The melanocortin pathway and energy homeostasis: From discovery to obesity therapy.
Giles S.H. Yeo,Daniela Herrera Moro Chao,Anna Maria Siegert,Zoe M. Koerperich,Mark D. Ericson,Stephanie E. Simonds,Courtney M Larson,Serge Luquet,Iain J. Clarke,Shubh D. Sharma,Karine Clément,Michael A. Cowley,Carrie Haskell-Luevano,Lex H.T. Van der Ploeg,Roger A.H. Adan +14 more
TLDR
In this article, the authors chart the history of the melanocortin pathway, explore its pharmacology, genetics and physiology, and tell the story of how a neuropeptidergic circuit managed to find its way to becoming an important druggable obesity target.Abstract:
Background Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in the control of mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variation influencing the population distribution of body-weight. At the end of 2020, the Food & Drug Administration (FDA) approved setmelanotide, a melanocortin 4 receptor agonist, for use in individuals with severe obesity due to either pro-opiomelanocortin (POMC), proprotein convertase subtilisin/kexin type 1 (PCSK1) or leptin receptor (LEPR) deficiency. Scope of review Here, we will chart the history of the melanocortin pathway, explore its pharmacology, genetics and physiology, and tell the story of how a neuropeptidergic circuit managed to find its way to becoming an important druggable obesity target. Conclusions Unravelling the genetics of the subset of severe obesity has revealed the importance of the melanocortin pathway in appetitive control; coupling this with studying the molecular pharmacology of compounds that bind the melanocortin receptors has brought a new drug to the market for obesity. This process provides a template of drug discovery for complex disorders, which in the case of setmelanotide took 25 years to go from a single gene to an approved drug.read more
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The genetics of obesity: from discovery to biology
Ruth J. F. Loos,Giles S.H. Yeo +1 more
TL;DR: Loos and Yeo as mentioned in this paper summarized the current understanding of the genetic underpinnings of monogenic and polygenic obesity and highlighted the commonalities revealed by recent studies and discuss the implications for treatment and prediction of obesity risk.
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Obesity: Epidemiology, Pathophysiology, and Therapeutics.
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A 2022 update on the epidemiology of obesity and a call to action: as its twin COVID-19 pandemic appears to be receding, the obesity and dysmetabolism pandemic continues to rage on
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Signaling pathways in obesity: mechanisms and therapeutic interventions
TL;DR: In this paper , the authors summarize recent advances in the pathogenesis of obesity from both experimental and clinical studies, focusing on signaling pathways and their roles in the regulation of food intake, glucose homeostasis, adipogenesis, thermogenesis, and chronic inflammation.
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The promise of new anti-obesity therapies arising from knowledge of genetic obesity traits
TL;DR: In this paper , the authors proposed novel pharmacological treatment options emerging for monogenic obesity syndromes that target the central melanocortin pathway, and genetic testing is recommended for patients with rapid weight gain in infancy and additional clinical suggestive features.
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