Inhibition of the central melanocortin system decreases brown adipose tissue activity

Sander Kooijman,Mariëtte R Boon,Edwin T Parlevliet,Janine J Geerling,Vera Van De Pol,Johannes A Romijn,Louis M Havekes,Illiana Meurs,Patrick C.N Rensen

doi:10.1194/jlr.m045989

Abstract

The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE*3-Leiden.CETP transgenic mice were fed a Western-type diet for 4 weeks and infused intracerebroventricularly with the melanocortin 3/4 receptor (MC3/4R) antagonist SHU9119 or vehicle for 2 weeks. SHU9119 increased food intake (+30%) and body fat (+50%) and decreased EE by reduction in fat oxidation (-42%). In addition, SHU9119 impaired the uptake of VLDL-TG by BAT. In line with this, SHU9119 decreased uncoupling protein-1 levels in BAT (-60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Finally, SHU9119-treated mice pair-fed to the vehicle-treated group still exhibited these effects, indicating that MC4R inhibition impairs BAT activity independent of food intake. These effects were not specific to the APOE*3-Leiden.CETP background as SHU9119 also inhibited BAT activity in wild-type mice. We conclude that inhibition of central MC3/4R signaling impairs BAT function, which is accompanied by reduced EE, thereby promoting adiposity. We anticipate that activation of MC4R is a promising strategy to combat obesity by increasing BAT activity.

Highlights

The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity
SHU9119 increased body weight in pair-fed mice when compared with vehicle-treated mice (4.14 ± 0.45 vs. 0.70 ± 0.14 g, P < 0.01) (Fig. 1B) indicating that the SHU9119-induced weight gain is independent of food intake
The SHU9119-induced increase in body weight and fat mass was accompanied by an increase in gonadal white adipose tissue weight, both in ad libitum feeding conditions (+124%; 1.32 ± 0.13 vs. 0.59 ± 0.12 g, P < 0.001) and pair-fed conditions (+124%; 1.32 ± 0.16 vs. 0.59 ± 0.12 g, P < 0.01) (Fig. 1D)

Summary

Introduction

The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. SHU9119-treated mice pair-fed to the vehicletreated group still exhibited these effects, indicating that MC4R inhibition impairs BAT activity independent of food intake. These effects were not specific to the APOE*3Leiden.CETP background as SHU9119 inhibited BAT activity in wild-type mice. Recent meta-analyses of genome-wide association studies identified common variants near MC4R to influence fat mass, obesity, and obesity risk [6, 7] These observations support an essential role for the melanocortin system in the regulation of energy homeostasis across mammalian species. In addition to the effects of the melanocortin system on food intake, this system affects energy balance via other pathways This notion is supported by the observation that pharmacological inhibition of central MC4R by.

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