Kitamura Tadahiro, Feng Yun, Kitamura Yukari Ido, Chua Streamson C, Xu Allison W, Barsh Gregory S, Rossetti Luciano, Accili Domenico
Department of Medicine, Columbia University Medical Center, 1150 St. Nicholas Avenue, New York, New York 10032, USA.
Nat Med. 2006 May;12(5):534-40. doi: 10.1038/nm1392. Epub 2006 Apr 9.
Leptin controls food intake by regulating the transcription of key neuropeptides in the hypothalamus. The mechanism by which leptin regulates gene expression is unclear, however. Here we show that delivery of adenovirus encoding a constitutively nuclear mutant FoxO1, a transcription factor known to control liver metabolism and pancreatic beta-cell function, to the hypothalamic arcuate nucleus of rodents results in a loss of the ability of leptin to curtail food intake and suppress expression of Agrp. Conversely, a transactivation-deficient FoxO1 mutant prevents induction of Agrp by fasting. We also find that FoxO1 and the transcription factor Stat3 exert opposing actions on the expression of Agrp and Pomc through transcriptional squelching. FoxO1 promotes opposite patterns of coactivator-corepressor exchange at the Pomc and Agrp promoters, resulting in activation of Agrp and inhibition of Pomc. Thus, FoxO1 represents a shared component of pathways integrating food intake and peripheral metabolism.
瘦素通过调节下丘脑关键神经肽的转录来控制食物摄入。然而，瘦素调节基因表达的机制尚不清楚。在这里，我们表明，将编码一种组成型核突变体FoxO1（一种已知可控制肝脏代谢和胰腺β细胞功能的转录因子）的腺病毒递送至啮齿动物的下丘脑弓状核，会导致瘦素减少食物摄入和抑制Agrp表达的能力丧失。相反，一种反式激活缺陷型FoxO1突变体可防止禁食诱导Agrp。我们还发现，FoxO1和转录因子Stat3通过转录抑制对Agrp和Pomc的表达发挥相反作用。FoxO1在Pomc和Agrp启动子处促进共激活因子 - 共抑制因子交换的相反模式，导致Agrp激活和Pomc抑制。因此，FoxO1代表了整合食物摄入和外周代谢途径的共同组成部分。
