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Inhibition of the central melanocortin system decreases brown adipose tissue activity

Author: Kooijman, S. · Boon, M.R. · Parlevliet, E.T. · Geerling, J.J. · Pol, V. van de · Romijn, J.A. · Havekes, L.M. · Meurs, I. · Rensen, P.C.N.
Source:Journal of Lipid Research, 10, 55, 2022-2032
Identifier: 517667
doi: doi:10.1194/jlr.M045989
Keywords: Biology · Energy expenditure · Liver · Triglycerides · Very low density lipoprotein · White adipose tissue · Apolipoprotein E · Fat droplet · Melanocortin · Melanocortin 3 receptor · Melanocortin 4 receptor · N acetyl alpha intermedin[4-10]cyclo[4 norleucine 5 aspartic acid 7 [3 (2 naphthyl)alanine] 10 lysinamide] · Triacylglycerol · Uncoupling protein 1 · Animal experiment · Animal tissue · Body fat · Brown adipose tissue · Central melanocortin system · Controlled study · Dyslipidemia · Endocrine system · Fat mass · Fatty liver · Female · Food intake · Hormone inhibition · Lipid analysis · Lipid oxidation · Lipid storage · Mouse · Nonhuman · Obesity · Signal transduction · Weight gain · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences


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 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∗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. Chemicals/CAS: melanocortin 3 receptor, 189235-81-2; melanocortin 4 receptor, 201099-18-5; n acetyl alpha intermedin[4-10]cyclo[4 norleucine 5 aspartic acid 7 [3 (2 naphthyl)alanine] 10 lysinamide], 168482-23-3