Novel α-MSH analog causes weight loss in obese rats and minipigs and improves insulin sensitivity

Keld Fosgerau,Birgitte S Wulff,Kirsten Raun,Kirsten Dahl,Cecilia Nilsson

doi:10.1530/joe-13-0284

Abstract

Obesity is a major burden to people and to health care systems around the world. The aim of the study was to characterize the effect of a novel selective α-MSH analog on obesity and insulin sensitivity. The subchronic effects of the selective MC4-R peptide agonist MC4-NN1-0182 were investigated in diet-induced obese (DIO) rats and DIO minipigs by assessing the effects on food intake, energy consumption, and body weight. The acute effect of MC4-NN1-0182 on insulin sensitivity was assessed by a euglycemic–hyperinsulinemic clamp study in normal rats. Three weeks of treatment of DIO rats with MC4-NN1-0182 caused a decrease in food intake and a significant decrease in body weight 7±1%, P<0.05 compared with 3±1% increase with the vehicle control. In DIO minipigs, 8 weeks of treatment with MC4-NN1-0182 resulted in a body weight loss of 13.3±2.5 kg (13±3%), whereas the vehicle control group had gained 3.7±1.4 kg (4±1%). Finally, clamp studies in normal rats showed that acute treatment with MC4-NN1-0182 caused a significant increase in glucose disposal (Rd) compared with vehicle control (Rd, mg/kg per min, 17.0±0.7 vs 13.9±0.6, P<0.01). We demonstrate that treatment of DIO rats or minipigs with a selective MC4-R peptide agonist causes weight loss. Moreover, we have demonstrated weight-independent effects on insulin sensitivity. Our observations identify MC4 agonism as a viable target for the treatment of obesity and insulin resistance.

Highlights

Introduction aMelanocyte-stimulating hormone (a-MSH) belongs to the melanocortins which are derived from a large precursor protein, pre-proopiomelanocortin. aMelanocyte-stimulating hormone (a-MSH) has been implicated in various behavioral and physiological responses such as pigmentation (Lerner & McGuire 1961), sexual behavior (Bertolini et al 1968), thermoregulation, and inflammatory responses, and feeding (Vergoni et al 1986) and control of body weight (Fan et al 1997, MacNeil et al 2002)
Mice, rats, and humans deficient in the MC4-R are obese (Huszar et al 1997, Vaisse et al 1998, Yeo et al 1998, Mul et al 2012), and data from studies on MC4-R knockout mice show that MC4-R is essential for the mediation of the effect of melanocortins on energy homeostasis; i.e. the presence of MC4-R is necessary for the effects of nonselective melanocortin agonists (melanotan II (MT-II) and BIM22511) on food intake (Marsh et al 1999, Chen et al 2000) and body weight (Kumar et al 2009)
We observed a dose-dependent decrease in food intake in diet-induced obese (DIO) rats treated with MC4-NN1-0182 as compared with vehicle control (Fig. 1B)

Summary

Introduction

Introduction aMelanocyte-stimulating hormone (a-MSH) belongs to the melanocortins which are derived from a large precursor protein, pre-proopiomelanocortin (pre-POMC). a-MSH has been implicated in various behavioral and physiological responses such as pigmentation (Lerner & McGuire 1961), sexual behavior (Bertolini et al 1968), thermoregulation, and inflammatory responses, and feeding (Vergoni et al 1986) and control of body weight (Fan et al 1997, MacNeil et al 2002). Melanocyte-stimulating hormone (a-MSH) belongs to the melanocortins which are derived from a large precursor protein, pre-proopiomelanocortin (pre-POMC). In vivo studies on rodents and data from MC4-R-deficient mice, rats, and humans emphasize the importance of MC4-R in body weight regulation. Mice, rats, and humans deficient in the MC4-R are obese (Huszar et al 1997, Vaisse et al 1998, Yeo et al 1998, Mul et al 2012), and data from studies on MC4-R knockout mice show that MC4-R is essential for the mediation of the effect of melanocortins on energy homeostasis; i.e. the presence of MC4-R is necessary for the effects of nonselective melanocortin agonists (melanotan II (MT-II) and BIM22511) on food intake (Marsh et al 1999, Chen et al 2000) and body weight (Kumar et al 2009)

Objectives

Methods

Results

Discussion

Conclusion