Asprosin promotes feeding through SK channel-dependent activation of AgRP neurons

Asprosin, a recently identified adipokine, activates agouti-related peptide (AgRP) neurons in the arcuate nucleus of the hypothalamus (ARH) via binding to protein tyrosine phosphatase receptor δ (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRP^ARH neurons remain unknown. Here, we demonstrate that the small-conductance calcium-activated potassium (SK) channel is required for the stimulatory effects of asprosin/Ptprd on AgRP^ARH neurons. Specifically, we found that deficiency or elevation of circulating asprosin increased or decreased the SK current in AgRP^ARH neurons, respectively. AgRP^ARH-specific deletion of SK3 (an SK channel subtype highly expressed in AgRP^ARH neurons) blocked asprosin-induced AgRP^ARH activation and overeating. Furthermore, pharmacological blockade, genetic knockdown, or knockout of Ptprd abolished asprosin's effects on the SK current and AgRP^ARH neuronal activity. Therefore, our results demonstrated an essential asprosin-Ptprd-SK3 mechanism in asprosin-induced AgRP^ARH activation and hyperphagia, which is a potential therapeutic target for the treatment of obesity.