Chronic Treatment With a Melanocortin-4 Receptor Agonist Causes Weight Loss, Reduces Insulin Resistance, and Improves Cardiovascular Function in Diet-Induced Obese Rhesus Macaques

Abstract

The melanocortin-4 receptor (MC4R) is well recognized as an important mediator of body weight homeostasis. Activation of MC4R causes dramatic weight loss in rodent models, and mutations in human are associated with obesity. This makes MC4R a logical target for pharmacological therapy for the treatment of obesity. However, previous studies in rodents and humans have observed a broad array of side effects caused by acute treatment with MC4R agonists, including increased heart rate and blood pressure. We demonstrate that treatment with a highly-selective novel MC4R agonist (BIM-22493 or RM-493) resulted in transient decreases in food intake (35%), with persistent weight loss over 8 weeks of treatment (13.5%) in a diet-induced obese nonhuman primate model. Consistent with weight loss, these animals significantly decreased adiposity and improved glucose tolerance. Importantly, we observed no increases in blood pressure or heart rate with BIM-22493 treatment. In contrast, treatment with LY2112688, an MC4R agonist previously shown to increase blood pressure and heart rate in humans, caused increases in blood pressure and heart rate, while modestly decreasing food intake. These studies demonstrate that distinct melanocortin peptide drugs can have widely different efficacies and side effects.

Green tea polyphenol epigallocatechin-3-gallate ameliorates insulin resistance in non-alcoholic fatty liver disease mice

“…However, the effect of EGCG on insulin resistance and its mechanism in treating NAFLD has rarely been discussed. In our study, EGCG allevi- (Table 1), as previously shown wherein weight loss induced by diet control, exercise, pharmacotherapy and bariatric surgery improves insulin resis tance [26,27] . However, more importantly, our study confirmed that an EGCG-induced increase in insulin clearance may contribute to the improvement of insulin resistance in NAFLD mice ( Figure 6).…”

Pharmacological Activation of the Melanocortin System Limits Plaque Inflammation and Ameliorates Vascular Dysfunction in Atherosclerotic Mice

“…This was further justified by several lines of evidence indicating that the melanocortin system has the ability to modulate blood glucose levels and to improve insulin sensitivity predominantly via central MC4-R signaling. [28][29][30] However, based on a series of analyses on metabolic parameters, we found no signs of treatment effect on glucose handling or plasma cholesterol levels in this atherosclerotic mouse model. Importantly, the blood glucose levels before the injection of 18 F-FDG were comparable between the treatment groups, allowing reliable interpretation of the 18 F-FDG results.…”

Astrocytes: new targets of melanocortin 4 receptor actions

“…D-Tyr MTII is another selective MC4R agonist recently proven to stimulate MC4R in hippocampal neurons (Shen et al 2013). Also, another highly selective MC4R agonist, BIM-22493, proved to be effective centrally (Kievit et al 2013). Of all the antagonists, SHU9119 is a widely used potent antagonist of both MC3R and MC4R (Schioth et al 1999).…”

“…Mc4r knockout mice are hyperphagic and obese with a decreased energy expenditure (Huszar et al 1997). Recently, treatment with a selective MC4R agonist (BIM-22493) was shown to induce transient decreases in food intake and weight loss over 8 weeks of treatment in diet-induced obese rhesus macaques, which also showed decreased adiposity and improved glucose tolerance (Kievit et al 2013). Mutations in MC4R gene are associated with severe early-onset obesity (Yeo et al 1998).…”