期刊
MOLECULAR METABOLISM
卷 48, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.molmet.2021.101206
关键词
Melanocortin; Hypothalamus; Obesity; Genetics; Pharmacology; Therapy
资金
- UK Medical Research Council (MRC Metabolic Diseases Unit) [MC_UU_00014/1]
- MRC [MR/S026193/1]
- UK MRC [MR/S026193/1]
- Centre National la Recherche Scientifique (CNRS)
- Universite de Paris
- Modern Diet and Physiology Research Center (MDPRC)
- National Research Agency National Research Agency [ANR-15-CE14-0030-01: Nutritpathos]
- Foundation pour la Recherche Medicale (FRM)
- NIH NIDDK [1R01DK108893]
- Australian NHMRC grant [1163341]
- European Union Seventh Framework Programme [607310]
- Netherlands Organisation for Scientific Research [ALWOP.137, OCENW.KLEIN.071]
- Swedish Research Council [2018e02588]
- ERANET NEURON (MiGBAN)
- National Health and Medical Research Council of Australia [1163341] Funding Source: NHMRC
- MRC [MR/S026193/1] Funding Source: UKRI
Insights from human and mouse genetics have highlighted the central role of the brain leptin-melanocortin pathway in controlling mammalian food intake, leading to the approval of setmelanotide as a drug for individuals with severe obesity due to specific genetic deficiencies. This research provides a template for drug discovery in complex disorders, showing how a single gene target can eventually lead to the development of an approved drug after 25 years of study.
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.
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