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

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 KATP channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1ΔIR mice). Whereas body weight and glucose homeostasis remained the same in SF-1ΔIR 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-1ΔIR 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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Figure 1: Insulin action in VMH neurons and generation of insulin receptorΔSF-1 mice.
Figure 2: Effects of insulin on electrical activity of VMH neurons.
Figure 3: Protection against diet-induced obesity in SF-1ΔIR mice.
Figure 4: Increased leptin sensitivity in young SF-1ΔIR mice.
Figure 5: Protection against diet-induced insulin resistance in SF-1ΔIR mice.
Figure 6: Enhanced PI3K activation in the VMH promotes hyperphagia and weight gain.
Figure 7: Higher firing rate of POMC neurons of SF-1ΔIR mice upon high-fat feeding compared to controls.

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Acknowledgements

We thank G. Schmall and T. Rayle for secretarial assistance and S. Irlenbusch and H. Wratil for technical assistance. We thank M. Low (Oregon Health & Science University) for providing POMCGFP mice. Recombinant mouse leptin was obtained from A.F. Parlow, the National Hormone and Peptide Program (NHPP), National Institute of Diabetes and Digestive and Kidney Diseases. This work was supported by grants from the Deutsche Forschungsgemeinschaft (KL 762/2-2 to P.K.); Cologne Center for Molecular Medicine (CMMC); under FP7-HEALTH-2009-241592 (European Union) EurOCHIP; under FP7-KBBE-2010-4-266408 (European Union) Full4Health and through the Kompetenznetz Adipositas (Competence Network for Adipositas) funded by the Federal Ministry of Education and Research (FKZ 01GI0845) to J.C.B.; and also through funds from the Deutsche Forschungsgemeinschaft (Br. 1492/7-1 to J.C.B.). This work was supported by US National Institute of Health grants R01DK53301 and RL1DK081185 (to J.K.E.); K01DK087780 (to K.W.W.); R01 DK071051, P30 DK046200 and P30 DK057521 (to B.B.L.); OD006850 and DK080000 (to T.L.H.); and PL1 DK081182, UL1RR024923 and K08 DK068069-01A2 (to J.M.Z.).

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T.K., S.H., B.F.B., L.P., L.A.W.V., A.H., J.-W.S., B.H. and T.L.H. performed experiments, analyzed data and contributed to writing the paper. H.D., J.M.Z., B.B.L., K.W.W. and J.K.E. provided reagents and transgenic mice for this study. P.K. analyzed data and contributed to writing the paper. T.K. and J.C.B. conceived the study and wrote the manuscript. All authors read and agreed on the final version of the manuscript.

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Correspondence to Jens C Brüning.

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Klöckener, T., Hess, S., Belgardt, B. et al. High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat Neurosci 14, 911–918 (2011). https://doi.org/10.1038/nn.2847

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