Butler Andrew A, Girardet Clemence, Mavrikaki Maria, Trevaskis James L, Macarthur Heather, Marks Daniel L, Farr Susan A
Department of Pharmacology and Physiology, Saint Louis University School of Medicine St. Louis, MO, USA.
In vivo Pharmacology, Cardiovascular and Metabolic Disease, Medimmune Gaithersburg, MD, USA.
Front Neurosci. 2017 Mar 16;11:128. doi: 10.3389/fnins.2017.00128. eCollection 2017.
Melanocortin neurons conserve body mass in hyper- or hypo-caloric conditions by conveying signals from nutrient sensors into areas of the brain governing appetite and metabolism. In mice, melanocortin-3 receptor (MC3R) deletion alters nutrient partitioning independently of hyperphagia, promoting accumulation of fat over muscle mass. Enhanced rhythms in insulin and insulin-responsive metabolic genes during hypocaloric feeding suggest partial insulin resistance and enhanced lipogenesis. However, exactly where and how MC3Rs affect metabolic control to alter nutrient partitioning is not known. The behavioral phenotypes exhibited by MC3R-deficient mice suggest a contextual role in appetite control. The impact of MC3R-deficiency on feeding behavior when food is freely available is minor. However, homeostatic responses to hypocaloric conditioning involving increased expression of appetite-stimulating (orexigenic) neuropeptides, binge-feeding, food anticipatory activity (FAA), entrainment to nutrient availability and enhanced feeding-related motivational responses are compromised with MC3R-deficiency. Rescuing transcription in hypothalamic and limbic neurons improves appetitive responses during hypocaloric conditioning while having minor effects on nutrient partitioning, suggesting orexigenic functions. Rescuing hypothalamic MC3Rs also restores responses of fasting-responsive hypothalamic orexigenic neurons in hypocaloric conditions, suggesting actions that sensitize fasting-responsive neurons to signals from nutrient sensors. MC3R signaling in ventromedial hypothalamic SF1(+ve) neurons improves metabolic control, but does not restore appetitive responses or nutrient partitioning. In summary, desensitization of fasting-responsive orexigenic neurons may underlie attenuated appetitive responses of MC3R-deficient mice in hypocaloric situations. Further studies are needed to identify the specific location(s) of MC3Rs controlling appetitive responses and partitioning of nutrients between fat and lean tissues.
促黑素神经元通过将营养传感器发出的信号传递到控制食欲和新陈代谢的脑区，在高热量或低热量条件下维持体重。在小鼠中，促黑素-3受体（MC3R）缺失会独立于食欲亢进改变营养分配，促进脂肪在肌肉量之上的积累。低热量喂养期间胰岛素和胰岛素反应性代谢基因的节律增强表明存在部分胰岛素抵抗和脂肪生成增强。然而，MC3R究竟在何处以及如何影响代谢控制以改变营养分配尚不清楚。MC3R缺陷小鼠表现出的行为表型表明其在食欲控制中具有情境作用。当食物可自由获取时，MC3R缺陷对进食行为的影响较小。然而，MC3R缺陷会损害对低热量条件的稳态反应，包括食欲刺激（促食欲）神经肽表达增加、暴饮暴食、食物预期活动（FAA）、对营养可利用性的同步以及增强的与进食相关的动机反应。在下丘脑和边缘神经元中挽救转录可改善低热量条件下的食欲反应，同时对营养分配影响较小，提示具有促食欲功能。挽救下丘脑MC3R还可恢复低热量条件下对禁食反应的下丘脑促食欲神经元的反应，提示其作用是使禁食反应神经元对营养传感器发出的信号敏感。下丘脑腹内侧SF1（阳性）神经元中的MC3R信号传导可改善代谢控制，但不能恢复食欲反应或营养分配。总之，禁食反应性促食欲神经元的脱敏可能是MC3R缺陷小鼠在低热量情况下食欲反应减弱的基础。需要进一步研究以确定控制食欲反应以及脂肪与瘦组织之间营养分配的MC3R的具体位置。
