TrpC5 Mediates Acute Leptin and Serotonin Effects via Pomc Neurons

The molecular mechanisms underlying acute leptin and serotonin 2C receptor-induced hypophagia remain unclear. Here, we show that neuronal and pro-opiomelanocortin (Pomc)-specific loss of transient receptor potential cation 5 (TrpC5) subunits is sufficient to decrease energy expenditure and increase food intake resulting in elevated body weight. Deficiency of Trpc5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr) agonists. The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons. We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons. Together, our results link TrpC5 subunits in the brain with leptin- and serotonin 2C receptor-dependent changes in neuronal activity, as well as energy balance, feeding behavior, and glucose metabolism. [Display omitted] •Leptin- and serotonin-induced activation of arcuate Pomc neurons requires TrpC5 subunits•Acute effects of leptin and serotonin on food intake require TrpC5 subunits•TrpC5 subunits are a physiological mechanism in the CNS to regulate metabolism Gao et al. show that TrpC5 subunits are essential for the negative energy balance associated with Pomc neuronal activation. TrpC5 subunits not only link the acute activities of leptin and serotonin receptors in Pomc neurons, but also modify direct effects on basal metabolism.TrpC5 subunits may provide an endogenous target to manipulate the activity of key neurons involved in the regulation of energy balance and glucose metabolism.