Panigrahi Sunil K, Meece Kana, Wardlaw Sharon L
Department of Medicine, Division of Endocrinology, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York.
J Endocr Soc. 2019 Jan 28;3(3):590-601. doi: 10.1210/js.2018-00379. eCollection 2019 Mar 1.
The hypothalamic melanocortin system composed of proopiomelanocortin (POMC) and agouti-related protein (AgRP) neurons plays a key role in maintaining energy homeostasis. The POMC-derived peptides, -MSH and -EP, have distinct roles in this process. -MSH inhibits food intake, whereas -EP, an endogenous opioid, can inhibit POMC neurons and stimulate food intake. A mouse model was used to examine the effects of opioid antagonism with naltrexone (NTX) on and gene expression and POMC peptide processing in the hypothalamus in conjunction with changes in energy balance. There were clear stimulatory effects of NTX on hypothalamic in mice receiving low- and high-fat diets, yet only transient decreases in food intake and body weight gain were noted. The effects on expression were accompanied by an increase in POMC prohormone levels and a decrease in levels of the processed peptides -MSH and -EP. Arcuate expression of the POMC processing enzymes , , and was not altered by NTX, but expression of , an enzyme that inactivates -MSH, increased after NTX exposure. NTX exposure also stimulated hypothalamic expression, but the effects of NTX on energy balance were not enhanced in -null mice. Despite clear stimulatory effects of NTX on expression in the hypothalamus, only modest transient decreases in food intake and body weight were seen. Effects of NTX on POMC processing, and possibly -MSH inactivation, as well as stimulatory effects on AgRP neurons could mitigate the effects of NTX on energy balance.
由阿黑皮素原（POMC）和刺鼠相关蛋白（AgRP）神经元组成的下丘脑黑皮质素系统在维持能量平衡中起关键作用。POMC衍生肽α-促黑素（α-MSH）和β-内啡肽（β-EP）在此过程中具有不同作用。α-MSH抑制食物摄入，而β-EP作为一种内源性阿片类物质，可抑制POMC神经元并刺激食物摄入。使用小鼠模型研究纳曲酮（NTX）拮抗阿片类物质对下丘脑POMC和AgRP基因表达以及POMC肽加工的影响，并结合能量平衡的变化。NTX对接受低脂和高脂饮食的小鼠下丘脑AgRP有明显的刺激作用，但仅观察到食物摄入量和体重增加出现短暂下降。对AgRP表达的影响伴随着POMC前体激素水平的增加以及加工后的肽α-MSH和β-EP水平的降低。POMC加工酶PC1、PC2和羧肽酶E的弓状核表达未被NTX改变，但使α-MSH失活的酶DPP-IV的表达在NTX暴露后增加。NTX暴露也刺激下丘脑POMC表达，但在POMC基因敲除小鼠中NTX对能量平衡的影响未增强。尽管NTX对下丘脑POMC表达有明显的刺激作用，但仅观察到食物摄入量和体重出现适度短暂下降。NTX对POMC加工以及可能的α-MSH失活的影响，以及对AgRP神经元的刺激作用可能会减轻NTX对能量平衡的影响。
