Insulin and leptin excite anorexigenic pro-opiomelanocortin neurones via activation of TRPC5 channels.

Abstract

Pro-opiomelanocortin (POMC) neurones within the hypothalamic arcuate nucleus are vital anorexigenic neurones. 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 depolarised POMC neurones via activation of transient receptor potential (TRPC)5 channels. TRPC5 channels have been rigorously characterised as the downstream effector based on their biophysical properties, pharmacological profile, and localisation by immunocytochemistry and single-cell reverse transcriptase-polymerase chain reaction. By contrast, insulin and leptin hyperpolarise and inhibit neuropeptide Y/agouti-related peptide neurones via activation of KATP channels. As proof of principle, insulin given i.c.v. robustly inhibits food intake and increases O2 utilisation, CO2 production and metabolic heat production. Therefore, these findings indicate that the depolarisation/excitation of POMC neurones 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.