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 delta (Ptprd) to increase food intake. However, the intracellular mechanisms responsible for asprosin/Ptprd-mediated activation of AgRPARH 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 AgRPARH neurons. Specifically, we found that deficiency or elevation of circulating asprosin increased or decreased the SK current in AgRPARH neurons, respec-tively. AgRPARH-specific deletion of SK3 (an SK channel subtype highly expressed in AgRPARH neurons) blocked asprosin-induced AgRPARH activation and overeating. Furthermore, pharmacological blockade, genetic knock-down, or knockout of Ptprd abolished asprosin's effects on the SK current and AgRPARH neuronal activity. There-fore, our results demonstrated an essential asprosin-Ptprd-SK3 mechanism in asprosin-induced AgRPARH activation and hyperphagia, which is a potential therapeutic target for the treatment of obesity.

Automated summary

Asprosin, a recently discovered adipokine, activates AgRP neurons in the ARH through binding to Ptprd, and the SK channel plays a crucial role in mediating this effect. Deficiency or elevation of circulating asprosin affects the SK current in AgRPARH neurons, and deletion of SK3 blocks asprosin-induced activation of AgRPARH neurons and overeating.