Abstract 202: Inhibition of Central Melanocortin 4 Receptor Signaling Severely Impairs Brown Adipose Tissue Activity and VLDL Metabolism

Abstract

Objectives: SNPs near the melanocortin 4 receptor (MC4R) gene are associated with cardiovascular diseases (CVD) and deficiency of MC4R is the most common monogenic cause of obesity, a major risk factor for the development of CVD. MC4R-deficient individuals not only show increased food intake but also lower basal energy expenditure. Furthermore, pharmacological inhibition of the central MC4R signaling by SHU9119 in mice increases weight gain independent of food intake. Since brown adipose tissue (BAT) importantly contributes to energy expenditure by combusting high amounts of triglycerides (TG) into heat, the aim of the study was to evaluate the effect of inhibiting MCR4 on VLDL-metabolism and BAT activity in mice. Methods and results: Female APOE*3-Leiden.CETP transgenic mice were fed a cholesterol-enriched Western-type diet for 4 weeks, matched on body weight and plasma lipids, and infused with either SHU9119 or vehicle for 2 weeks via an osmotic mini-pump into the lateral ventricle while being fed the same diet. SHU9119 increased body fat (+50%) and decreased fat oxidation (-42%). Shu9119 increased plasma VLDL-TG levels (+30%). Whereas hepatic VLDL-TG production rate was not affected, Shu9119 severely impaired clearance of VLDL-TG, explained by reduced uptake of [ 3 H]TG by BAT (-25%). In BAT, SHU9119 decreased UCP-1 protein (-60%) and induced large intracellular lipid droplets, indicative of severely disturbed BAT activity. Since SHU9119 increased food intake (+30%), SHU9119 was also administered in mice that were pair-fed with the vehicle-treated group. Under these conditions, SHU9119 still exhibited these effects, indicating MC4R inhibition impairs BAT activity independent of food intake. Conclusion: Inhibition of central MC4R signaling by SHU9119 increases VLDL-TG levels and decreases energy expenditure specifically by impairing BAT function. We anticipate that MC4R regulates adiposity and VLDL metabolism not only by regulating food intake, but also by modulating BAT activity, and that activation of MC4R is a promising strategy to combat obesity and CVD by increasing BAT activity.