Institute of Biomedicine, Research Center for Integrative Physiology and Pharmacology and Turku Center for Disease Modeling, University of Turku, Turku, Finland
Turku Centre for Biotechnology, University of Turku, Turku, Finland
J Endocrinol. 2018 Oct 1;239(1):19–31. doi: 10.1530/JOE-18-0009.
γ-Melanocyte stimulating hormone (γ-MSH) is an endogenous agonist of the melanocortin 3-receptor (MC3R). Genetic disruption of MC3Rs increases adiposity and blunts responses to fasting, suggesting that increased MC3R signaling could be physiologically beneficial in the long term. Interestingly, several studies have concluded that activation of MC3Rs is orexigenic in the short term. Therefore, we aimed to examine the short- and long-term effects of γ-MSH in the hypothalamic arcuate nucleus (ARC) on energy homeostasis and hypothesized that the effect of MC3R agonism is dependent on the state of energy balance and nutrition. Lentiviral gene delivery was used to induce a continuous expression of γ-Msh only in the ARC of male C57Bl/6N mice. Parameters of body energy homeostasis were monitored as food was changed from chow (6 weeks) to Western diet (13 weeks) and back to chow (7 weeks). The γ-MSH treatment decreased the fat mass to lean mass ratio on chow, but the effect was attenuated on Western diet. After the switch back to chow, an enhanced loss in weight (−15% vs −6%) and fat mass (−37% vs −12%) and reduced cumulative food intake were observed in γ-MSH-treated animals. Fasting-induced feeding was increased on chow diet only; however, voluntary running wheel activity on Western diet was increased. The γ-MSH treatment also modulated the expression of key neuropeptides in the ARC favoring weight loss. We have shown that a chronic treatment intended to target ARC MC3Rs modulates energy balance in nutritional state-dependent manner. Enhancement of diet-induced weight loss could be beneficial in treatment of obesity.
γ-黑素细胞刺激素（γ-MSH）是黑素皮质素 3 受体（MC3R）的内源性激动剂。MC3R 的基因缺失会增加肥胖，并削弱对禁食的反应，这表明长期增加 MC3R 信号可能对生理有益。有趣的是，几项研究得出结论，MC3R 的激活在短期内具有食欲刺激作用。因此，我们旨在研究 γ-MSH 在下丘脑弓状核（ARC）中对能量平衡的短期和长期影响，并假设 MC3R 激动作用的效果取决于能量平衡和营养的状态。慢病毒基因传递用于诱导雄性 C57Bl/6N 小鼠 ARC 中 γ-Msh 的持续表达。当食物从普通饲料（6 周）改为西方饮食（13 周）并再回到普通饲料（7 周）时，监测身体能量平衡的参数。γ-MSH 处理降低了普通饲料时的脂肪量与瘦肉量比，但在西方饮食时效果减弱。当回到普通饲料时，与对照组相比，γ-MSH 处理组的体重（-15%比-6%）和脂肪量（-37%比-12%）的损失增加，累积食物摄入量减少。仅在普通饲料饮食时，禁食诱导的摄食增加；然而，在西方饮食时，自愿跑步轮活动增加。γ-MSH 处理还调节了 ARC 中关键神经肽的表达，有利于体重减轻。我们已经表明，旨在靶向 ARC MC3R 的慢性治疗以营养状态依赖的方式调节能量平衡。增强饮食诱导的体重减轻可能有益于肥胖的治疗。
