Cover Story Current Issue

The high prevalence of obesity is associated with increased mortality because of various comorbidities evoked by an increase in adiposity. Type II diabetes and cardiovascular disease are major medical conditions commonly linked to alterations in the homeostatic pathways that regulate energy homeostasis. As a master regulator of energy balance, the brain integrates peripheral signals and, in turn, modulates feeding behavior and the activity of the autonomic nervous system. The hypothalamus acts as the main hub that receives and integrates peripheral signals.

Mohamed Rouabhi, Deng-Fu Guo, Donald A. Morgan, Zhiyong Zhu, ... Kamal Rahmouni

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Current Issue

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, ... Roger A.H. Adan

Background

Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and 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

Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target.

Major 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 melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.

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, ... Roger A.H. Adan

Background

Over the past 20 years, insights from human and mouse genetics have illuminated the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, with genetic disruption resulting in extreme obesity, and more subtle polymorphic variations influencing the population distribution of body weight. At the end of 2020, the U.S. Food and 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

Herein, we chart the melanocortin pathway's history, explore its pharmacology, genetics, and physiology, and describe how a neuropeptidergic circuit became an important druggable obesity target.

Major 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 melanocortin receptors has brought a new obesity drug to the market. This process provides a drug discovery template for complex disorders, which for setmelanotide took 25 years to transform from a single gene into an approved drug.

The 60 Second Metabolist

In this section authors briefly report on their work recently published in Molecular Metabolism.

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