Abstract
ObjectivePro-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, 1–5% of severely obese individuals harbor heterozygous mutations in MC4R. We sought to assess the efficacy of Setmelanotide in human MC4R deficiency. MethodsWe 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. ResultsIn 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. ConclusionsSetmelanotide 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.
Highlights
Neural circuits in the hypothalamus play a critical role in the regulation of energy homeostasis [1,2]
We found that melanocortin-4 receptor (MC4R) variant homozygotes were significantly more obese than heterozygotes (p < 0.001); there was no significant difference in BMI between those carrying heterozygous complete vs partial loss of function (LOF) variants (Figure 1E)
Our findings demonstrate that the melanocortin 4 receptor agonist, Setmelanotide can lead to weight loss in obese people with MC4R deficiency
Summary
Neural circuits in the hypothalamus play a critical role in the regulation of energy homeostasis [1,2]. Treatment of obese volunteers with the agonist LY2112688 at the maximum dose of 1.0 mg/day led to significant increases of systolic (mean 9.3 Æ SD 1.9 mmHg) and diastolic (mean 6.6 Æ SD 1.1 mmHg) blood pressure after only 24 h of treatment compared with placebo [18] These adverse effects halted the development of the first generation of MC4R agonists. In a recent proof-of-principle study, two rare POMC deficient individuals treated with Setmelanotide experienced significant weight loss (51.0 kg of body weight loss after 42 weeks in patient 1 and 20.5 kg of body weight after 12 weeks in a second patient) without any adverse effects on cardiovascular parameters [23] These results established that while obesity due to complete POMC deficiency is very rare, it is potentially very responsive to treatment with Setmelanotide.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
