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Obesity Due to MC4R Pathway Disruption

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Obesity Due to MC4R Pathway Disruption. Core disease mechanisms, molecular...

2026-04-09
Asta MONDO:0011122 Model: Asta Scientific Corpus Retrieval 18 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Obesity Due to MC4R Pathway Disruption. Core disease mechanisms, molecular...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Molecular Analysis and Conformational Dynamics of Human MC4R Disease-Causing Mutations

  • Authors: M. Fatima, Z. Islam, P. Kolatkar, A. AL-SHABEEB AKIL
  • Year: 2022
  • Venue: Molecules
  • URL: https://www.semanticscholar.org/paper/9fcecda60c5c1ec50ba8ebafd77d1fe1f13a7d16
  • DOI: 10.3390/molecules27134037
  • PMID: 35807283
  • PMCID: 9268210
  • Citations: 2
  • Summary: Insight is provided into the potential direction toward understanding the molecular basis of MC4R dysfunction in disease progression and obesity by performing molecular dynamics simulations of the wild-type and selected mutations to delineate the conformational changes.
  • Evidence snippets:
  • Snippet 1 (score: 0.566) > Obesity is a chronic disease with increasing cases among children and adolescents. Melanocortin 4 receptor (MC4R) is a G protein-coupled transporter involved in solute transport, enabling it to maintain cellular homeostasis. MC4R mutations are associated with early-onset severe obesity, and the identification of potential pathological variants is crucial for the clinical management of patients with obesity. A number of mutations have been reported in MC4R that are responsible for causing obesity and related complications. Delineating these mutations and analyzing their effect on MC4R’s structure will help in the clinical intervention of the disease condition as well as designing potential drugs against it. Sequence-based pathogenicity and structure-based protein stability analyses were conducted on naturally occurring variants. We used computational tools to analyze the conservation of these mutations on MC4R’s structure to map the structural variations. Detailed structural analyses were carried out for the active site mutations (i.e., D122N, D126Y, and S188L) and their influence on the binding of calcium and the agonist or antagonist. We performed molecular dynamics (MD) simulations of the wild-type and selected mutations to delineate the conformational changes, which provided us with possible reasons for MC4R’s instability in these mutations. This study provides insight into the potential direction toward understanding the molecular basis of MC4R dysfunction in disease progression and obesity.

[2] Unraveling the relationship between head circumference and MC4R deficiency from infancy to adulthood: a case–control study

  • Authors: Eline E P L van der Walle, Cornelis J de Groot, L. Kleinendorst, Hester de Klerk, M. Welling et al.
  • Year: 2025
  • Venue: Obesity (Silver Spring, Md.)
  • URL: https://www.semanticscholar.org/paper/e6d188f79b7369e43f6c7e3e7877dbccabbe18da
  • DOI: 10.1002/oby.24263
  • PMID: 40231439
  • PMCID: 12015652
  • Citations: 2
  • Summary: The objective of this study was to investigate head circumference (HC) in patients with melanocortin 4 receptor (MC4R) deficiency, the most common cause of monogenetic obesity.
  • Evidence snippets:
  • Snippet 1 (score: 0.564) > Obesity is a highly prevalent and complex disease characterized by excessive body fat accumulation. Obesity often has a multifactorial cause such as common genetic factors, dietary factors, insufficient physical activity, or use of weight-inducing medication. However, in a minority of patients, obesity has an underlying genetic cause [1]. Identification can be difficult as genetic obesity disorders encompass a heterogeneous group of conditions and phenotypes, classically divided into nonsyndromic and syndromic genetic obesity. It is important to identify the molecular defect in these patients as early as possible because they are often refractory to conventional lifestyle intervention and need specific treatment in specialized centers [2]. However, novel pharmacotherapeutic treatment options have become available for genetic obesity [2,3]. > Because genetic obesity disorders are rare, they can be challenging to diagnose. The majority of patients with genetic obesity are probably still undiagnosed, as has been shown for leptin receptor deficiency, which is much more prevalent in Europe (n = 998 predicted patients) than currently known in literature (n = 21 patients) [4]. Therefore, more knowledge on the clinical phenotype and core features is needed. > One of the most common types of nonsyndromic monogenetic obesity is melanocortin 4 receptor (MC4R) deficiency [5][6][7]. This receptor is a key part of the leptin-melanocortin pathway, which plays a major role in weight regulation, satiety, and energy homeostasis [8,9]. Defects in this pathway cause the following characteristic features of monogenetic obesity: severe early-onset obesity and hyperphagia. So far, almost 200 different (likely) pathogenic variants in MC4R have been reported [10,11]. The severity of obesity in patients with MC4R deficiency is variable, and a distinctive clinical extended phenotype has not yet been described [12,13]. Whereas severe early-onset obesity and hyperphagia are indeed features of MC4R deficiency, studies have also shown that pathogenic MC4R variants can cause increased linear growth, hyperinsulinemia, and increased lean body mass [8,11,14,15].

[3] Weight Management in a Patient With Smith-Magenis Syndrome: The Role of GLP-1 Receptor Agonists

  • Authors: J. Correia, T. Frayling, Z. Pataky
  • Year: 2025
  • Venue: JCEM Case Reports
  • URL: https://www.semanticscholar.org/paper/29c5568467a1c5e5aa22494da624901fbc984e0d
  • DOI: 10.1210/jcemcr/luaf094
  • PMID: 40443456
  • PMCID: 12119458
  • Citations: 1
  • Summary: This case underscores the potential of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) in managing both obesity and behavioral symptoms in SMS and shows promise in injectable GLP-1 RAs.
  • Evidence snippets:
  • Snippet 1 (score: 0.554) > Obesity in SMS arises from a combination of genetic, behavioral, and neuroendocrine factors. The RAI1 gene haploinsufficiency, which underlies SMS, disrupts regulatory pathways involved in appetite and energy balance, particularly affecting brain-derived neurotrophic factor expression in the hypothalamus [7,8]. This disruption contributes to hyperphagia, reduced energy expenditure, and altered satiety signaling [7,8]. Additionally, behavioral characteristics of SMS, including compulsive eating and food-seeking behaviors, further promote weight gain [9]. Neuroendocrine dysfunction also plays a role, particularly through dysregulation of the melanocortin-4 receptor (MC4R) pathway, which is central to appetite control and energy homeostasis [7,8]. Although specific MC4R mutations are not typically associated with SMS, altered functioning of this pathway may contribute to the increased obesity risk observed in affected individuals. These combined factors make weight management in SMS particularly challenging and necessitate targeted interventions. > Patients with SMS appear to develop type 2 diabetes, MASLD, and dyslipidemia at a lower BMI compared to the general population, also due to the combination of genetic, metabolic, and neuroendocrine dysfunctions [3]. The RAI1 gene has also been implicated in glucose and lipid metabolism, potentially predisposing individuals to insulin resistance even in the absence of severe obesity [3,10]. Additionally, chronic hyperphagia and altered energy balance contribute to persistent metabolic stress, exacerbating insulin resistance and increasing the risk of diabetes. Neuroendocrine dysfunction, particularly involving the MC4R pathway, may also impair metabolic homeostasis, leading to dyslipidemia and an increased propensity for hepatic steatosis [7]. Furthermore, circadian rhythm disturbances, a hallmark of SMS due to the inversion of melatonin secretion, may further disrupt glucose metabolism and promote hepatic fat accumulation [11,12]. Together, these factors create a state of metabolic vulnerability, where even modest weight gain can accelerate the onset of metabolic diseases, making early screening and intervention crucial in this population.

[4] Pro-Opiomelanocortin and Melanocortin Receptor 3 and 4 Mutations in Genetic Obesity

  • Authors: T. Yanik, S. T. Durhan
  • Year: 2025
  • Venue: Biomolecules
  • URL: https://www.semanticscholar.org/paper/2b375e75fc550e21fb0628b15f4dc23d2200f78a
  • DOI: 10.3390/biom15020209
  • PMID: 40001512
  • PMCID: 11853658
  • Citations: 3
  • Summary: This narrative review focuses on recent developments in two key areas related to POMC regulation and the leptin–melanocortin pathway: genetic variations in and functions of POMC, and MC3R and MC4R variants that lead to genetic obesity in humans.
  • Evidence snippets:
  • Snippet 1 (score: 0.550) > The leptin-melanocortin pathway regulates energy expenditure and food intake. As the key regulators of the leptin-melanocortin pathway, MCRs and POMC-derived hormones are crucial for metabolism [70]. Loss-of-function mutations in the POMC, MC4R, and MC3R genes cause severe obesity, lowering the length and quality of life of the patients due to complications such as cardiovascular disease, type 2 diabetes, and NAFLD. Loss-offunction variants of POMC, MCRs, and other genes in the leptin-melanocortin pathway require broad therapeutic approaches. For a complete understanding of these mechanisms, the physical interactions between MCRs and their ligands, and the reaction kinetics and genetic regulation of these interactions, must be investigated. To this end, the recently discovered second promoter of POMC and the novel variant in the KKRRP motif create new diagnostic and therapeutic research opportunities. For example, KRRP motif mutations could provide an opportunity for the development of simple and efficient PCR-based approaches similar to COVID-19 tests or quick enzyme-linked immunosorbent assays (ELISAs) for the diagnosis of genetic obesity [49,71]. > When the phenotypes of patients with MC3R and MC4R mutations were compared, both genes were found to be involved in severe early-onset obesity. However, MC4R-related obesity was often associated with linear growth; fasting hyperinsulinemia; an increased risk of hypertension; reduced energy expenditure; and increases in lean mass, fat mass, and visceral fat. Interestingly, adult MC4R carriers are not at an increased risk of obesity-related complications such as diabetes but linked to cardiovascular dysfunctions [72]. On the other hand, MC3R carriers had the following phenotypic characteristics: an increased fat mass, decreased lean mass, no change in energy expenditure, and delayed sexual maturity. Moreover, MC3R was found to be crucial for the activation of AgRP neurons during fasting, cold exposure, or ghrelin stimulation [73].

[5] Molecular remodeling of the myocardium in mice with melanocortin-4 receptor deletion before cardiac function impairment

  • Authors: Xiaomei Wang, Yuanmin Qi, Ziming Zhu, Caiqin Wang, Zhimin Zhang et al.
  • Year: 2026
  • Venue: PLOS One
  • URL: https://www.semanticscholar.org/paper/329c278f1c88e30609607d33f6f6356bcd2c6a37
  • DOI: 10.1371/journal.pone.0340465
  • PMID: 41615915
  • PMCID: 12857938
  • Summary: This study analyzed the effects of Mc4r knockout on cardiac function, cardiomyocyte morphology, fibrosis, and apoptosis in mice and explored the possible early molecular mechanisms by which Mc4r affects cardiac dysfunction via transcriptome sequencing of cardiac cells combined with bioinformatics analysis.
  • Evidence snippets:
  • Snippet 1 (score: 0.543) > The melanocortin-4 receptor (MC4R) is highly expressed in the hypothalamus, and mutations in this gene are closely associated with the development of hereditary obesity and early-onset severe obesity in humans. Mc4r has been shown to be involved in the development of dilated cardiomyopathy. However, the current system for the early diagnosis and treatment of heart disease is not well established. In this study, we analyzed the effects of Mc4r knockout on cardiac function, cardiomyocyte morphology, fibrosis, and apoptosis in mice. Moreover, we explored the possible early molecular mechanisms by which Mc4r affects cardiac dysfunction via transcriptome sequencing of cardiac cells combined with bioinformatics analysis. Although the overall heart does not show organic changes, our study suggested that cardiomyocytes already show early abnormal changes at the molecular level. The sequencing results revealed that the genes that were differentially expressed between the two groups of mice were enriched mainly in the p53 signaling pathway and the hypoxia-inducible factor 1 (HIF-1) signaling pathway. We screened 10 key target genes via a protein–protein interaction (PPI) network and module analysis. Drugs targeting key genes were subsequently screened, and angiotensinogen (Agt) and Kit were identified as potential drug targets. We analyze relevant data through bioinformatics to screen for signaling pathways and key hub genes that are enriched in differentially expressed genes (DEGs), as well as molecules targeting the hub genes, in order to provide ideas for early prevention of heart disease caused by Mc4r gene defects or related obesity.

[6] Cumulative Effects of Genetic Variants Detected in a Child with Early-Onset Non-Syndromic Obesity Due to SIM-1 Gene Mutation

  • Authors: G. Luppino, M. Wasniewska, Mara Giordano, G. Pepe, L. Morabito et al.
  • Year: 2025
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/35baabc7caa370310851f25ea51d509b22feabd7
  • DOI: 10.3390/genes16050588
  • PMID: 40428410
  • PMCID: 12110950
  • Citations: 2
  • Summary: The interactive and cumulative effects of the identified variants could coexist in the determination of severe obesity through abnormalities in the development and function of hypothalamic melanocortin circuits related to energy homeostasis.
  • Evidence snippets:
  • Snippet 1 (score: 0.534) > Genetic causes of hypothalamic dysfunction (HD) are due to mutations in genes implicated in the leptinmelanocortin pathway [14]. Autosomal dominant SIM1 gene mutations cause monogenic non-syndromic hypothalamic obesity with a primary mechanism characterized by the disruption of the hypothalamic development, particularly of the PVN and SON, with a reduction in MC4R expression and OXT, AVP, corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and somatostatin (SS) neurons [15]. In vitro, SIM1 factor is a crucial molecular mechanism in a specific melanocortin-signaling pathway that regulates food intake independently of energy expenditure and without interfering with the thermogenesis pathway [16]. The SIM1 gene is predominantly involved in satiety alertness (thus hyperphagia) and resting energy expenditure, although the details regarding SIM1 gene activity are still not completely clear [9]. In addition, despite the molecular targets of SIM1 not being completely known, the anorexigenic neuropeptide oxytocin mediates part of the actions of SIM1, which lies downstream of MC4R. Oxytocin neurons in the PVN are stimulated by an MC4R agonist in mice, and the hyperphagia in SIM1-haploinsufficient mice is reduced after the central administration of oxytocin (Figure 1) [8]. SIM1 acts downstream of MC4R, and both can cause monogenic obesity via autosomal dominant inheritance. The MC4R gene mutation is the most frequent cause of monogenic obesity, and it shares several clinical aspects with forms of multifactorial obesity [17]. However, patients with SIM1 gene mutation present different clinical features from patients with MC4R variants. While neurobehavioral disorders are present in patients with the SIM1 gene mutation, they are not reported in patients with the MC4R gene mutation [9,18]. Patients with the MC4R variant have better accelerated linear growth in the pre-pubertal phase and greater final height than patients with SIM1 gene mutations [18].

[7] Pathogenesis and Therapeutic Perspectives of Tubular Injury in Diabetic Kidney Disease: An Update

  • Authors: Jiamian Geng, Sijia Ma, Hui Tang, Chun-di Zhang
  • Year: 2025
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/889b3498a05a86b303b0fc3bd0f89915c65f39f0
  • DOI: 10.3390/biomedicines13061424
  • PMID: 40564143
  • PMCID: 12189843
  • Citations: 3
  • Summary: Advances in stem cell-based interventions and precision gene editing techniques have unveiled novel therapeutic paradigms for DKD, fundamentally expanding the treatment arsenal beyond conventional pharmacotherapy and highlighting promising therapeutic strategies for managing this condition.
  • Evidence snippets:
  • Snippet 1 (score: 0.518) > The adaptive mechanisms of cellular stress responses play a pivotal role in maintaining organismal homeostasis, conferring remarkable resilience against pathological processes and disease progression [65]. In the context of DKD, three primary forms of stress response mechanisms have been implicated in disease pathogenesis and clinical progression. These maladaptive responses manifest as oxidative stress-mediated cellular damage, ERS-induced protein homeostasis disruption, and mitochondrial dysfunction-related metabolic disturbances. Each pathway contributes distinctively to the complex pathophysiology of DKD through interconnected mechanisms of cellular injury and aberrant signaling cascades.

[8] Evaluation of the Obesity Genes FTO and MC4R for Contribution to the Risk of Large Artery Atherosclerotic Stroke in a Chinese Population

  • Authors: Zhi Song, Li-Na Qiu, Zhong-yang Hu, Jia Liu, Ding Liu et al.
  • Year: 2016
  • Venue: Obesity Facts
  • URL: https://www.semanticscholar.org/paper/2163c823ea1e706a2a05bec3bc7a8037f8048db6
  • DOI: 10.1159/000448588
  • PMID: 27701175
  • PMCID: 5644882
  • Citations: 11
  • Summary: The study indicated that the synergistic effects of MC4R variants, hypertension, and smoking habit contribute significantly to the risk of LAA stroke in the Chinese Han population.
  • Evidence snippets:
  • Snippet 1 (score: 0.509) > From the perspective of stroke prevention, the risk factors can be divided into various categories: congenital or acquired, modifiable or not, classical or non-classical [29,30] . It is well known that interventions of acquired and modifiable risk factors, such as managements of hypertension and smoking cessation, are efficient strategies for stroke prevention [31][32][33] . Our finding revealed that obesity-prone genes such as MC4R contribute to the risk of LAA stroke via a synergistic mechanism, indicating that congenital risk factors, such as MC4R polymorphism, may also play an important role in the pathogenesis of LAA stroke. Although the MC4R polymorphism is not modifiable for clinic practice at present, several treatment options have been investigated in subjects with MC4R mutation-related obesities. A study showed that an intensive lifestyle intervention induces similar weight reduction in MC4R mutation carriers in comparison to MC4R mutation non-carriers [34] . However, long-term body weight maintenance is hardly ever achieved in MC4R mutation carriers [35] . Meanwhile, a variety of in vitro experimental studies on the management of MC4R disruption have been conducted. In vitro studies with melanocortin agonists showed that mutated human MC4R with impaired endogenous agonist functional response can be activated by some of these agonists and may represent a valuable therapeutic target [36] . Furthermore, another study indicated that pharmacological chaperones that recover cell surface expression of MC4R may represent a candidate for the development of a targeted therapy suitable for patients with MC4R-deficient obesity [37] . It is postulated that chemical chaperones and pharmacological agonists efficiently restore cell surface expression and that endogenous agonist response of mutated MC4R may be effective in the treatment of adiposity. However, further research in the development of drugs for MC4R variations is needed. Although pharmacotherapy targeting obesityprone genes such as MC4R has not clinically been tested in the prevention of cerebrovascular disease, identification of pertinent genes may unravel new therapeutic strategies to counter the influence of gene polymorphism on obesity and hence minimize its notable vascular complications, such as

[9] Improving the diagnosis of hyperphagia in melanocortin‐4 receptor pathway diseases

  • Authors: M. J. Abuzzahab, Béatrice Dubern, A. P. Goldstone, A. Haqq, S. Heymsfield et al.
  • Year: 2025
  • Venue: Obesity (Silver Spring, Md.)
  • URL: https://www.semanticscholar.org/paper/8b0cff90a4c94e3b976ff258f598fc2c6f093ba6
  • DOI: 10.1002/oby.24287
  • PMID: 40528426
  • PMCID: 12210103
  • Citations: 4
  • Summary: Characteristics of hyperphagia include heightened and prolonged hunger, longer time to satiation, shorter duration of satiety, severe preoccupation with food (i.e., hyperphagic drive), abnormal food‐seeking behaviors, and distress or functional impairment when food is unavailable. Patients with melanocortin‐4 receptor (MC4R) pathway diseases including those caused by variants in one of multiple key genes of the pathway often present with hyperphagia that results in early‐onset, severe obesity...
  • Evidence snippets:
  • Snippet 1 (score: 0.508) > Obesity is a multifactorial disease with diverse etiologies, including social, environmental, behavioral, and genetic factors [2]. Monogenic and syndromic obesities with established etiologies are caused by variants in a small number of genes (as few as one gene) and/or deletions of chromosomal regions encompassing genes that are involved in key obesity pathogenesis pathways [3,4]. Patients with these genetic variants or deletions generally exhibit early-onset, severe obesity. The pathophysiology of obesity related to genetic dysfunction involves disruptions in key regulatory pathways of energy balance, which can be affected to varying degrees, depending on the specific genetic abnormality and its functional consequences [4]. > Individuals with melanocortin-4 receptor (MC4R) pathway diseases represent a distinct subset among those with monogenic and syndromic obesities [4][5][6]. A hallmark of such MC4R pathway diseases is the presence of hyperphagia, a pathologic condition characterized by heightened and prolonged hunger, longer time to reach satiation, shorter duration of satiety, severe preoccupation with food, abnormal food-seeking behaviors, and distress and/or functional impairment when food is unavailable; these symptoms can be extreme and persistent [2,3,5,[1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]. > In contrast to behavioral, psychological, and/or social challenges in other forms of overeating that are regulated by conscious or higher-order brain functions, hyperphagia results from dysregulation of hypothalamic pathways involving energy balance [1, [16][17][18][19]. This review focuses on the unmet need for fit-for-purpose tools to assess and diagnose hyperphagia in patients with monogenic, syndromic, and acquired forms of obesity associated with MC4R pathway diseases that affect energy balance.
  • Snippet 2 (score: 0.507) > Monogenic obesity is defined as obesity that results from disruption in the function of a single gene [4]. Loss-of-function variants in genes in the leptin-melanocortin pathway, including LEP, LEPR, POMC, PCSK1, NCOA1 (associated with steroid receptor coactivator 1 deficiency), SH2B1, and SIM1, may result in monogenic MC4R pathway diseases and cause hyperphagia and early-onset obesity [2][3][4]52]. > In an epidemiologic analysis of known and predicted loss-of-function variants in POMC, PCSK1, and LEPR, the number of individuals in the United States who had MC4R pathway diseases associated with obesity was estimated to be 12,800 out of a total population of 300 million (0.004%), most of whom remain undiagnosed [21]. > However, the true prevalence of MC4R pathway diseases is unknown because genetic testing is often unavailable or not obtained for individuals with obesity [21,53]. The underutilization of genetic testing for patients with MC4R pathway diseases may result from a lack of understanding or awareness of these diseases among health care professionals [53]. Consequently, clinicians infrequently consider genetic testing as a diagnostic method and may misdiagnose patients as having obesity without a monogenic or oligogenic origin [53].
  • Snippet 3 (score: 0.498) > Characteristics of hyperphagia include heightened and prolonged hunger, longer time to satiation, shorter duration of satiety, severe preoccupation with food (i.e., hyperphagic drive), abnormal food‐seeking behaviors, and distress or functional impairment when food is unavailable. Patients with melanocortin‐4 receptor (MC4R) pathway diseases including those caused by variants in one of multiple key genes of the pathway often present with hyperphagia that results in early‐onset, severe obesity because this pathway plays a critical role in regulation of hunger/satiation and energy balance. Patients with syndromic obesity (e.g., Bardet‐Biedl syndrome) may also have hyperphagia as a result of neurodevelopmental disruptions in the MC4R pathway. Genetic testing is suggested in patients with early‐onset, severe obesity and clinical features of genetic obesity (e.g., hyperphagia, neurodevelopmental differences, dysmorphic features); however, only a small percentage of individuals who meet these criteria undergo testing, potentially owing to limited availability, overlapping symptoms with other obesity types, and infrequent use of genetic testing during diagnosis. Diagnosing hyperphagia may be challenging, as no guidelines have been established for individuals with MC4R pathway diseases. Identifying these individuals is crucial to addressing the challenges of hyperphagia and associated obesity, which often limit quality of life and place overwhelming burdens on patients and families.

[10] Major Advances and Discoveries in Diabetes - 2019 in Review

  • Authors: J. Zierath
  • Year: 2019
  • Venue: Current Diabetes Reports
  • URL: https://www.semanticscholar.org/paper/cf8f4db259ba3491a9f7057cd17a5e588dc44d55
  • DOI: 10.1007/s11892-019-1255-x
  • PMID: 31686269
  • PMCID: 6828626
  • Citations: 11
  • Summary: This review is based on a recent invited lecture at the American Diabetes Association’s 79th annual Scientific Sessions entitled “Major Advances and Discoveries in Diabetes - The Year in Review.” Here I provide a written account of my presentation entitled “Major Discoveries in Diabetes over the Past Year.” I highlight several recent advances in basic science that are relevant for the diabetes field, with insight into how the key takeaways impact basic science. I also speculate on how these b...
  • Evidence snippets:
  • Snippet 1 (score: 0.505) > Obesity is a chronic lifelong condition that results from the interaction between heritable factors with environmental influences. Excess fat accumulation due to an imbalance between energy intake and expenditure causes obesity. The increasing prevalence of obesity is recognized as a major risk for a variety of diseases including type 2 diabetes, cardiovascular disease, cancer, and musculoskeletal disorders. Given that obesity is a driving force behind the diabetes epidemic, better adherence to exercise and diet regimes, as well as safe, effective and durable weight loss therapies are needed. To this end, I. Sadaf Farooqi and colleagues [2] studied the melanocortin 4 receptor (MC4R), a brain-expressed G protein coupled receptor (GPCR) involved in weight regulation. The authors were interested in gaining a more refined understanding of MC4R signaling and its impact on clinical phenotypes. Such knowledge could inform the design of drugs targeting this pathway to treat common obesity and its complications. Earlier studies report a frameshift mutation in MC4R that reduces Gαs-mediated cyclic adenosine monophosphate accumulation is associated with dominantly inherited obesity in humans [3,4]. Here, the authors characterized 61 MC4R variants identified in 0.5 million people from the UK Biobank and examined the associations of these variants with BMI and obesity-related cardiometabolic diseases. They found that gain-of-function variants in the MC4R gene were associated with lower BMI and lower odds of obesity, type 2 diabetes, and coronary artery disease. These variants exhibited a signaling bias for the recruitment of β-arrestin, rather than canonical Gαs-mediated cAMP production. One limitation of the study is that the functional characterization of this obesity protective variant was performed in cell culture models. Thus, the authors provide indirect evidence for a genetic association between the variant and the clinical features of the carriers. To move this discovery into the clinic, additional functional validation using in vivo models would be required to confirm the protective effects of this variant on energy homeostasis and the de- Pharmacological studies are also warranted, with exploratory efforts directed towards the development of preferential agonists rather than broad spectrum agonists with a bias towards β-arrestin signaling for weight loss and for the treatment of obesity-associated

[11] Human MC4R variants affect endocytosis, trafficking and dimerization revealing multiple cellular mechanisms involved in weight regulation

  • Authors: B. B, D. Em, M. M, Monteiro Fbf, Laurin Sa et al.
  • Year: 2021
  • Venue: Cell Reports
  • URL: https://www.semanticscholar.org/paper/d00b445e4dee8f6901b26954ab38703aa56df32d
  • DOI: 10.1016/j.celrep.2021.108862
  • PMID: 33761344
  • PMCID: 7994375
  • Citations: 55
  • Influential citations: 5
  • Summary: Human genetic studies reveal that endocytosis, intracellular trafficking, and homodimerization regulateMC4R function to a level that is physiologically relevant, supporting the development of chaperones, agonists, and allosteric modulators of MC4R for weight loss therapy.
  • Evidence snippets:
  • Snippet 1 (score: 0.503) > Obesity-associated metabolic complications such as type 2 diabetes and cardiovascular disease contribute to significant morbidity, mortality, and health care costs (Heymsfield and Wadden, 2017). As such, there is a substantial unmet need for safe and effective weight loss therapies. G-protein-coupled receptors (GPCRs) are the largest family of cell surface proteins involved in signal transduction (Hauser et al., 2017) and are targeted by more than 30% of prescribed medicines. In the last decade, new insights into GPCR pharmacology and structurefunction relationships have paved the way for the development of compounds with diverse mechanisms of action, increasing treatment options in the clinic. > Here, we focused on the brain-expressed Melanocortin-4 Receptor (MC4R), a GPCR that plays a pivotal role in weight regulation and is a major target for drug development. With multiple potentially druggable sites accessible at the cell surface (Hauser et al., 2017) and informed by the recently published 3D structure of MC4R (Yu et al., 2020) that provides a template for structurebased drug discovery, it is timely to investigate new opportunities to target MC4R for weight loss therapy. It is well-established that binding of Pro-opiomelanocortin (POMC)-derived peptides (a-/b-MSH [melanocyte-stimulating hormone]) to membrane-bound MC4R activates G proteins (Ga s ) and stimulates the production of cyclic AMP (cAMP) to reduce food intake in the fed state (Schwartz et al., 2000). In classical models of GPCR activation, G-protein-dependent signaling is regulated by intracellular scaffolding proteins, b-arrestins, whose interaction with the receptor drives its endocytosis and targeting to early endosomes (EEs) followed by subsequent recycling to the plasma membrane (PM) or sorting to lysosomes for degradation (Shinyama et al., 2003). Endocytosis of GPCRs also contributes to mitogen-activated protein kinase (MAPK) pathway Article ll activation, facilitating a second wave of signaling and gene transcription by Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation (

[12] Monogenic obesity due to MC4R deficiency: lessons from a multigenerational case

  • Authors: Eleni Giannopoulou, Stefanie Zorn, Melanie Schirmer, Stephanie Brandt-Heunemann, J. Schnurbein et al.
  • Year: 2026
  • Venue: Molecular and Cellular Pediatrics
  • URL: https://www.semanticscholar.org/paper/194a0dd5164c87733d55c9729dec3f267c26df73
  • DOI: 10.1186/s40348-025-00214-z
  • PMID: 41489710
  • PMCID: 12770134
  • Citations: 1
  • Summary: This case underscores the importance of early genetic testing in severe childhood obesity to avoid ineffective treatments and enable targeted therapies (e.g., GLP-1 analogues).
  • Evidence snippets:
  • Snippet 1 (score: 0.492) > Monogenic obesity due to monoallelic MC4R variants can present with severe early-onset obesity yet often remains undiagnosed for generations. In the presented case, genetic testing in the youngest affected family member led to a diagnosis in three older relatives. This highlights the importance of genetic testing in children with severe obesity and hyperphagia, as it can guide targeted treatment and help establish a diagnosis for other family members. > MC4R is a G-protein coupled receptor with seven transmembrane domains that plays a central role in the leptin-melanocortin pathway, primarily regulating satiety, feeding behavior, and energy homeostasis [22,23]. Expressed predominantly in the hypothalamus, MC4R is a key mediator of body weight regulation, and loss-of-function variants in this gene represent the most frequent cause of monogenic obesity [22,24]. While biallelic MC4R variants are exceedingly rare, pathogenic monoallelic MC4R variants are present in up to 5.8% of individuals with severe, early-onset obesity [22,25]. Most recently, a population-based study have found their prevalence at around 0.3% in a UK birth cohort [24], indicating that MC4R deficiency should no longer be classified as a "rare disease". > The clinical manifestation of monoallelic MC4R deficiency shows considerable variability in obesity severity. Although biallelic carriers are rare and typically present with more severe phenotypes, certain individuals with monoallelic variants may remain unaffected by obesity [22,24,26,27]. In addition to severe early-onset obesity and hyperphagia -the hallmark features -pathogenic MC4R variants have also been linked to accelerated linear growth during childhood (but normal final height), hyperinsulinemia, lower total and LDL-cholesterol levels, increased lean body mass and increased bone mineral density [10,22,28,29]. Interestingly, both hyperinsulinemia and hyperphagia associated with MC4R deficiency appear to be age-dependent, tending to diminish over time, with the underlying mechanisms remaining unclear [22].

[13] The Role of Obesity in Renal Cell Carcinoma Patients: Clinical-Pathological Implications

  • Authors: G. Aurilio, F. Piva, M. Santoni, A. Cimadamore, G. Sorgentoni et al.
  • Year: 2019
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/2a1490476ee326033515981a61b0ac89b8db6dfb
  • DOI: 10.3390/ijms20225683
  • PMID: 31766196
  • PMCID: 6888048
  • Citations: 52
  • Influential citations: 2
  • Summary: Retrospective clinical evidence in metastatic RCC patients with higher body mass index (BMI) and treated with targeted therapies and/or immune checkpoint inhibitors showed advantageous survival outcomes, suggesting obesity may influence the course of R CC patients, although the interplay between obesity/BMI and RCC warrants a large prospective confirmation.
  • Evidence snippets:
  • Snippet 1 (score: 0.487) > Notwithstanding, the link between microbiota and obesity or obesity-related conditions (including type 2 diabetes) has not yet been completely clarified. Among the proposed mechanisms, altered integrity of the gut barrier and of the capacity to extract energy from foods, together with changes in the modulation of chronic inflammation, seem to be the most probable candidates [60]. > Promising results in in vivo models have recently been observed with novel therapeutics targeting adipocytes, ASCs, and adipose endothelium [61,62], paving the way for tailored therapies for obese patients. In the near future, the challenge will be that of targeting cellular pathways of WAT growth prone to cancer induction and progression in an attempt to reduce cancer risk [63]. Novel evidence has recently reinforced the role of insulin as risk factor; however, it appears clear that there is an unequivocal need to understand how the insulin pathway increases the risk of RCC and to discover further biological pathways as well as obesity-related mechanisms involved in RCC growth. Of interest, cellular pathways involved in the switch of cancer cells to lipid metabolism could be potential targets along with conventional therapies. Areas of investigation for explaining how obesity affects clinical outcomes should consider both pharmocokinetics and drug bioavailability, in addition to the concomitance of cardiovascular disease and diabetes. It is conventionally known that obesity elicits a biological condition of inflammation with consequent increases in TNF, interleukins, C-reactive protein, etc. However, it is important to note that not all obese patients express inflammation of the adipose tissue or metabolic complications. > To conclude, since the incidence of obesity is rising, and its implications can have serious medical consequences, the interplay between obesity and cancer warrants further investigation by the scientific community worldwide. Although several studies are focused on the treatment and prevention of RCC, the first stones on the path toward targeted therapy development for RCC patients are only just beginning to be laid.

[14] Human Gain-of-Function MC4R Variants Show Signaling Bias and Protect against Obesity

  • Authors: L. Lotta, J. Mokrosiński, Edson Mendes de Oliveira, Chen Li, S. Sharp et al.
  • Year: 2019
  • Venue: Cell
  • URL: https://www.semanticscholar.org/paper/6231fd402faa631dea9a0d50828a33ed3c70e21b
  • DOI: 10.1016/j.cell.2019.03.044
  • PMID: 31002796
  • PMCID: 6476272
  • Citations: 228
  • Influential citations: 14
  • Summary: Protective associations were driven by MC4R variants exhibiting signaling bias toward β-arrestin recruitment and increased mitogen-activated protein kinase pathway activation, which may represent an effective strategy for weight loss and the treatment of obesity-related cardiometabolic diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.485) > 4R agonists caused weight loss but increased BP (Greenfield et al., 2009), which halted their development. A second-generation MC4R agonist reduced weight in rare patients with obesity due to genetic disruption of the melanocortin pathway (Clé ment et al., 2018;Collet et al., 2017;Kü hnen et al., 2016) without affecting BP (Chen et al., Kievit et al., 2013); however, off-target effects on the melanocortin-1 receptor (skin pigmentation) may limit its wider use. We hypothesized that a more refined understanding of MC4R signaling and its impact on clinical phenotypes in the general population may inform the design of drugs targeting this pathway to treat common obesity and its complications. > We performed genetic association studies in approximately 0.5 million people from UK Biobank, focusing on 61 nonsynonymous variants identified in MC4R. 12 of the 61 were nonsense/frameshift variants; the remainder (n = 49) were missense variants whose functional properties were characterized in cells quantifying canonical Ga s -mediated cAMP production and the recruitment of b-arrestin to MC4R. In meta-regression analyses using the functional consequence of MC4R variants as the predictor, we found that 88% of the variance in the association of different MC4R variants with BMI was explained by their effect on b-arrestin recruitment. A subset of individuals (6%, n = 28,161) were carriers for gain-of-function (GoF) alleles that exhibited signaling bias, preferentially increasing b-arrestin recruitment rather than cAMP production. These individuals had significantly lower BMI (p = 2 3 10 À42 ) and up to 50% lower risk of obesity, type 2 diabetes, and coronary artery disease. Cumulatively, the characterization of BMI-lowering variants in MC4R demonstrates the pivotal role of b-arrestin-mediated MC4R signaling in human energy homeostasis. These findings have relevance for the development of b-arrestin-biased MC4R agonists for weight loss and for the treatment of obesity-associated metabolic disease.

[15] Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice

  • Authors: Christoffer Clemmensen, Brian Finan, K. Fischer, R. Tom, B. Legutko et al.
  • Year: 2015
  • Venue: EMBO Molecular Medicine
  • URL: https://www.semanticscholar.org/paper/a543100aef18e1f66bcca0521ac79d06c1ee3a4d
  • DOI: 10.15252/emmm.201404508
  • PMID: 25652173
  • PMCID: 4364946
  • Citations: 78
  • Influential citations: 3
  • Summary: Findings suggest potential opportunities for employing combination treatments that comprise parallel MC4R and GLP‐1R agonism for the treatment of obesity and diabetes and increases expression of each receptor, indicative of minimized receptor desensitization.
  • Evidence snippets:
  • Snippet 1 (score: 0.478) > The worldwide prevalence of obesity and its associated metabolic complications is an increasing threat to public health (Wang et al, 2011). As a result, the development of safe and effective pharmacotherapies is a global priority. The etiology of metabolic disease is complex, with diverse pathophysiological mechanisms, emphasizing the challenges inherent in the development of medicinal options for the disorder (Kopelman, 2000;Scheen & Van Gaal, 2014). This is exemplified by the poor success rate in the development of antiobesity drugs, as less than a handful of pharmacotherapies for obesity have progressed through regulatory approval (Rueda-Clausen et al, 2013). Recent clinical and pre-clinical advances indicate that simultaneously targeting more than one signaling pathway could lead to superior metabolic efficacy and fewer adverse events compared to traditional mono-therapies (Greenway & Bray, 2010;Rodgers et al, 2012;Sadry & Drucker, 2013). Simultaneous targeting of multiple metabolic pathways can be realized either via coadministration of distinct hormones Clemmensen et al, 2014) or through employing unimolecular co-agonists that combine and integrate several hormone action profiles as well as different modes of pharmacological action (Day et al, 2009;Pocai et al, 2009;Finan et al, 2012Finan et al, , 2013Finan et al, , 2015. > The melanocortin-4 receptor (MC4R) plays a seminal role in regulating energy metabolism (Tao, 2010). Stimulation of pro-opiomelanocortin (POMC) expressing neurons in the hypothalamic arcuate nucleus results in the synthesis, cleavage and release of several bioactive peptides, including the endogenous MC4R-agonists a-MSH, b-MSH and c-MSH (Castro & Morrison, 1997). Ligand-induced activation of MC4R results in inhibition of food intake and stimulation of energy expenditure, promoting a negative energy balance (McMinn et al, 2000;Balthasar et al, 2005). These observations and the finding that a plethora of MC4R loss-of-function variants predispose to human obesity have made the MC4R an attractive target for the

[16] Targeting PI3K/AKT signaling pathway in obesity.

  • Authors: M. Savova, L. Mihaylova, D. Tews, M. Wabitsch, M. Georgiev
  • Year: 2023
  • Venue: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
  • URL: https://www.semanticscholar.org/paper/3feb59a0b961596f01fa335adad0ea8c43bdfc70
  • DOI: 10.1016/j.biopha.2023.114244
  • PMID: 36638594
  • Citations: 208
  • Influential citations: 7
  • Summary: The druggability of PI3K as a target for compounds with anti-obesity potential is evaluated and Perspectives on the strategies and limitations for clinical implementation of obesity management using natural compounds modulating the PI3k/AKT pathway are suggested.
  • Evidence snippets:
  • Snippet 1 (score: 0.472) > Obesity is a disorder with an increasing prevalence, which impairs the life quality of patients and intensifies societal health care costs. The development of safe and innovative prevention strategies and therapeutic approaches is thus of great importance. The complex pathophysiology of obesity involves multiple signaling pathways that influence energy metabolism in different tissues. The phosphatidylinositol 3-kinases (PI3K)/protein kinase B (AKT) pathway is critical for the metabolic homeostasis and its function in insulin-sensitive tissues is described in the context of health, obesity and obesity-related complications. The PI3K family participates in the regulation of diverse physiological processes including but not limited to cell growth, survival, differentiation, autophagy, chemotaxis, and metabolism depending on the cellular context. AKT is downstream of PI3K in the insulin signaling pathway, and promotes multiple cellular processes by targeting a plethora of regulatory proteins that control glucose and lipid metabolism. Natural products are essential for prevention and treatment of many human diseases, including obesity. Anti-obesity natural compounds effect multiple pathophysiological mechanisms involved in obesity development. Numerous recent preclinical studies reveal the advances in using plant secondary metabolites to target the PI3K/AKT signaling pathway for obesity management. In this paper the druggability of PI3K as a target for compounds with anti-obesity potential is evaluated. Perspectives on the strategies and limitations for clinical implementation of obesity management using natural compounds modulating the PI3K/AKT pathway are suggested.

[17] G-Protein-Coupled Receptor (GPCR) Signaling and Pharmacology in Metabolism: Physiology, Mechanisms, and Therapeutic Potential

  • Authors: Yun Yeong Cho, Soyeon Kim, Pankyung Kim, Min Jeong Jo, Song-E Park et al.
  • Year: 2025
  • Venue: Biomolecules
  • URL: https://www.semanticscholar.org/paper/7118cc76ba94da8ea8aade6a7c3de8b88049b7d6
  • DOI: 10.3390/biom15020291
  • PMID: 40001594
  • PMCID: 11852853
  • Citations: 21
  • Influential citations: 1
  • Summary: This review focuses on six GPCRs, GPR40, GPR120, GLP-1R, and ß-adrenergic receptors (ADRB1, ADRB2, and ADRB3), with GLP-1R recognized as a prominent regulator of system-level metabolism, while the roles of GPR40, GPR120 and ß-adrenergic receptors in central carbon metabolism and energy homeostasis are increasingly appreciated.
  • Evidence snippets:
  • Snippet 1 (score: 0.471) > Obesity and associated chronic metabolic diseases, including type 2 diabetes, have emerged as critical global health concerns. These pathophysiologies are driven by imbalanced energy metabolism resulting from high-calorie intake, decreased physical activityexacerbated during the recent COVID-19 pandemic-and increased life span as aging predisposes individuals to metabolic disorders [1][2][3]. Type 2 diabetes is characterized by insulin resistance and pancreatic β-cell failure [4,5]. During insulin resistance, the body's tissues become unresponsive to insulin's effects despite its production, while β-cell dysfunction impairs the pancreas's ability to secrete sufficient insulin [6][7][8][9][10][11]. Since obesity exacerbates both these mechanisms, the global increase in obesity rates is considered a major contributor to the growing prevalence of type 2 diabetes [11,12]. Understanding the molecular mechanisms underlying obesity and its progression to type 2 diabetes is, therefore, crucial for developing effective prevention and treatment strategies. By uncovering the pathways linking obesity to insulin resistance and β-cell dysfunction, researchers can identify potential therapeutic targets to combat these interconnected diseases. > Given their central roles in cellular communication and metabolic regulation, Gprotein coupled receptors (GPCRs) have emerged as key players in the pathophysiology of obesity and type 2 diabetes. GPCRs, also known as seven transmembrane receptors, are integral membrane proteins expressed on nearly all cell types throughout the body, translating extracellular signals into intracellular responses. GPCR activation typically involves an agonist binding to the receptor, stabilizing its conformation to recruit and activate intracellular signaling transducers [11,[13][14][15]. GPCRs respond to a wide range of agonists, extending beyond classic peptide hormones (e.g., glucagon and GLP1) to include endogenous and exogenous metabolites such as sugars, free fatty acids, nucleotides, and microbial products, as well as synthetic agents [16][17][18][19].

[18] The Related Metabolic Diseases and Treatments of Obesity

  • Authors: Ming Yang, Shuai Liu, Chunye Zhang
  • Year: 2022
  • Venue: Healthcare
  • URL: https://www.semanticscholar.org/paper/dcc752ecd7148ba648c2d793802bc233a7716779
  • DOI: 10.3390/healthcare10091616
  • PMID: 36141228
  • PMCID: 9498506
  • Citations: 133
  • Influential citations: 3
  • Summary: Prevention and early treatment of obesity are the best options to prevent its progression to many comorbidities and psychological management, especially for patients with obesity and distress, is a good option.
  • Evidence snippets:
  • Snippet 1 (score: 0.465) > Genes encoding leptin (LEP), leptin receptor (LEPR), melanocortin 4 receptor (MC4R), proprotein convertase subtilisin/kexin type 1 (PCSK1), proopiomelanocortin (POMC), kinase suppressor of ras 2 (KSR2), adenylate cyclase 3 (ADCY3), and others contribute to the development and progression of obesity [7]. For example, mutations of the ADCY3 gene cause obesity in children from consanguineous Pakistani families, while heterozygous mutations are associated with the severity of obesity in children of European-American descent [8]. In addition, the ADCY3 variant is associated with a significantly increased risk of obesity and T2D in the Greenlandic population [9]. ADCY3 mutations play a pivotal role in neuronal primary cilia (microtubule-based cellular organelles) in neuronal function, which causes a predisposition to obesity [10]. > Obesity is commonly associated with many other metabolic disorders, including type 2 diabetes (T2D), non-alcoholic fatty liver disease (NAFLD), cardiovascular diseases (CVDs), chronic kidney diseases (CKDs), and cancers [11,12]. In addition, obesity is positively associated with the severity and mortality of the coronavirus disease 2019 (COVID- 19) in patients [13]. Adipose tissues secrete many inflammatory cytokines such as tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6), which are a group of major contributing factors to metabolic disorders [14]. Obesity also causes other complications, such as dysfunction of vascular epithelial cells and lipid accumulation in organs except for adipose tissues. In the following sections, many factors that contribute to obesity-associated comorbidities are first reviewed. Then, molecular signaling pathways that are involved in the pathogenesis of obesity are discussed. Finally, current management and treatment options for obesity are summarized.

Notes

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  • No synthesis or second-stage model call is performed.