In addition to its peripheral effects in regulating glucose metabolism, insulin also influences metabolism by acting in the brain (see Yi et al.). Klöckener et al. determined that a subset of steroidogenic factor 1 (SF-1)–positive neurons in the ventromedial hypothalamus (VMH) responded to insulin injection with increased immunoreactivity for phosphatidylinositol 3,4,5-trisphosphate (PIP3), an indication of active signaling by the insulin receptor (IR) through the phosphatidylinositol 3-kinase (PI3K) pathway. Comparing the activity of control neurons in hypothalamic slices with those in slices in which the IR was knocked out (SF-1ΔIR) revealed that, without the IR, these SF-1 neurons failed to exhibit insulin-induced hyperpolarization and reduction in firing rate. Analysis of the neurons in slice preparations from the control animals showed that the reduction in firing rate and hyperpolarization was mediated by the KATP channel, which is similar to the mechanism by which insulin inhibits the activity of another class of neurons, the POMC neurons of the arcuate nucleus, which are also implicated in the regulation of metabolism. The SF-1ΔIR mice exhibited normal reproductive function, which is also regulated by the VMH, and normal metabolism and weight gain when fed a normal diet. However, when fed a high-fat diet (HFD), the SF-1ΔIR mice were protected from HFD-induced obesity, ate less, and exhibited improved leptin sensitivity (leptin regulates appetite and feeding) and glucose tolerance compared with the control mice on the HFD. Control mice fed a HFD had more SF-1 neurons with strong PIP3 immunoreactivity compared with the SF-1ΔIR mice, which had more neurons with moderate immunoreactivity for PIP3. Knockout of PTEN, the gene encoding the lipid phosphatase that degrades PIP3, in SF-1 neurons to promote PI3K signaling triggered the development of obesity in mice fed a HFD, and double knockout of PTEN and IR in SF-1 neurons eliminated the protective effects of IR knockout. POMC neurons inhibit food intake, and a HFD reduced the firing rate of POMC neurons in control mice but not in the SF-1ΔIR mice, suggesting that these insulin-responsive neurons in the VMH contribute to the obesity under conditions of HFD by reducing the activity of POMC neurons.
T. Klöckener, S. Hess, B. F. Belgardt, L. Paeger, L. A. W. Verhagen, A. Husch, J.-W. Sohn, B. Hampel, H. Dhillon, J. M. Zigman, B. B. Lowell, K. W. Williams, J. K. Elmquist, T. L. Horvath, P. Kloppenburg, J. C. Brüning, High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons. Nat. Neurosci. 14, 911–918 (2011). [PubMed]
C.-X. Yi, T. Scherer, M. H. Tschöp, Cajal revisited: Does the VMH make us fat? Nat. Neurosci. 14, 806–808 (2011). [PubMed]