期刊
NATURE NEUROSCIENCE
卷 14, 期 7, 页码 911-U139出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2847
关键词
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资金
- Federal Ministry of Education and Research [KL 762/2-2, FP7-HEALTH-2009-241592, FP7-KBBE-2010-4-266408, FKZ 01GI0845]
- Deutsche Forschungsgemeinschaft [Br. 1492/7-1]
- US National Institute of Health [R01DK53301, RL1DK081185, K01DK087780, R01 DK071051, P30 DK046200, P30 DK057521, OD006850, DK080000, PL1 DK081182, UL1RR024923, K08 DK068069-01A2]
Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K-ATP channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(Delta IR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(Delta IR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(Delta IR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development.
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