Regulation of energy rheostasis by the melanocortin-3 receptor

Ghamari‐Langroudi, Masoud; Çakır, Işın; Lippert, Rachel N.; Sweeney, Patrick J.; Litt, M.; Ellacott, Kate L. J.; Cone, Roger D.

doi:10.1126/sciadv.aat0866

Cited by 49 publications

(95 citation statements)

References 40 publications

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“…The three patients (0.65%) with missense mutations in MC3R had a similar degree of obesity, which was milder than those harbouring RSVs in MC4R, and no overgrowth or advanced skeletal maturation. These patients did not exhibit measurable hyperphagia, similar to what was observed in MC3R-deficient mice [47]. However, as with mice, an inadequate diet could contribute to the excess weight gain.…”

Section: Discussionsupporting

confidence: 67%

“…MC3R-knockout mice were shown to have dysregulation of energy expenditure, feeding responses and neuroendocrine responses to metabolic challenges such as fasting, high fat diet intake, pregnancy and the loss of estrogens. For example, these mice lost more weight during fasting than wild-type mice, but gained more weight when put on a high fat diet [47]. The three patients (0.65%) with missense mutations in MC3R had a similar degree of obesity, which was milder than those harbouring RSVs in MC4R, and no overgrowth or advanced skeletal maturation.…”

Section: Discussionmentioning

confidence: 95%

“…Like MC4R, MC3R has a critical role in regulating energy balance [46]. It was recently reported to regulate the upper and lower limits of an individual's homeostatic setpoints and the response to external metabolic challenges [47]. MC3R-knockout mice were shown to have dysregulation of energy expenditure, feeding responses and neuroendocrine responses to metabolic challenges such as fasting, high fat diet intake, pregnancy and the loss of estrogens.…”

Section: Discussionmentioning

confidence: 99%

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Heterozygous rare genetic variants in non-syndromic early-onset obesity

et al. 2019

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Background Obesity is a very heterogeneous disorder at both the clinical and molecular levels and with high heritability. Several monogenic forms and genes with strong effects have been identified for non-syndromic severe obesity. Novel therapeutic interventions are in development for some genetic forms, emphasizing the importance of determining genetic contributions. Objective We aimed to define the contribution of rare single-nucleotide genetic variants (RSVs) in candidate genes to nonsyndromic severe early-onset obesity (EOO; body mass index (BMI) >+3 standard deviation score, <3 years). Methods Using a pooled DNA-sequencing approach, we screened for RSVs in 15 obesity candidate genes in a series of 463 EOO patients and 480 controls. We also analysed exome data from 293 EOO patients from the "Viva la Familia" (VLF) study as a replication dataset. Results Likely or known pathogenic RSVs were identified in 23 patients (5.0%), with 7 of the 15 genes (BDNF, FTO, MC3R, MC4R, NEGR1, PPARG and SIM1) harbouring RSVs only in cases (3.67%) and none in controls. All were heterozygous changes, either de novo (one in BDNF) or inherited from obese parents (seven maternal, three paternal), and no individual carried more than one variant. Results were replicated in the VLF study, where 4.10% of probands carried RSVs in the overrepresented genes. RSVs in five genes were either absent (LEP) or more common in controls than in cases (ADRB3, LEPR, PCSK1 and PCSK2) in both obese datasets. Conclusions Heterozygous RSVs in several candidate genes of the melanocortin pathway are found in~5.0% patients with EOO. These results support the clinical utility of genetic testing to identify patients who might benefit from targeted therapeutic intervention.

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Section: Discussionsupporting

confidence: 67%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

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Heterozygous rare genetic variants in non-syndromic early-onset obesity

et al. 2019

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“…Skorczyk et al [ 140 ] conducted a candidate gene study on the gene encoding melanocortin receptor 3 ( MC3R) . The MC3R gene is a reasonable candidate, although it is notable that rodent and human phenotypes associated with MC3R variants are more subtle than for the related MC4R, with MC3R most likely affecting the maintenance of body mass within the homeostatically controlled upper and lower limits [ 141 , 142 , 143 , 144 ].…”

Section: Canine Obesity Geneticsmentioning

confidence: 99%

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

Wallis

Raffan

2020

Genes

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Obesity is one of the most prevalent health conditions in humans and companion animals globally. It is associated with premature mortality, metabolic dysfunction, and multiple health conditions across species. Obesity is, therefore, of importance in the fields of medicine and veterinary medicine. The regulation of adiposity is a homeostatic process vulnerable to disruption by a multitude of genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarise the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats, and horses, we compare the similarities in obesity pathophysiology to humans and review the genetic studies that have been previously reported in those species. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research.

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“…MC3R is a reasonable candidate gene although it is notable that rodent and human phenotypes associated with MC3R variants are more subtle than for the related MC4R, with MC3R most likely affecting the maintenance of body mass within the homeostatically-controlled upper and lower 'bounds' [126,127]. [128,129].…”

Section: Mc3rmentioning

confidence: 99%

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

Wallis

Raffan

2020

Preprint

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Obesity is one of the most prevalent health conditions in humans and companion animals across the world. Obesity is associated with multiple health conditions across species including premature mortality. It is therefore of importance across the fields of medicine and veterinary medicine. The regulation of body weight is a homeostatic process vulnerable to disruption by genetic and environmental factors. It is well established that the heritability of obesity is high in humans and laboratory animals, with ample evidence that the same is true in companion animals. In this review, we provide an overview of how genes link to obesity in humans, drawing on a wealth of information from laboratory animal models, and summarising the mechanisms by which obesity causes related disease. Throughout, we focus on how large-scale human studies and niche investigations of rare mutations in severely affected patients have improved our understanding of obesity biology and can inform our ability to interpret results of animal studies. For dogs, cats and horses, we review the similarities in obesity pathophysiology to humans and review those genetic studies that have been done to investigate them. Finally, we discuss how veterinary genetics may learn from humans about studying precise, nuanced phenotypes and implementing large-scale studies, but also how veterinary studies may be able to look past clinical findings to mechanistic ones and demonstrate translational benefits to human research.

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Regulation of energy rheostasis by the melanocortin-3 receptor

Abstract: The melanocortin-3 receptor acts as a rheostat on energy homeostasis through presynaptic inhibition of MC4R neuronal activity.

Cited by 49 publications

References 40 publications

Heterozygous rare genetic variants in non-syndromic early-onset obesity

Heterozygous rare genetic variants in non-syndromic early-onset obesity

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

The Genetic Basis of Obesity and Related Metabolic Diseases in Humans and Companion Animals

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