15 research outputs found
Evaluation of a Melanocortin-4 Receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency
Pro-opiomelanocortin (POMC)-derived peptides act on neurons expressing the Melanocortin 4 receptor (MC4R) to reduce body weight. Setmelanotide is a highly potent MC4R agonist that leads to weight loss in diet-induced obese animals and in obese individuals with complete POMC deficiency. While POMC deficiency is very rare, 1e5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency.
We studied the effects of Setmelanotide on mutant MC4Rs in cells and the weight loss response to Setmelanotide administration in rodent studies and a human clinical trial. We annotated the functional status of 369 published MC4R variants.
In cells, we showed that Setmelanotide is significantly more potent at MC4R than the endogenous ligand alpha-melanocyte stimulating hormone and can disproportionally rescue signaling by a subset of severely impaired MC4R mutants. Wild-type rodents appear more sensitive to Setmelanotide when compared to MC4R heterozygous deficient mice, while MC4R knockout mice fail to respond. In a 28-day Phase 1b clinical trial, Setmelanotide led to weight loss in obese MC4R variant carriers. Patients with POMC defects upstream of MC4R show significantly more weight loss with Setmelanotide than MC4R deficient patients or obese controls.
Setmelanotide led to weight loss in obese people with MC4R deficiency; however, further studies are justified to establish whether Setmelanotide can elicit clinically meaningful weight loss in a subset of the MC4R deficient obese population.This work was supported by the Wellcome Trust (I.S.F.), the National Institute for Health Research Cambridge Biomedical Research Centre (S.O’R., I.S.F.), the Bernard Wolfe Health Neuroscience Fund (I.S.F.), the European Research Council (I.S.F.), and the Swiss National Science Foundation (PBLAP3-145870, P3SMP3-155318, PZ00P3-167826 to T.-H.C.). Funds were also obtained from the Clinical Research Programs on Obesity (Assistance Publique-Hôpitaux de Paris, and the Direction of Clinical Research (CRC) (PHRC 02076 to K.C.), as well as the Institut Benjamin Delessert and the Fondation pour la Recherche Médicale and the National Agency of Research (program “Investissements d’Avenir” with the reference ANR-10-IAHU-05). The clinical trial was supported by Rhythm Pharmaceuticals
Melanocortin agonists stimulate lipolysis in human adipose tissue explants but not in adipocytes
Production of a Bioengineered G-Protein Coupled Receptor of Human Formyl Peptide Receptor 3
Genetic variants help define the role of the MC4R C-terminus in signaling and cell surface stability
T4-Lysozyme Fusion for the Production of Human Formyl Peptide Receptors for Structural Determination
Changes in feeding habits promoted the differentiation of the composition and function of gut microbiotas between domestic dogs (Canis lupus familiaris) and gray wolves (Canis lupus)
Evaluation of Live Recombinant Nonpathogenic Leishmania tarentolae Expressing Cysteine Proteinase and A2 Genes as a Candidate Vaccine against Experimental Canine Visceral Leishmaniasis
Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour
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