term:
      id: hgnc:6553
      label: LEP
  - preferred_term: LEPR
    term:
      id: hgnc:6554
      label: LEPR
  - preferred_term: POMC
    term:
      id: hgnc:9201
      label: POMC
  - preferred_term: MC4R
    term:
      id: hgnc:6932
      label: MC4R
  cell_types:
  - preferred_term: Hypothalamus Cell
    term:
      id: CL:2000030
      label: hypothalamus cell
  - preferred_term: Microglial Cell
    term:
      id: CL:0000129
      label: microglial cell
  biological_processes:
  - preferred_term: Feeding Behavior
    term:
      id: GO:0007631
      label: feeding behavior
  evidence:
  - reference: PMID:38490517
    reference_title: "Novel mechanisms involved in leptin sensitization in obesity."
    supports: SUPPORT
    snippet: "Leptin acts through its receptor LepRb, expressed mainly in the hypothalamus, and induces a negative energy balance by potent inhibition of feeding and activation of energy expenditure."
    explanation: Describes the central hypothalamic mechanism by which leptin normally regulates energy balance.
  - reference: PMID:38490517
    reference_title: "Novel mechanisms involved in leptin sensitization in obesity."
    supports: SUPPORT
    snippet: "However, the majority of patients with obesity presents elevated leptin production, suggesting that in this setting leptin is ineffective in the regulation of energy balance."
    explanation: Explains leptin resistance in obesity where elevated leptin fails to regulate energy balance through hypothalamic circuits.
  - reference: PMID:35528826
    reference_title: "Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity."
    explanation: >-
      Supports binding POMC and MC4R to this node: the melanocortin-4 receptor
      pathway is the hypothalamic circuit whose failure produces hyperphagia, and
      biallelic defects in it are the clearest demonstration of that circuit's
      role in human appetite regulation.
  - reference: PMID:29031731
    reference_title: "Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight."
    explanation: >-
      States the POMC-to-MC4R step of the circuit this node represents, which is
      why both genes are bound here. Graded BACKGROUND because the sentence is the
      framing of a setmelanotide trial rather than that trial's own result.
- name: Adipocyte Mitochondrial Dysfunction
  description: >
    Obesity causes mitochondrial fragmentation in white adipocytes through
    RalA-mediated activation of the fission protein DRP1 (DNM1L). This leads
    to reduced oxidative capacity and contributes to weight gain and insulin
    resistance. Mitochondrial dynamics shift toward excessive fission.
  cell_types:
  - preferred_term: Adipocyte
    term:
      id: CL:0000136
      label: adipocyte
  biological_processes:
  - preferred_term: Mitochondrial Fission
    term:
      id: GO:0000266
      label: mitochondrial fission
  - preferred_term: Fatty Acid Oxidation
    term:
      id: GO:0019395
      label: fatty acid oxidation
  evidence:
  - reference: PMID:38286821
    reference_title: "Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation."
    supports: SUPPORT
    snippet: "Here we show that high-fat diet (HFD) feeding causes mitochondrial fragmentation in inguinal white adipocytes from male mice, leading to reduced oxidative capacity by a process dependent on the small GTPase RalA."
    explanation: Demonstrates that obesity causes mitochondrial fragmentation through RalA in white adipocytes.
  - reference: PMID:38286821
    reference_title: "Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation."
    supports: SUPPORT
    snippet: "Mechanistically, RalA increases fission in adipocytes by reversing the inhibitory Ser637 phosphorylation of the fission protein Drp1, leading to more mitochondrial fragmentation."
    explanation: Describes the molecular mechanism by which RalA promotes mitochondrial fission through DRP1 dephosphorylation.
  - reference: PMID:38286821
    reference_title: "Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation."
    supports: SUPPORT
    snippet: "Adipose tissue expression of the human homolog of Drp1, DNM1L, is positively correlated with obesity and insulin resistance."
    explanation: Provides human evidence linking DNM1L expression to obesity and insulin resistance.
- name: Depletion of Mucosal Symbiont Akkermansia muciniphila
  description: >
    Akkermansia muciniphila is a mucin-degrading symbiont of the colonic mucus
    layer that uses host-derived mucus as its primary carbon and nitrogen source,
    placing it directly at the host-microbe interface. Its relative abundance is
    reduced in obesity, type 2 diabetes and metabolic syndrome and correlates
    inversely with body weight in rodents and humans. Loss of this population
    removes a signal that supports mucus-layer thickness and epithelial barrier
    integrity, and is the state that A. muciniphila-directed interventions are
    designed to compensate for.
  biological_processes:
  - preferred_term: mucus-layer maintenance at the colonic epithelium
    modifier: DECREASED
    term:
      id: GO:0030277
      label: maintenance of gastrointestinal epithelium
  notes: >
    The taxon (Akkermansia muciniphila, phylum Verrucomicrobiota; 1-5% of the
    healthy adult fecal microbiome) is deliberately not bound in cell_types, which
    is CL-only and covers host cells. Depletion is consistently reported but the
    direction of causation in humans is not settled: the cohort associations are
    cross-sectional, and the causal evidence that restoring the organism improves
    metabolism is from rodents.
  downstream:
  - target: Intestinal Barrier Dysfunction and Metabolic Endotoxemia
    description: >
      Fewer mucus-resident Akkermansia is associated with a thinner mucus layer
      and a more permeable epithelium in rodent models of diet-induced obesity.
  evidence:
  - reference: PMID:23671105
    reference_title: "Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "This study demonstrated that the abundance of A. muciniphila decreased in obese and type 2 diabetic mice."
    explanation: Direct measurement showing the symbiont is depleted in obese and diabetic animals.
  - reference: PMID:31263284
    reference_title: "Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension"
    explanation: >
      States the human cohort evidence for depletion in obesity. The quoted sentence
      is this trial report's summary of prior human studies rather than its own
      measurement, hence quote_role BACKGROUND; the correlation is also
      cross-sectional, so it bears on the depletion claim only indirectly.
  - reference: PMID:32167023
    reference_title: "Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The abundance of A. muciniphila is severely reduced in several pathological conditions (i.e., obesity, type 2 diabetes, inflammatory bowel diseases, and appendicitis)."
    explanation: >
      Restates the human disease-state depletion across conditions. Quoted from the
      introduction of a mouse study, so the paper is MODEL_ORGANISM work but the
      sentence reports the human clinical picture.
- name: Intestinal Barrier Dysfunction and Metabolic Endotoxemia
  biological_scale: TISSUE
  description: >
    Thinning of the colonic mucus layer and loss of epithelial barrier integrity
    allow bacterial lipopolysaccharide to reach the systemic circulation, producing
    the low-grade endotoxemia that couples the gut to adipose inflammation and
    insulin resistance. A. muciniphila supports barrier function at least partly
    through its abundant outer-membrane protein Amuc_1100, a Toll-like receptor 2
    ligand that survives pasteurization.
  biological_processes:
  - preferred_term: lipopolysaccharide-mediated signaling pathway
    modifier: INCREASED
    term:
      id: GO:0031663
      label: lipopolysaccharide-mediated signaling pathway
  downstream:
  - target: Chronic Low-Grade Inflammation
    description: >
      Circulating lipopolysaccharide engages innate immune receptors and sustains
      the systemic inflammatory tone already established in expanded adipose tissue.
  evidence:
  - reference: PMID:23671105
    reference_title: "Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "we demonstrated that A. muciniphila treatment reversed high-fat diet-induced metabolic disorders, including fat-mass gain, metabolic endotoxemia, adipose tissue inflammation, and insulin resistance"
    explanation: >
      The barrier/endotoxemia step is inferred from the therapeutic result: restoring
      the symbiont reverses metabolic endotoxemia and adipose inflammation in mice.
      Graded INDIRECT because the claim follows from the response to treatment rather
      than from a measurement of the untreated mechanism.
  - reference: PMID:27892954
    reference_title: "A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium."
    explanation: >
      Identifies the molecular route from the symbiont to barrier function, and the
      thermostability that makes a pasteurized preparation plausible.
- name: Efficient Intestinal Energy Harvest
  biological_scale: ORGANISM
  description: >
    The share of ingested energy that is absorbed rather than excreted in feces is a
    determinant of energy balance that sits upstream of adipose expansion. In
    diet-induced obese mice, pasteurized A. muciniphila lowers food energy efficiency
    and raises fecal energy excretion, apparently through reduced carbohydrate
    absorption and faster intestinal epithelial turnover, implying that the untreated
    state retains a correspondingly larger fraction of ingested energy.
  biological_processes:
  - preferred_term: intestinal absorption
    modifier: INCREASED
    term:
      id: GO:0050892
      label: intestinal absorption
  notes: >
    The human evidence for this node is weaker than the rodent evidence. In the
    weight-maintenance trial (PMID:42120725) the rise in fecal energy content under
    pasteurized MucT did not reach significance, and total daily fecal output was not
    measured; only the within-group inverse association between change in fecal energy
    and change in body weight pointed this way.
  downstream:
  - target: Energy Imbalance
    description: >
      Energy retained rather than excreted adds to the positive balance that drives
      fat accumulation.
  evidence:
  - reference: PMID:32167023
    reference_title: "Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "we observed that treatment with pasteurized A. muciniphila increased energy excretion in the feces"
    explanation: >
      The absorption step is inferred from its modification: treatment shifts energy
      from absorption to excretion, so the untreated state absorbs more.
  - reference: PMID:32167023
    reference_title: "Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "we demonstrated that this effect was not due to the modulation of intestinal lipid absorption or chylomicron synthesis but likely involved a reduction of carbohydrates absorption and enhanced intestinal epithelial turnover"
    explanation: >
      Localizes the effect to carbohydrate absorption and epithelial turnover rather
      than to lipid handling.
- name: Post-Weight-Loss Weight Regain
  biological_scale: ORGANISM
  description: >
    After energy restriction the body defends its previous mass through a coordinated
    set of responses: resting energy expenditure falls disproportionately to fat-free
    mass, anorexigenic signals fall while orexigenic signals rise, and shrinking
    adipocytes generate extracellular-matrix stress and immune activation in
    subcutaneous adipose tissue. Adipose tissue additionally retains a transcriptional
    and epigenetic memory of the prior obese state that primes it for accelerated
    regain. This node, rather than weight loss itself, is what maintenance therapy
    targets.
  biological_processes:
  - preferred_term: defense of pre-diet body mass
    term:
      id: GO:0097009
      label: energy homeostasis
  downstream:
  - target: Increased Body Mass Index
    description: >
      Regain restores the adiposity phenotype that the weight-loss phase reduced.
  evidence:
  - reference: PMID:30655624
    reference_title: "Mechanisms of weight regain after weight loss - the role of adipose tissue."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "we show that weight loss-induced variations in cellular stress, extracellular matrix remodelling, inflammatory responses, adipokine secretion and lipolysis seem to be associated with the amount of weight that is regained after successful weight loss"
    explanation: >
      Synthesis of the human adipose-tissue responses associated with how much weight
      is regained. It is a review's synthesis of work it did not perform, hence
      quote_role REVIEW_SYNTHESIS.
  - reference: PMID:39558077
    reference_title: "Adipose tissue retains an epigenetic memory of obesity after weight loss."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    snippet: "Mice carrying this obesogenic memory show accelerated rebound weight gain"
    explanation: >
      Shows the adipose memory is not merely correlative: animals carrying it regain
      weight faster. The corresponding human data in the same study are
      transcriptional rather than an observed regain rate.

mechanistic_hypotheses:
- hypothesis_group_id: pgs_context_amplification
  hypothesis_label: Amplification of polygenic obesity risk in adverse contexts
    via shared energy-imbalance convergence
  status: EMERGING
  description: >-
    Polygenic-score-by-context (PGS×C) interactions reported for obesity in the
    UK Biobank appear to reflect amplification rather than context-specific
    causal variants: the same susceptibility loci (e.g. FTO, MC4R, and other
    appetite/CNS-acting variants) exert systematically larger effects in
    disease-promoting contexts. This entry proposes that the amplification arises
    because polygenic liability and adverse exposures — obesogenic diet, physical
    inactivity, alcohol intake and socioeconomic deprivation — converge on the
    shared Energy Imbalance node, so their joint effect on the liability-threshold
    scale is super-additive rather than additive. Nagpal & Gibson (Nat Genet
    2026, PMID:42443528) show amplifying context pairs for BMI-defined obesity
    (e.g. glucose with omega-3 fatty acids, and walking pace with beer intake)
    and note that the major contexts differ between BMI- and waist-to-hip-ratio
    definitions, consistent with BMI polymorphisms acting on central appetite
    regulation versus WHR variants acting on peripheral metabolic traits.
  evidence:
  - reference: PMID:42443528
    reference_title: "Pervasive interactions between exposures and polygenic risk can inform more effective clinical and behavioral interventions."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: The predominant mechanism for PGS×C is the amplification of genetic
      effects in adverse contexts, such as low polyunsaturated fatty acids or social
      determinants of ill health
    explanation: >-
      Direct source (Nagpal & Gibson 2026): across seven UK Biobank diseases and
      75 contexts, amplification of genetic effects in adverse contexts is
      identified as the predominant mechanism of PGS×context interaction — the
      mechanism applied in this hypothesis.
  - reference: PMID:37228747
    reference_title: "Amplification is the primary mode of gene-by-sex interaction in complex human traits."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: GxSex is pervasive but acts primarily through systematic sex differences
      in the magnitude of many genetic effects
    explanation: >-
      Corroborates amplification — systematic differences in the magnitude of
      polygenic effects rather than in the identity of causal variants — as the
      primary mode of gene-by-context interaction.
  notes: >-
    EMERGING hypothesis motivated by population-scale PGS×context analyses
    (primary source PMID:42443528; general amplification mechanism corroborated
    by PMID:37228747). The convergence claim (polygenic liability + adverse
    exposures → Energy Imbalance) is a mechanistic interpretation and is not
    itself established as causal — see the reverse-causation knowledge gap under
    discussions.
phenotypes:
- name: Increased Body Mass Index
  category: Metabolic
  frequency: VERY_FREQUENT
  diagnostic: true
  notes: BMI greater than or equal to 30 kg/m2
  phenotype_term:
    preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
- name: Insulin Resistance
  category: Metabolic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Insulin Resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: PMID:14679177
    reference_title: "Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance."
    supports: SUPPORT
    snippet: "Insulin resistance arises from the inability of insulin to act normally in regulating nutrient metabolism in peripheral tissues."
    explanation: Defines insulin resistance as a key metabolic phenotype in obesity.
  - reference: PMID:27503945
    reference_title: "Adipose tissue inflammation: a cause or consequence of obesity-related insulin resistance?"
    supports: SUPPORT
    snippet: "Insulin resistance may link accumulation of adipose tissue in obesity to metabolic diseases, although the underlying mechanisms are not completely understood."
    explanation: Links adipose tissue accumulation in obesity to insulin resistance and metabolic disease.
- name: Dyslipidemia
  category: Metabolic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Dyslipidemia
    term:
      id: HP:0003077
      label: Hyperlipidemia
- name: Hypertension
  category: Cardiovascular
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hypertension
    term:
      id: HP:0000822
      label: Hypertension
  evidence:
  - reference: PMID:19320986
    reference_title: "The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Statistically significant associations with obesity were found with the incidence of type II diabetes, all cancers except esophageal and prostate cancer, all cardiovascular diseases, asthma, gallbladder disease, osteoarthritis and chronic back pain."
    explanation: Systematic review and meta-analysis linking obesity to incident cardiovascular disease, supporting hypertension as an obesity-related complication.
- name: Obstructive Sleep Apnea
  category: Respiratory
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Sleep Apnea
    term:
      id: HP:0010535
      label: Sleep apnea
- name: Joint Pain
  category: Musculoskeletal
  frequency: FREQUENT
  notes: Weight-bearing joint stress
  phenotype_term:
    preferred_term: Arthralgia
    term:
      id: HP:0002829
      label: Arthralgia
  evidence:
  - reference: PMID:19320986
    reference_title: "The incidence of co-morbidities related to obesity and overweight: a systematic review and meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The meta-analysis determined statistically significant associations for overweight with the incidence of type II diabetes, all cancers except esophageal (female), pancreatic and prostate cancer, all cardiovascular diseases (except congestive heart failure), asthma, gallbladder disease, osteoarthritis and chronic back pain."
    explanation: Meta-analysis linking excess weight to incident osteoarthritis and chronic back pain, supporting joint pain as an obesity-related musculoskeletal complication.
- name: Fatigue
  category: Systemic
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
biochemical:
- name: Leptin
  presence: Elevated
  context: Leptin resistance present despite high levels
- name: Adiponectin
  presence: Decreased
  context: Reduced with adipose dysfunction
- name: C-Reactive Protein
  presence: Elevated
  context: Chronic inflammation marker
- name: Fasting Insulin
  presence: Elevated
  context: Compensatory hyperinsulinemia
genetic:
- name: FTO
  gene_term:
    preferred_term: FTO
    term:
      id: hgnc:24678
      label: FTO
  association: Risk Factor
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    The strongest common-variant association with body mass index. FTO acts as a
    susceptibility locus rather than a Mendelian cause: homozygotes for the risk
    allele carry a 1.67-fold increased odds of obesity, so the effect is a shift
    in population risk rather than a sufficient cause. No pathophysiology node in
    this entry models the FTO mechanism, so the gene is deliberately not bound to
    one.
  evidence:
  - reference: PMID:17434869
    reference_title: "A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele."
    explanation: Large genome-wide association study establishing the common FTO variant as a robust risk factor for higher BMI and obesity.
- name: MC4R
  gene_term:
    preferred_term: MC4R
    term:
      id: hgnc:6932
      label: MC4R
  association: Risk Factor
  relationship_type: RISK_FACTOR
  variant_origin: GERMLINE
  notes: >-
    Heterozygous MC4R variants are carried by 1-5% of severely obese individuals
    and act here as a risk factor rather than a sufficient cause.
    Receptor-level MC4R deficiency as a monogenic disease in its own right is
    curated as the MC4R subtype of Obesity_Due_to_MC4R_Pathway_Disruption.
  evidence:
  - reference: PMID:29031731
    reference_title: "Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "While POMC deficiency is very rare, 1-5% of severely obese individuals harbor heterozygous mutations in MC4R."
    explanation: >-
      Quantifies the contribution of heterozygous MC4R variants to severe obesity.
      Graded BACKGROUND because the sentence is the framing of a setmelanotide
      trial rather than that trial's own result.
- name: LEP
  gene_term:
    preferred_term: LEP
    term:
      id: hgnc:6553
      label: LEP
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Biallelic LEP loss of function is a rare monogenic cause of severe
    early-onset obesity, curated in full as Congenital_Leptin_Deficiency.
  evidence:
  - reference: PMID:9202122
    reference_title: "Congenital leptin deficiency is associated with severe early-onset obesity in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The severe obesity found in these congenitally leptin-deficient subjects provides the first genetic evidence that leptin is an important regulator of energy balance in humans."
    explanation: First human evidence that a homozygous LEP frameshift mutation causes severe early-onset obesity via leptin deficiency.
- name: LEPR
  gene_term:
    preferred_term: LEPR
    term:
      id: hgnc:6554
      label: LEPR
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Biallelic LEPR variants are a rare monogenic cause of severe early-onset
    obesity, curated as the LEPR subtype of
    Obesity_Due_to_MC4R_Pathway_Disruption.
  evidence:
  - reference: PMID:17229951
    reference_title: "Clinical and molecular genetic spectrum of congenital deficiency of the leptin receptor."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%."
    explanation: >-
      Establishes how much of severe early-onset obesity biallelic LEPR deficiency
      accounts for in a systematically screened cohort.
- name: POMC
  gene_term:
    preferred_term: POMC
    term:
      id: hgnc:9201
      label: POMC
  association: Causative
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Biallelic POMC variants remove the melanocortin ligand input to MC4R and are a
    rare monogenic cause of severe early-onset obesity, curated as the POMC
    subtype of Obesity_Due_to_MC4R_Pathway_Disruption.
  evidence:
  - reference: PMID:35528826
    reference_title: "Natural History of Obesity Due to POMC, PCSK1, and LEPR Deficiency and the Impact of Setmelanotide."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare homozygous or biallelic variants in POMC, PCSK1, and LEPR can disrupt signaling through the melanocortin-4 receptor (MC4R) pathway, resulting in hyperphagia and severe early-onset obesity."
    explanation: >-
      Supports POMC as a causative gene acting through the melanocortin-4 receptor
      pathway in severe early-onset obesity.
environmental:
- name: High-Calorie Diet
  exposure_term:
    preferred_term: high-calorie dietary pattern
    modifier: INCREASED
    term:
      id: XCO:0000013
      label: diet
  notes: Especially ultra-processed foods
  evidence:
  - reference: PMID:31105044
    reference_title: "Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "participants gaining 0.9 ± 0.3 kg (p = 0.009) during the ultra-processed diet and losing 0.9 ± 0.3 kg (p = 0.007) during the unprocessed diet"
    explanation: "Inpatient randomized crossover trial with diets matched for presented calories, energy density, macronutrients, sugar, sodium and fibre -- so the 508 kcal/day excess intake and the weight change are attributable to processing itself rather than to nutrient composition. This is the strongest available design for the annotation claim."
  influences_mechanisms:
  - target: Energy Imbalance
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: Ultra-processed diets drive excess energy intake and weight gain even when calories presented, energy density and macronutrients are matched.
    evidence:
    - reference: PMID:31105044
      reference_title: "Ultra-Processed Diets Cause Excess Calorie Intake and Weight Gain: An Inpatient Randomized Controlled Trial of Ad Libitum Food Intake."
      supports: SUPPORT
      directness: DIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: participants gaining 0.9 ± 0.3 kg (p = 0.009) during the ultra-processed diet and losing 0.9 ± 0.3 kg (p = 0.007) during the unprocessed diet
      explanation: Inpatient randomised crossover trial in which the excess intake and weight gain are attributable to food processing itself rather than nutrient composition. This is direct experimental support for the energy-imbalance node.
- name: Sedentary Lifestyle
  exposure_term:
    preferred_term: sedentary lifestyle
    term:
      id: ECTO:6000004
      label: exposure to sedentary lifestyle
  notes: Sedentary behaviour is associated with becoming overweight or obese (OR 1.33
    highest vs lowest category), though its association with body weight itself is
    small and inconsistent
  evidence:
  - reference: PMID:29189928
    reference_title: "Sedentary Behavior and Body Weight and Composition in Adults: A Systematic Review and Meta-analysis of Prospective Studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Meta-analysis of data from prospective cohort studies showed small, inconsistent and non-significant associations between sedentary behavior and body weight"
    explanation: "PARTIAL, and the note was rewritten, because this is less settled than it is usually assumed to be. The same meta-analysis did find a significant odds ratio of 1.33 for becoming overweight or obese in the highest versus lowest sedentary category, and a small waist-circumference effect -- but not an association with body weight, and it does not evidence the reduced-energy-expenditure mechanism the note previously asserted."
  - reference: PMID:29189928
    reference_title: "Sedentary Behavior and Body Weight and Composition in Adults: A Systematic Review and Meta-analysis of Prospective Studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The odds ratio of becoming overweight or obese was 1.33 (95% CI 1.11-1.60; p = 0.001) in the highest compared with lowest categories of sedentary behavior"
    explanation: "Quotes the odds ratio the rewritten note states, so the note is self-supporting rather than relying on a figure the reader must go to the abstract to find. Paired deliberately with the PARTIAL item above: this is the positive signal, that one is the null result it sits inside."
- name: Obesogenic Environment
  notes: Food availability, marketing, built environment
  evidence:
  - reference: PMID:35290815
    reference_title: "The impact of the consumer and neighbourhood food environment on dietary intake and obesity-related outcomes: A systematic review of causal impact studies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the number of and distance to unhealthy food outlets increased the likelihood of fast-food consumption and higher BMI for children of any SES"
    explanation: "Systematic review restricted to causal-inference studies. PARTIAL on two counts: the BMI effect is established for children of any socioeconomic status but among adults only for selected groups (females, black and Hispanic residents of low and medium density areas), and the marketing component of this annotation is not covered."
  influences_mechanisms:
  - target: Increased Body Mass Index
    environmental_effect: PREDISPOSES
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: Density of and proximity to unhealthy food outlets raises fast-food consumption and body mass index.
    evidence:
    - reference: PMID:35290815
      reference_title: "The impact of the consumer and neighbourhood food environment on dietary intake and obesity-related outcomes: A systematic review of causal impact studies."
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: the number of and distance to unhealthy food outlets increased the likelihood of fast-food consumption and higher BMI for children of any SES
      explanation: Systematic review restricted to causal-inference studies. The environment acts through consumption and the energy-imbalance node rather than on body mass directly, and the BMI effect is established for children of any socioeconomic status but among adults only for selected groups.
- name: Sleep Deprivation
  exposure_term:
    preferred_term: sleep deprivation
    term:
      id: XCO:0001069
      label: sleep restriction
  notes: Alters appetite hormones
  evidence:
  - reference: PMID:15602591
    reference_title: "Short sleep duration is associated with reduced leptin, elevated ghrelin, and increased body mass index."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In Western societies, where chronic sleep restriction is common and food is widely available, changes in appetite regulatory hormones with sleep curtailment may contribute to obesity."
    explanation: Population cohort study showing short sleep duration reduces leptin and elevates ghrelin, linking sleep deprivation to increased BMI and obesity risk.
- name: Psychological Stress
  exposure_term:
    preferred_term: psychological stress
    term:
      id: XCO:0001265
      label: stress
  notes: Emotional eating
  evidence:
  - reference: PMID:19926299
    reference_title: "Stress-induced obesity and the emotional nervous system."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Stress and emotional brain networks foster eating behaviors that can lead to obesity"
    explanation: "States the emotional-eating route this annotation names, and gives the mechanism: stressors bias cognition toward emotional activity and degraded executive function, favouring habitual over deliberate food choice. OTHER because the quoted sentence is a review's mechanistic synthesis rather than a measurement."
diagnosis:
- name: Body mass index
  description: >-
    In clinical practice adult obesity is identified by body mass index,
    measured weight in kilograms divided by measured height in metres squared,
    against the WHO classification: a BMI of 30 kg/m2 or more defines obesity,
    graded I to III, and 25.0-29.9 kg/m2 defines overweight (pre-obesity).
    BMI estimates body fatness and does not capture its distribution, for
    which waist circumference is added.
  diagnosis_term:
    preferred_term: body mass index measurement
    term:
      id: NCIT:C219071
      label: Anthropometric Measurement
  presence: Diagnostic
  measurements:
  - preferred_term: body mass index
    term:
      id: LOINC:39156-5
      label: Body mass index (BMI) [Ratio]
  reference_ranges:
  - loinc_term:
      id: LOINC:39156-5
      label: Body mass index (BMI) [Ratio]
    unit: kg/m2
    population: WHO BMI classification (WHO 1997), adults over 18 years, as tabulated in the 2015 European Guidelines for Obesity Management in Adults
    notes: >-
      Source phrasing, from Table 1 "BMI categories (WHO 1997)" of the 2015
      European guidelines: "Healthy weight | 18.5–24.9", "Pre-obese state |
      25.0–29.9", "Obesity grade I | 30.0–34.9", "Obesity grade II |
      35.0–39.9", "Obesity grade III | >40". Half-open bands, so "25.0–29.9" is
      recorded as [25, 30) and so on. The table writes grade III as ">40",
      which leaves exactly 40.0 in no category; the half-open band places it
      in grade III. The same table's underweight row (printed "<1.8.5" in the
      cached text, evidently 18.5) is a cut-off for underweight, not for
      obesity, and is not recorded; the healthy-weight band therefore starts
      at 18.5. The guideline text adds that lower BMI cut-off points apply to
      some ethnic groups. The WHO expert consultation on Asian populations
      (PMID:14726171) retained the WHO cut-off points as the international
      classification and proposed additional public health action points at
      23.0, 27.5, 32.5 and 37.5 kg/m2 without redefining the categories for
      Asian populations, so no separate Asian range is recorded. The 2000 WHO
      technical report that set out the classification (PMID:11234459) is
      PubMed-indexed, but its abstract does not state the cut-off values.
    evidence:
    - reference: PMID:26641646
      reference_title: European Guidelines for Obesity Management in Adults.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "In adults (age over 18 years) obesity is defined by a BMI 30 kg/m2 and overweight (also termed pre-obesity) by a BMI between 25 and 29.9 kg/m2."
      explanation: >-
        States the adult obesity and overweight cut-offs. The cached text
        lacks a comparison sign before 30 kg/m2; the guideline's Table 1 gives
        obesity as BMI 30.0 and above.
    - reference: PMID:26641646
      reference_title: European Guidelines for Obesity Management in Adults.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Pre-obese state | 25.0–29.9"
      explanation: >-
        The WHO pre-obese (overweight) category as tabulated in the guideline.
    - reference: PMID:26641646
      reference_title: European Guidelines for Obesity Management in Adults.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Obesity grade I | 30.0–34.9"
      explanation: >-
        The WHO obesity grade I category.
    - reference: PMID:26641646
      reference_title: European Guidelines for Obesity Management in Adults.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Obesity grade II | 35.0–39.9"
      explanation: >-
        The WHO obesity grade II category.
    - reference: PMID:26641646
      reference_title: European Guidelines for Obesity Management in Adults.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "Obesity grade III | >40"
      explanation: >-
        The WHO obesity grade III category.
    - reference: PMID:14726171
      reference_title: Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies.
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The consultation also agreed that the WHO BMI cut-off points should be retained as international classifications. The consultation identified further potential public health action points (23.0, 27.5, 32.5, and 37.5 kg/m2) along the continuum of BMI, and proposed methods by which countries could make decisions about the definitions of increased risk for their population."
      explanation: >-
        Records why the WHO categories are kept for Asian populations and the
        lower action points the consultation proposed instead of a separate
        classification; these are carried in the range notes, not as bands.
    interpretation_bands:
    - name: Healthy weight
      lower_bound: 18.5
      upper_bound: 25.0
      unit: kg/m2
      abnormal_flag: NORMAL
    - name: Pre-obese state (overweight)
      lower_bound: 25.0
      upper_bound: 30.0
      unit: kg/m2
      abnormal_flag: HIGH
      interpretation: Overweight, not obesity.
    - name: Obesity grade I
      lower_bound: 30.0
      upper_bound: 35.0
      unit: kg/m2
      abnormal_flag: HIGH
    - name: Obesity grade II
      lower_bound: 35.0
      upper_bound: 40.0
      unit: kg/m2
      abnormal_flag: HIGH
    - name: Obesity grade III
      lower_bound: 40.0
      unit: kg/m2
      abnormal_flag: HIGH
  evidence:
  - reference: PMID:11234459
    reference_title: "Obesity: preventing and managing the global epidemic. Report of a WHO consultation."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In particular, the Consultation considered the system for classifying overweight and obesity based on the body mass index, and concluded that a coherent system is now available and should be adopted internationally."
    explanation: >-
      The WHO consultation that adopted the BMI-based classification of
      overweight and obesity bound on this row.
  - reference: PMID:26641646
    reference_title: European Guidelines for Obesity Management in Adults.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In clinical practice, the body fatness is usually estimated by BMI. BMI is calculated as measured body weight (kg) divided by measured height squared (m2)."
    explanation: >-
      BMI as the clinical measurement of body fatness and its definition.
  - reference: PMID:26641646
    reference_title: European Guidelines for Obesity Management in Adults.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Lower BMI cut-off points apply for some ethnic groups (e.g. Southeast Asians)"
    explanation: >-
      The guideline's caveat that the WHO cut-offs are not universal.
  notes: >-
    LOINC:39156-5 is the method-less BMI code. The bands are the adult WHO
    classification only (the cited guideline applies it from age 18); no
    paediatric BMI cut-off is recorded here. The phenotype Increased Body Mass Index on this entry carries the same 30
    kg/m2 threshold as free text.
treatments:
- name: Lifestyle Modification
  therapeutic_modality: BEHAVIORAL
  description: Dietary changes and increased physical activity as foundation of treatment.
  treatment_term:
    preferred_term: Lifestyle Therapy
    term:
      id: NCIT:C15900
      label: Lifestyle Therapy
  target_mechanisms:
  - target: Energy Imbalance
    treatment_effect: INHIBITS
    description: >
      Reducing energy intake and raising expenditure acts directly on the energy
      balance node. The link is definitional rather than empirical, so it carries
      no evidence of its own; the treatment's efficacy evidence is on the
      treatment itself.
  evidence:
  - reference: PMID:25182101
    reference_title: "Comparison of weight loss among named diet programs in overweight and obese adults: a meta-analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Significant weight loss was observed with any low-carbohydrate or low-fat diet."
    explanation: Meta-analysis of randomized trials showing dietary lifestyle modification produces significant weight loss in overweight and obese adults.
- name: GLP-1 Receptor Agonists
  therapeutic_modality: PEPTIDE
  description: Semaglutide, liraglutide provide substantial weight loss through central appetite suppression and metabolic effects.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: semaglutide
      term:
        id: CHEBI:167574
        label: semaglutide
    - preferred_term: liraglutide
      term:
        id: CHEBI:71193
        label: liraglutide
  target_mechanisms:
  - target: Hypothalamic Dysregulation
    treatment_effect: MODULATES
    description: >
      GLP-1 receptor agonism acts on central appetite and food-reward circuits,
      restoring the satiety signalling that leptin resistance has blunted.
    evidence:
    - reference: PMID:28266779
      reference_title: "Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Semaglutide was associated with less hunger and food cravings, better control of eating and a lower preference for high-fat foods."
      explanation: Mechanism-of-action crossover trial measuring the appetite and food-reward changes this node describes.
  - target: Energy Imbalance
    treatment_effect: INHIBITS
    description: >
      The appetite effect converts into a measured reduction in ad libitum energy
      intake, which is what moves the energy balance node.
    evidence:
    - reference: PMID:28266779
      reference_title: "Effects of once-weekly semaglutide on appetite, energy intake, control of eating, food preference and body weight in subjects with obesity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "ad libitum energy intake was substantially lower with semaglutide vs placebo with a corresponding loss of body weight observed with semaglutide"
      explanation: Directly measures energy intake, the quantity the Energy Imbalance node is about.
  - target: Post-Weight-Loss Weight Regain
    treatment_effect: INHIBITS
    description: >
      Suppression of regain is contingent on continued dosing: in the STEP 1
      off-treatment extension participants regained two-thirds of their lost weight
      within a year of stopping, and cardiometabolic gains reverted with it. The
      drug holds the regain node down rather than resolving it.
    evidence:
    - reference: PMID:35441470
      reference_title: "Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: "participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables"
      explanation: >
        That regain resumes on withdrawal establishes that the treatment had been
        acting on this node. Graded INDIRECT because the suppression is inferred
        from what happens when the drug is stopped.
  evidence:
  - reference: PMID:33567185
    reference_title: "Once-Weekly Semaglutide in Adults with Overweight or Obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In participants with overweight or obesity, 2.4 mg of semaglutide once weekly plus lifestyle intervention was associated with sustained, clinically relevant reduction in body weight."
    explanation: STEP 1 randomized trial demonstrating substantial, sustained weight loss with the GLP-1 receptor agonist semaglutide in obesity.
  - reference: PMID:41782434
    reference_title: "Joint TOS/OMA/OAC Expert Guidance Statement on the Pharmacological Management of United States Adults With Overweight or Obesity Using the GRADE Approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Strong recommendations were made for bupropion-naltrexone, semaglutide, tirzepatide, and setmelanotide, with moderate-certainty evidence."
    explanation: The joint TOS/OMA/OAC pharmacological-management guidance makes a strong recommendation for semaglutide (a GLP-1 receptor agonist) for adults with obesity.
- name: GLP-1/GIP Dual Agonists
  therapeutic_modality: PEPTIDE
  description: Tirzepatide offers enhanced weight loss of 15-25% through dual incretin receptor activation.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: tirzepatide
      term:
        id: CHEBI:194186
        label: tirzepatide
  target_mechanisms:
  - target: Energy Imbalance
    treatment_effect: INHIBITS
    description: >
      Dual GIP/GLP-1 receptor agonism reduces energy intake and produces sustained
      weight reduction. No tirzepatide-specific energy-intake measurement is cited
      here, so the link carries no evidence of its own.
  - target: Post-Weight-Loss Weight Regain
    treatment_effect: INHIBITS
    description: >
      SURMOUNT-4 is a randomized withdrawal design and so measures this node
      directly: after a 36-week lead-in, participants switched to placebo regained
      weight while those continuing treatment did not.
    evidence:
    - reference: PMID:38078870
      reference_title: "Continued Treatment With Tirzepatide for Maintenance of Weight Reduction in Adults With Obesity: The SURMOUNT-4 Randomized Clinical Trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: "In participants with obesity or overweight, withdrawing tirzepatide led to substantial regain of lost weight, whereas continued treatment maintained and augmented initial weight reduction."
      explanation: A randomized withdrawal trial whose endpoint is weight-loss maintenance, which is this node.
  evidence:
  - reference: PMID:35658024
    reference_title: "Tirzepatide Once Weekly for the Treatment of Obesity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight."
    explanation: SURMOUNT-1 randomized trial showing the GLP-1/GIP dual agonist tirzepatide produces substantial, sustained weight loss in obesity.
  - reference: PMID:41782434
    reference_title: "Joint TOS/OMA/OAC Expert Guidance Statement on the Pharmacological Management of United States Adults With Overweight or Obesity Using the GRADE Approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Strong recommendations were made for bupropion-naltrexone, semaglutide, tirzepatide, and setmelanotide, with moderate-certainty evidence."
    explanation: The joint TOS/OMA/OAC pharmacological-management guidance makes a strong recommendation for tirzepatide (a GLP-1/GIP dual agonist) for adults with obesity.
- name: Bariatric Surgery
  therapeutic_modality: SURGERY
  description: Roux-en-Y gastric bypass, sleeve gastrectomy for severe obesity.
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  target_mechanisms:
  - target: Hypothalamic Dysregulation
    treatment_effect: MODULATES
    description: >
      Rerouting the gut alters the entero-hypothalamic endocrine axis: postprandial
      PYY and GLP-1 rise after Roux-en-Y gastric bypass but not after gastric
      banding producing equivalent weight loss, so the effect is anatomical rather
      than a consequence of having lost weight.
    evidence:
    - reference: PMID:16371744
      reference_title: "Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: "Compared with lean and obese controls, patients following Roux-en-Y gastric bypass (RYGB) had increased postprandial plasma PYY and GLP-1 favoring enhanced satiety."
      explanation: Measures the gut-hormone change that acts on central satiety signalling.
  - target: Energy Imbalance
    treatment_effect: INHIBITS
    description: >
      Restriction plus the anorectic hormone profile lowers energy intake. Carried
      as a description rather than evidence because the cited trials measure weight
      and risk factors, not energy intake.
  evidence:
  - reference: PMID:15616203
    reference_title: "Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As compared with conventional therapy, bariatric surgery appears to be a viable option for the treatment of severe obesity, resulting in long-term weight loss, improved lifestyle, and, except for hypercholesterolemia, amelioration in risk factors that were elevated at baseline."
    explanation: Swedish Obese Subjects study showing bariatric surgery produces durable weight loss and risk-factor improvement in severe obesity.
- name: Behavioral Therapy
  therapeutic_modality: BEHAVIORAL
  description: Cognitive behavioral therapy for eating behaviors.
  treatment_term:
    preferred_term: behavioral counseling
    term:
      id: NCIT:C181743
      label: Behavioral Counseling
  notes: >
    Deliberately carries no target_mechanisms. The schema reserves those links for
    therapeutic actions and excludes counseling and informational interventions,
    and this entry is bound to a counseling action term.
  evidence:
  - reference: PMID:38285378
    reference_title: "Comparative Effectiveness of Cognitive Behavioral Therapy and Behavioral Therapy in Obesity: A Systematic Review and Network Meta-Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Our results indicated that CBT and BT are effective interventions for weight loss, and that successful weight loss requires more aggressive interventions such as BT or CBT than MC and UC."
    explanation: >
      Network meta-analysis of randomized trials placing CBT and behavioral therapy
      above usual and minimal care for weight loss. REVIEW_SYNTHESIS because the
      pooled estimate synthesizes trials the authors did not run.
- name: Orlistat
  therapeutic_modality: SMALL_MOLECULE
  description: Lipase inhibitor reducing fat absorption.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: orlistat
      term:
        id: CHEBI:94686
        label: orlistat
  target_mechanisms:
  - target: Efficient Intestinal Energy Harvest
    treatment_effect: INHIBITS
    description: >
      Gastrointestinal lipase inhibition blocks hydrolysis of dietary triglyceride,
      so ingested fat leaves in the stool instead of being absorbed. Orlistat and
      pasteurized A. muciniphila MucT both act on this node by unrelated routes:
      one blocks a digestive enzyme, the other is reported to reduce carbohydrate
      absorption and raise epithelial turnover.
    evidence:
    - reference: PMID:39783852
      reference_title: "A Comparative Analysis of the Pharmacodynamic and Pharmacokinetic Properties of 2 Controlled-Release Formulations Versus a Marketed Orlistat Product."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: "MR-O and Conv-O similarly increased fecal fat percentage from 3.8% to 13.5%, confirming pharmacodynamic equivalence."
      explanation: Human pharmacodynamic measurement of the shift from absorption to fecal excretion that defines this node.
  - target: Post-Weight-Loss Weight Regain
    treatment_effect: INHIBITS
    description: >
      The European Multicentre trial's second year is a maintenance phase, in which
      continuing orlistat halved the regain seen after switching to placebo.
    evidence:
    - reference: PMID:9683204
      reference_title: "Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: "During year 2, patients who continued with orlistat regained, on average, half as much weight as those patients switched to placebo"
      explanation: Second-year maintenance result, measuring regain directly.
  evidence:
  - reference: PMID:9683204
    reference_title: "Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orlistat taken with an appropriate diet promotes clinically significant weight loss and reduces weight regain in obese patients over a 2-year period."
    explanation: European Multicentre Orlistat randomized trial demonstrating the lipase inhibitor orlistat produces clinically significant weight loss in obese patients.
- name: Naltrexone-Bupropion
  therapeutic_modality: SMALL_MOLECULE
  description: >
    Fixed-dose sustained-release naltrexone plus bupropion, developed to act on two
    complementary central pathways: bupropion stimulates hypothalamic POMC neurons,
    and naltrexone blocks the opioid-mediated autoinhibitory feedback that otherwise
    limits that stimulation. Approved for chronic weight management and strongly
    recommended in the joint TOS/OMA/OAC guidance already cited elsewhere in this
    entry.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: naltrexone
      term:
        id: CHEBI:7465
        label: naltrexone
    - preferred_term: bupropion
      term:
        id: CHEBI:3219
        label: bupropion
  notes: >
    Added because this entry already quotes a guideline strongly recommending
    bupropion-naltrexone while curating only two of the four drugs that sentence
    names. Setmelanotide, the fourth, is curated in
    Obesity_Due_to_MC4R_Pathway_Disruption, where its indication sits. The
    POMC/opioid-feedback mechanism in the description is the development rationale
    reported by the COR-I authors, not something that trial measured.
  target_mechanisms:
  - target: Hypothalamic Dysregulation
    treatment_effect: MODULATES
    description: >
      Both components act on central circuits regulating body weight rather than on
      peripheral energy handling, which is what places this treatment on the
      hypothalamic node.
    evidence:
    - reference: PMID:20673995
      reference_title: "Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: BACKGROUND
      directness: INDIRECT
      snippet: "Combination treatment with sustained-release naltrexone and bupropion was developed to produce complementary actions in CNS pathways regulating bodyweight."
      explanation: >
        States the central mechanism the combination was designed around. It is the
        trial's framing of prior pharmacology rather than a result of the trial, so
        it is graded BACKGROUND and OTHER, and bears on the node only indirectly.
  evidence:
  - reference: PMID:20673995
    reference_title: "Effect of naltrexone plus bupropion on weight loss in overweight and obese adults (COR-I): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "84 (16%) participants assigned to placebo had a decrease in bodyweight of 5% or more compared with 226 (48%) assigned to naltrexone 32 mg plus bupropion"
    explanation: COR-I co-primary endpoint, the proportion achieving at least 5% weight loss.
  - reference: PMID:41782434
    reference_title: "Joint TOS/OMA/OAC Expert Guidance Statement on the Pharmacological Management of United States Adults With Overweight or Obesity Using the GRADE Approach."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Strong recommendations were made for bupropion-naltrexone, semaglutide, tirzepatide, and setmelanotide, with moderate-certainty evidence."
    explanation: The joint TOS/OMA/OAC guidance makes a strong recommendation for bupropion-naltrexone for adults with obesity.
- name: Pasteurized Akkermansia muciniphila MucT Supplementation
  therapeutic_modality: OTHER
  description: >
    Daily oral capsules of pasteurized Akkermansia muciniphila MucT (heat-treated 30
    minutes at 70 C; 3 x 10^10 inactivated cells per capsule) taken during the weight
    maintenance phase that follows a low-energy diet. Heat inactivation removes the
    oxygen sensitivity and manufacturing constraints of the live organism while
    preserving the thermostable outer-membrane protein Amuc_1100, and in rodents it
    increased rather than abolished the metabolic benefit. The indication tested is
    maintenance of weight already lost, not weight loss itself.
  treatment_term:
    preferred_term: pasteurized Akkermansia muciniphila MucT supplementation
    term:
      id: NCIT:C15433
      label: Nutritional Support
    qualifiers:
    - predicate:
        preferred_term: dietary supplement
        term:
          id: NCIT:C1505
          label: Dietary Supplement
      value:
        preferred_term: pasteurized Akkermansia muciniphila MucT
        term:
          id: NCIT:C200541
          label: Akkermansia muciniphila Probiotic
  notes: >
    The agent term NCIT:C200541 is carried as a qualifier rather than in
    therapeutic_agent because it sits under Dietary Supplement (NCIT:C1505) and is not
    reachable from NCIT:C1909 (Pharmacologic Substance), the root of the
    ChemicalEntityTerm enum that binds therapeutic_agent. Two limits on the claim:
    pasteurized cells are non-viable and do not colonize, so the effect is
    host-directed rather than a restoration of the endogenous Akkermansia population,
    and the trial found no between-group difference in fecal microbiota composition;
    and no arm received a MucT strain lacking Amuc_1100, so specificity to that
    protein is not established in humans.
  target_mechanisms:
  - target: Post-Weight-Loss Weight Regain
    treatment_effect: INHIBITS
    description: >
      The registered primary outcome. Over 24 weeks of ad libitum healthy diet after
      an 8-week low-energy diet, the supplemented group regained less weight than
      placebo and ended with greater net weight loss from baseline.
    evidence:
    - reference: PMID:42120725
      reference_title: "Pasteurized Akkermansia muciniphila Muc(T) for weight loss maintenance in people with overweight and obesity: a controlled randomized trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: "Here we show that MucT led to lower body weight regain versus placebo at the end of the weight maintenance period (MucT: 1.2 ± 0.7 kg, placebo: 3.2 ± 0.4 kg, P = 0.012)."
      explanation: Primary outcome of the randomized trial, stating the effect on the targeted mechanism.
  - target: Efficient Intestinal Energy Harvest
    treatment_effect: INHIBITS
    description: >
      Proposed mechanism: a shift of ingested energy from absorption to fecal
      excretion. Established in diet-induced obese mice; in the human trial the
      increase in fecal energy content did not reach significance, and only the
      within-group inverse association with weight change supported it.
    evidence:
    - reference: PMID:32167023
      reference_title: "Pasteurized Akkermansia muciniphila increases whole-body energy expenditure and fecal energy excretion in diet-induced obese mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "We confirmed that daily oral administration of pasteurized A. muciniphila alleviated diet-induced obesity and decreased food energy efficiency."
      explanation: Shows the treatment acts on how efficiently ingested energy is retained.
  - target: Intestinal Barrier Dysfunction and Metabolic Endotoxemia
    treatment_effect: RESTORES
    description: >
      Proposed mechanism: the thermostable outer-membrane protein Amuc_1100 signals
      through TLR2 and improves gut barrier function, which is the route by which a
      non-viable preparation can act on host metabolism without colonizing.
    evidence:
    - reference: PMID:27892954
      reference_title: "A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      snippet: "We demonstrated that Amuc_1100, a specific protein isolated from the outer membrane of A. muciniphila, interacts with Toll-like receptor 2, is stable at temperatures used for pasteurization, improves the gut barrier and partly recapitulates the beneficial effects of the bacterium."
      explanation: Establishes the barrier-directed mechanism and that it survives pasteurization.
  evidence:
  - reference: PMID:42120725
    reference_title: "Pasteurized Akkermansia muciniphila Muc(T) for weight loss maintenance in people with overweight and obesity: a controlled randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Additionally, the MucT group had a greater net weight loss from baseline to end of maintenance than the placebo group (3.1 ± 0.7 kg, P = 0.009)."
    explanation: Net weight loss from baseline to the end of maintenance, the secondary anthropometric outcome.
  - reference: PMID:42120725
    reference_title: "Pasteurized Akkermansia muciniphila Muc(T) for weight loss maintenance in people with overweight and obesity: a controlled randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "No serious adverse events related to the treatment were observed."
    explanation: Safety outcome of the 24-week maintenance trial.
  - reference: PMID:31263284
    reference_title: "Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity"
    explanation: >
      The earlier proof-of-concept human trial in metabolic syndrome, which found the
      metabolic signal without a significant weight effect on an unchanged ad libitum diet.
  - reference: PMID:31263284
    reference_title: "Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "we demonstrated that daily oral supplementation of 1010 A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated"
    explanation: First-in-human safety and tolerability of the supplementation route used here.
clinical_trials:
- name: NCT05417360
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >
    Double-blind, placebo-controlled randomized trial at Maastricht University
    (n = 90 enrolled, 84 randomized, 80 completed). Participants first lost at least
    8% of body weight on an 8-week low-energy diet, then took daily pasteurized
    A. muciniphila MucT or matched placebo for 24 weeks of ad libitum healthy diet.
    The primary outcome was change in body weight during the maintenance period.
  target_phenotypes:
  - preferred_term: Obesity
    term:
      id: HP:0001513
      label: Obesity
  - preferred_term: Insulin Resistance
    term:
      id: HP:0000855
      label: Insulin resistance
  evidence:
  - reference: clinicaltrials:NCT05417360
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "investigators hypothesize that pasteurized A. muciniphila will be superior to placebo intervention in maintaining body weight after a phase of weight loss (low caloric diet) in adult participants with overweight or obesity."
    explanation: Registered hypothesis and population of the trial reported in PMID:42120725.
  - reference: PMID:42120725
    reference_title: "Pasteurized Akkermansia muciniphila Muc(T) for weight loss maintenance in people with overweight and obesity: a controlled randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "adults with overweight/obesity (n = 90) underwent an 8-week low-energy diet for ≥8% weight loss, followed by a 24-week healthy ad libitum diet with daily supplementation of pasteurized A. muciniphila MucT or placebo"
    explanation: Design and population of the trial as reported in the primary publication.

discussions:
- discussion_id: obesity_pgsxc_reverse_causation
  prompt: >-
    Are the obesity PGS×context interactions driven by adverse exposures causally
    amplifying genetic risk, or are some "contexts" (e.g. fasting insulin, leptin,
    reduced physical activity) actually downstream consequences of adiposity
    (reverse causation)?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Energy Imbalance
  - biochemical#Leptin
  - biochemical#Fasting Insulin
  - environmental#Sedentary Lifestyle
  rationale: >-
    Population PGS×context analyses (Nagpal & Gibson 2026, PMID:42443528) are
    largely unable to establish the causality of specific contexts. For obesity
    this is acute for the biochemical "contexts": leptin and fasting insulin rise
    as a consequence of increased fat mass and are modelled in this entry as
    readouts of adipose dysfunction rather than upstream drivers, and reduced
    physical activity or slower walking pace may be consequences of established
    obesity rather than causes. Distinguishing genuine amplification of genetic
    effects from reverse causation determines whether the modelled lifestyle
    interventions would actually reduce risk.
  proposed_experiments:
  - experiment_id: obesity_pgsxc_mr_direction
    name: Mendelian randomization of exposure-to-obesity direction across PGS strata
    description: >-
      Use bidirectional / multivariable Mendelian randomization to test whether
      each candidate context (physical activity, alcohol, fasting insulin, leptin)
      causally affects adiposity versus being a consequence of it, and whether the
      causal effect estimate scales with polygenic liability as the amplification
      model predicts.
    decision_criterion: >-
      A context is retained as a causal amplifier if MR supports
      exposure-to-disease directionality and the exposure-attributable risk
      difference increases across increasing PGS strata; it is flagged as a
      reverse-causation suspect otherwise.
  - experiment_id: obesity_pgsxc_prospective_temporal
    name: Prospective incident-obesity analysis restricted to pre-onset exposure
      windows
    description: >-
      Restrict exposures to measurements taken well before obesity onset and
      repeat the PGS×context liability-threshold modelling on incident cases only,
      to reduce the chance that exposure values (particularly activity and
      metabolic biomarkers) reflect established adiposity rather than antecedent
      risk.
    decision_criterion: >-
      Amplification is supported if the PGS×context deviation from additivity
      persists when only pre-onset exposure windows and incident cases are used.
- discussion_id: akkermansia_baseline_abundance_responder
  prompt: >-
    Does baseline fecal Akkermansia muciniphila abundance decide who benefits from
    A. muciniphila supplementation, and if so, is the mechanism headroom for
    improvement or something about the resident community?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#Pasteurized Akkermansia muciniphila MucT Supplementation
  - pathophysiology#Depletion of Mucosal Symbiont Akkermansia muciniphila
  rationale: >-
    Two independent trials of different preparations point the same way. In the
    weight-maintenance trial (PMID:42120725) participants stratified below the median
    fecal A. muciniphila level after weight loss regained less weight and improved
    more in insulin sensitivity, blood pressure and fecal energy content than those
    above it, with no such split in the placebo arm; that analysis was exploratory and
    post hoc. In a separate trial of live AKK-WST01 in overweight/obese type 2
    diabetes (PMID:39879980), benefit and colonization were likewise confined to the
    low-baseline group. If this holds prospectively it makes baseline abundance a
    pre-treatment stratifier rather than an incidental covariate, and it would change
    how a maintenance trial is powered and who is enrolled. The competing readings are
    not distinguished by the current data: greater room for improvement in depleted
    individuals, versus a resident community in high-abundance individuals that
    resists an added preparation. Note the mechanism cannot simply be colonization for
    the pasteurized product, which is non-viable.
  evidence:
  - reference: PMID:42120725
    reference_title: "Pasteurized Akkermansia muciniphila Muc(T) for weight loss maintenance in people with overweight and obesity: a controlled randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "Initial Akkermansia spp. abundance was associated with cardiometabolic response to MucT."
    explanation: States the baseline-abundance dependence that this gap is about.
  - reference: PMID:39879980
    reference_title: "Akkermansia muciniphila supplementation in patients with overweight/obese type 2 diabetes: Efficacy depends on its baseline levels in the gut."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: "AKK-WST01 supplementation showed high colonization efficiency and significant reductions in body weight, fat mass, and HbA1c, which were not found in the placebo group."
    explanation: >
      Independent trial of a live preparation showing the same restriction of benefit
      to participants with low baseline abundance.
  proposed_experiments:
  - experiment_id: akkermansia_baseline_stratified_rct
    name: Prospectively stratified maintenance trial by baseline fecal A. muciniphila
    description: >-
      Randomize weight-loss-maintenance participants to pasteurized MucT or placebo
      within strata defined prospectively by quantitative fecal A. muciniphila
      measured before randomization, powered on the stratum-by-treatment interaction
      rather than on the marginal effect, with fecal energy excretion measured against
      total daily fecal output.
    decision_criterion: >-
      Baseline abundance is a genuine response modifier if the stratum-by-treatment
      interaction on weight regain is significant in a prospectively powered design;
      it is an artifact of the post hoc median split otherwise.

datasets:
# Obesity Gut Microbiome Studies
- accession: bioproject:PRJNA290729
  title: Gut microbiome in obesity after weight-loss intervention
  description: >-
    Whole metagenome shotgun sequencing characterizing gut microbial community
    of obese patients following weight-loss intervention. Tracks microbiome
    changes with weight loss.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  conditions:
  - obese pre-intervention
  - obese post-weight loss
  publication: PMID:26934690
  notes: PLOS ONE 2016 - weight loss microbiome dynamics

- accession: bioproject:PRJNA328258
  title: Gut microbiome in pediatric NAFLD and obesity
  description: >-
    Shotgun metagenomics examining taxonomic and functional differences
    between microbiomes of youth with obesity with and without non-alcoholic
    fatty liver disease (NAFLD).
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 36
  conditions:
  - obese with NAFLD
  - obese without NAFLD
  - healthy controls
  publication: PMID:35344283
  notes: Hepatology Communications 2022

- accession: bioproject:PRJNA881023
  title: Gut microbiome of metabolically healthy obese individuals
  description: >-
    Metagenomic characterization of gut microbiome in metabolically healthy
    obese (MHO) patients and correlations with metabolic and inflammatory
    profiles. 120 obese individuals without metabolic comorbidities.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  data_type: WGS
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  sample_count: 120
  conditions:
  - metabolically healthy obese
  notes: Scientific Reports 2024 - MHO microbiome signatures

- accession: bioproject:PRJNA417579
  title: Clostridia diversity and obesity association
  description: >-
    High-resolution analysis of intra-species diversity in gut microbiome
    focusing on Clostridia class associations with obesity. 16S rRNA, dnaK,
    and gyrB gene sequencing.
  organism:
    preferred_term: human gut metagenome
    term:
      id: NCBITaxon:408170
      label: human gut metagenome
  sample_types:
  - preferred_term: fecal sample
    term:
      id: UBERON:0001988
      label: feces
    tissue_term:
      preferred_term: feces
      term:
        id: UBERON:0001988
        label: feces
  conditions:
  - obese individuals
  - lean controls
  notes: mSystems 2024 - Clostridia negatively associated with obesity
references:
- reference: DOI:10.3390/biom14101223
  title: 'Adipose Tissue Plasticity: A Comprehensive Definition and Multidimensional Insight'
  findings: []
- reference: DOI:10.3390/cimb47050343
  title: Key Roles of Brown, Subcutaneous, and Visceral Adipose Tissues in Obesity and Insulin Resistance
  findings: []
- reference: DOI:10.3390/diagnostics15121482
  title: 'Unraveling the Genetic Architecture of Obesity: A Path to Personalized Medicine'
  findings: []
- reference: DOI:10.3390/ijms25126681
  title: 'Adipocyte Mitochondria: Deciphering Energetic Functions across Fat Depots in Obesity and Type 2 Diabetes'
  findings: []
- reference: DOI:10.3390/ijms25158202
  title: Molecular Mechanisms behind Obesity and Their Potential Exploitation in Current and Future Therapy
  findings: []
- reference: DOI:10.3390/medicines12030019
  title: 'Obesity: Clinical Impact, Pathophysiology, Complications, and Modern Innovations in Therapeutic Strategies'
  findings: []

📚

References & Deep Research