Insulin and Leptin Excite Anorexigenic Proopiomelanocortin Neurons via Activation of TRPC5 Channels

Abstract

Proopiomelanocortin (POMC) neurons within the hypothalamic arcuate nucleus are vital anorexigenic neurons. Both the insulin receptor and leptin receptor are coupled to activation of phosphatidylinositide-3 kinase (PI3K) to regulate multiple functions that increase POMC neuronal excitability. Using whole-cell recording in several mammalian species, we have found that both insulin and leptin depolarized POMC neurons via activation of TRPC5 channels. TRPC5 channels have been rigorously characterized as the downstream effector based on their biophysical properties, pharmacological profile and localization by immunocytochemistry and scRT-PCR. In contrast, insulin and leptin hyperpolarize and inhibit NPY/AgRP neurons via activation of K_ATP channels. As proof of principle, insulin given intracerebroventrically robustly inhibits food intake and increases O₂ utilization, CO₂ production and metabolic heat production. Therefore, these findings indicate that the depolarization/excitation of POMC neurons by insulin and leptin is preserved across mammalian species and the activation of TRPC5 channels is likely a major mechanism by which insulin and leptin regulate energy homeostasis in mammals.

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