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JCI:发现转录因子调节机体能量平衡的机制

来源:生物谷 2012-06-04 23:14

近日,来自美国德克萨斯大学西南医学中心的研究人员表示,他们发现在下丘脑腹内侧核神经元内转录因子FOXO1参与调节了机体的能量平衡。相关研究成果于6月1日发表在The Journal of Clinical Investigation上。

之前的研究就已经发现,在包括神经细胞在内的许多类型的细胞中,转录因子FOXO1通过调节瘦素及胰岛素的活性,对代谢的平衡具有至关重要的作用。然而,介导了FOXO1的调节作用的神经元及分子靶点目前还不明确。

在这项研究里,研究人员Joel K. Elmquist表示,下丘脑的腹内侧核(VMH)是FOXO1作用的一个关键位点。他们发现,VMH缺失了FOXO1的小鼠表现消瘦,这归因于能量消耗增加所致。而且,在禁食期间,这种小鼠不能够适当地抑制能量的过度消耗。此外,由于骨骼肌以及心肌胰岛素敏感性的增加,这些小鼠的葡萄糖耐受性表现升高。而进一步的基因表达谱及测序分析表明,有几种通路被FOXO1所调节。除此以外,他们还发现,在下丘脑的腹内侧核,核受体SF-1是FOXO1的直接转录靶点。

该研究表明,在下丘脑的腹内侧核神经元,由FOXO1所调节的转录网络是调节能量平衡以及血糖稳态的关键环节。(生物谷Deepblue编译)

FOXO1 in the ventromedial hypothalamus regulates energy balance

Ki Woo Kim, Jose Donato Jr., Eric D. Berglund, Yun-Hee Choi, Daisuke Kohno, Carol F. Elias, Ronald A. DePinho, Joel K. Elmquist.

The transcription factor FOXO1 plays a central role in metabolic homeostasis by regulating leptin and insulin activity in many cell types, including neurons. However, the neurons mediating these effects and the identity of the molecular targets through which FOXO1 regulates metabolism remain to be defined.Here, we show that the ventral medial nucleus of the hypothalamus (VMH) is a key site of FOXO1 action. We found that mice lacking FOXO1 in steroidogenic factor 1 (SF-1) neurons of the VMH are lean due to increased energy expenditure. The mice also failed to appropriately suppress energy expenditure in response to fasting.Furthermore, these mice displayed improved glucose tolerance due to increased insulin sensitivity in skeletal muscle and heart. Gene expression profiling and sequence analysis revealed several pathways regulated by FOXO1.In addition, we identified the nuclear receptor SF-1 as a direct FOXO1 transcriptional target in the VMH. Collectively, our data suggest that the transcriptional networks modulated by FOXO1 in VMH neurons are key components in the regulation of energy balance and glucose homeostasis.

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