胰島素調控對于節(jié)食和進食的代謝和行為反應的一個新穎機制已被發(fā)現(xiàn)。在節(jié)食期間,，神經(jīng)肽阿立新（亦稱“苯基二氫喹唑啉”）和MCH（黑色素濃縮激素）在“下丘腦外側區(qū)”（大腦中傳統(tǒng)中被認為是“進食中心”的區(qū)域）釋放,，在那里它們誘導有動機的行為和刺激食物攝取,。
用小鼠所做的研究表明,，阿立新和MCH的表達由轉錄因子Foxa2調控。進食之后,，胰島素信號作用會使Foxa2無效,，使阿立新和MCH的生成停止。Foxa2的活性被永久打開的小鼠有更多的阿立新和MCH,，吃的更多,，身體更活潑,，對胰島素的敏感度也有所提高。打開肥胖小鼠身體中的Foxa2,，會增加身體中瘦肉含量,，減少脂肪含量。因此,，通過藥理手段阻斷Foxa2的磷酸化,，可能會增強身體活動水平，提高總體健康狀況,。（生物谷Bioon.com）
生物谷推薦原始出處：
Nature 462, 646-650 (3 December 2009) | doi:10.1038/nature08589
Regulation of adaptive behaviour during fasting by hypothalamic Foxa2
Jose P. Silva1,4, Ferdinand von Meyenn2,5, Jessica Howell1,2,5, Bernard Thorens3, Christian Wolfrum2 & Markus Stoffel1,2
1 The Rockefeller University, Laboratory of Metabolic Diseases, 1230 York Avenue, New York, New York 10021, USA
2 Swiss Federal Institute of Technology, ETH Zürich, Institute for Molecular Systems Biology, Wolfgang Pauli Strasse 16, 8093 Zürich, Switzerland
3 Center of Integrative Genomics, University of Lausanne, 1015 Lausanne, Switzerland
4 Present address: Department of Neuroscience, The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA.
5 These authors contributed equally to this work.
Correspondence to: Markus Stoffel1,2 Correspondence and requests for materials should be addressed to M.S.
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)1, 2, 3. 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 signalling4, 5, 6, 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/+;Foxa2T156Aflox/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.
