Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis
Serotonin 2C receptors in pro-opiomelanocortin neurons regulate energy and glucose homeostasis
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DOI：
10.1172/jci70338
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发表时间：
2013-12-01
影响因子：
15.9
通讯作者：
Elmquist, Joel K.
中科院分区：
文献类型：
--
作者：
Berglund, Eric D.;Liu, Chen;Elmquist, Joel K.
能量和葡萄糖稳态由中枢5-羟色胺2C受体调节。这些受体是治疗肥胖的有吸引力的药理学靶点;然而，介导5-羟色胺和5-羟色胺2C受体激动剂对能量和葡萄糖稳态的作用的5-羟色胺2C受体表达神经元的身份尚不清楚。在这里，我们表明，缺乏血清素2C受体（Htr 2c），特别是在前阿黑皮素（POMC）神经元的小鼠体重正常，但发展葡萄糖调节缺陷，包括高胰岛素血症，高胰高血糖素血症，高血糖症和胰岛素抵抗。此外，当这些小鼠被喂食高脂肪/高糖饮食时，它们对抑制食欲的β-肾上腺素能药物没有表现出厌食反应，并出现了食欲过盛和肥胖。当使用他莫昔芬诱导的POMC-cre系统在成年小鼠的POMC神经元中诱导Htr 2c损失时，进一步证明了POMC神经元中5-羟色胺2C受体对维持正常能量和葡萄糖稳态的需求。这些数据表明，5-羟色胺2C受体表达的POMC神经元需要控制能量和葡萄糖稳态，并牵连POMC神经元作为5-羟色胺2C受体激动剂对减肥诱导和改善血糖控制的作用的目标。
Energy and glucose homeostasis are regulated by central serotonin 2C receptors. These receptors are attractive pharmacological targets for the treatment of obesity; however, the identity of the serotonin 2C receptor-expressing neurons that mediate the effects of serotonin and serotonin 2C receptor agonists on energy and glucose homeostasis are unknown. Here, we show that mice lacking serotonin 2C receptors (Htr2c) specifically in pro-opiomelanocortin (POMC) neurons had normal body weight but developed glucoregulatory defects including hyperinsulinemia, hyperglucagonemia, hyperglycemia, and insulin resistance. Moreover, these mice did not show anorectic responses to serotonergic agents that suppress appetite and developed hyperphagia and obesity when they were fed a high-fat/high-sugar diet. A requirement of serotonin 2C receptors in POMC neurons for the maintenance of normal energy and glucose homeostasis was further demonstrated when Htr2c loss was induced in POMC neurons in adult mice using a tamoydfen-inducible POMC-cre system. These data demonstrate that serotonin 2C receptor-expressing POMC neurons are required to control energy and glucose homeostasis and implicate POMC neurons as the target for the effect of serotonin 2C receptor agonists on weight-loss induction and improved glycemic control.