Metabolic Signal Research Center, Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, Japan.
Endocr J. 2010;57(11):939-46. doi: 10.1507/endocrj.k10e-320. Epub 2010 Oct 30.
The hypothalamus is the center of controlling food intake and energy expenditure by integrating information on energy status, i.e. adiposity and nutrient signals. Especially, two types of neurons in the arcuate nucleus of the hypothalamus, anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons, play vital roles in regulating feeding and energy expenditure. On the other hand, insulin and leptin are hormones that control food intake via regulating POMC and AgRP expression. FoxO1 is a downstream effecter of insulin signaling and Sirt1 is an NAD(+)-dependent deacetylase, both of which have been reported to play important roles in the regulation of metabolism in various organs including liver, pancreas, muscle, adipose tissue and hypothalamus. Histological analyses revealed that FoxO1 and Sirt1 are expressed in both AgRP and POMC neurons where FoxO1 localizes to the nucleus in the fasted, while to the cytoplasm in the refed condition. In contrast, hypothalamic Sirt1 protein is decreased in the fasted condition due to increased ubiquitination of Sirt1. In rodents, overexpression of FoxO1 in the hypothalamus by adenovirus microinjection induces hyperphagia and body weight gain, and simultaneous overexpression of Sirt1 suppresses these phenotypes. FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of AgRP and POMC through transcriptional squelching, and Sirt1 suppresses AgRP expression. In conclusion, we propose that FoxO1 and Sirt1 in hypothalamus are key regulators of energy homeostasis and are molecular targets for the development of new strategy of treating obesity.
下丘脑通过整合能量状态（即肥胖和营养信号）的信息来控制食物摄入和能量消耗。特别是，下丘脑弓状核中的两种神经元，即食欲抑制性的 proopiomelanocortin (POMC) 神经元和食欲刺激性的 agouti 相关肽 (AgRP) 神经元，在调节摄食和能量消耗方面起着至关重要的作用。另一方面，胰岛素和瘦素是通过调节 POMC 和 AgRP 表达来控制食物摄入的激素。FoxO1 是胰岛素信号的下游效应器，Sirt1 是一种 NAD(+) 依赖性去乙酰化酶，两者都被报道在包括肝脏、胰腺、肌肉、脂肪组织和下丘脑在内的各种器官的代谢调节中发挥重要作用。组织学分析表明，FoxO1 和 Sirt1 在 AgRP 和 POMC 神经元中均有表达，FoxO1 在禁食时定位于细胞核，而在进食时则定位于细胞质。相比之下，由于 Sirt1 的泛素化增加，下丘脑的 Sirt1 蛋白在禁食时减少。在啮齿动物中，通过腺病毒微注射在下丘脑过度表达 FoxO1 会导致过度进食和体重增加，而同时过度表达 Sirt1 会抑制这些表型。FoxO1 和转录因子 Stat3 通过转录抑制对 AgRP 和 POMC 的表达发挥相反的作用，而 Sirt1 抑制 AgRP 的表达。总之，我们提出下丘脑中的 FoxO1 和 Sirt1 是能量平衡的关键调节剂，是开发治疗肥胖新策略的分子靶标。
