High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons

Tim Klöckener, Simon Hess, Bengt F. Belgardt, Lars Paeger, Linda A W Verhagen, Andreas Husch, Jong Woo Sohn, Brigitte Hampel, Harveen Dhillon, Jeffrey M. Zigman, Bradford B. Lowell, Kevin W. Williams, Joel K. Elmquist, Tamas L. Horvath, Peter Kloppenburg, Jens C. Brüning

Research output: Contribution to journalArticlepeer-review

145 Scopus citations

Abstract

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 Î "IR mice). Whereas body weight and glucose homeostasis remained the same in SF-1 Î "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 Î "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.

Original languageEnglish (US)
Pages (from-to)911-918
Number of pages8
JournalNature neuroscience
Volume14
Issue number7
DOIs
StatePublished - Jul 2011

ASJC Scopus subject areas

  • Neuroscience(all)

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