Silva Jose P, von Meyenn Ferdinand, Howell Jessica, Thorens Bernard, Wolfrum Christian, Stoffel Markus
The Rockefeller University, Laboratory of Metabolic Diseases, 1230 York Avenue, New York, New York 10021, USA.
Nature. 2009 Dec 3;462(7273):646-50. doi: 10.1038/nature08589.
The lateral hypothalamic area is considered the classic 'feeding centre', regulating food intake, arousal and motivated behaviour through the actions of orexin and melanin-concentrating hormone (MCH). These neuropeptides are inhibited in response to feeding-related signals and are released during fasting. However, the molecular mechanisms that regulate and integrate these signals remain poorly understood. Here we show that the forkhead box transcription factor Foxa2, a downstream target of insulin signalling, regulates the expression of orexin and MCH. During fasting, Foxa2 binds to MCH and orexin promoters and stimulates their expression. In fed and in hyperinsulinemic obese mice, insulin signalling leads to nuclear exclusion of Foxa2 and reduced expression of MCH and orexin. Constitutive activation of Foxa2 in the brain (Nes-Cre/+;Foxa2T156A(flox/flox) genotype) results in increased neuronal MCH and orexin expression and increased food consumption, metabolism and insulin sensitivity. Spontaneous physical activity of these animals in the fed state is significantly increased and is similar to that in fasted mice. Conditional activation of Foxa2 through the T156A mutation expression in the brain of obese mice also resulted in improved glucose homeostasis, decreased fat and increased lean body mass. Our results demonstrate that Foxa2 can act as a metabolic sensor in neurons of the lateral hypothalamic area to integrate metabolic signals, adaptive behaviour and physiological responses.
外侧下丘脑区域被认为是经典的“进食中枢”，通过食欲素和促黑素细胞激素（MCH）调节食物摄入、觉醒和动机行为。这些神经肽在对进食相关信号作出反应时受到抑制，并在禁食期间释放。然而，调节和整合这些信号的分子机制仍知之甚少。在这里，我们表明叉头框转录因子Foxa2作为胰岛素信号的下游靶点，调节食欲素和MCH的表达。在禁食期间，Foxa2与MCH和食欲素启动子结合并刺激它们的表达。在进食和高胰岛素血症肥胖小鼠中，胰岛素信号导致Foxa2被排除在细胞核外，MCH和食欲素的表达降低。大脑中Foxa2的组成型激活（Nes-Cre/+;Foxa2T156A(flox/flox)基因型）导致神经元MCH和食欲素表达增加，食物消耗、代谢和胰岛素敏感性增加。这些动物在进食状态下的自发体力活动显著增加，与禁食小鼠相似。通过在肥胖小鼠大脑中表达T156A突变来条件性激活Foxa2也导致葡萄糖稳态改善、脂肪减少和瘦体重增加。我们的结果表明，Foxa2可以作为外侧下丘脑区域神经元中的代谢传感器，整合代谢信号、适应性行为和生理反应。
