High‐intensity interval training improves hypothalamic inflammation by suppressing HIF‐1α signaling in microglia of male C57BL/6J mice

Abstract Repeated bouts of high‐intensity interval training (HIIT) induce an improvement in metabolism via plasticity of melanocortin circuits and attenuated hypothalamic inflammation. HIF‐1α, which plays a vital role in hypothalamus‐mediated regulation of peripheral metabolism, is enhanced in the hypothalamus by HIIT. This study aimed to investigate the effects of HIIT on hypothalamic HIF‐1α expression and peripheral metabolism in obese mice and the underlying molecular mechanisms. By using a high‐fat diet (HFD)‐induced obesity mouse model, we determined the effect of HIIT on energy balance and the expression of the hypothalamic appetite‐regulating neuropeptides, POMC and NPY. Moreover, hypothalamic HIF‐1α signaling and its downstream glycolytic enzymes were explored after HIIT intervention. The state of microglia and microglial NF‐κB signaling in the hypothalamus were also examined in vivo. In vitro by using an adenovirus carrying shRNA‐HIF1β, we explored the impact of HIF‐1 signaling on glycolysis and NF‐κB inflammatory signaling in BV2 cells. Food intake was suppressed and whole‐body metabolism was improved in exercised DIO mice, accompanied by changes in the expression of POMC and NPY. Moreover, total and microglial HIF‐1α signaling were obviously attenuated in the hypothalamus, consistent with the decreased levels of glycolytic enzymes. Both HFD‐induced microglial activation and hypothalamic NF‐κB signaling were significantly suppressed following HIIT in vivo. In BV2 cells, after HIF‐1 complex knockdown, glycolysis and NF‐κB inflammatory signaling were significantly attenuated. The data indicate that HIIT improves peripheral metabolism probably via attenuated HFD‐induced microglial activation and microglial NF‐κB signaling in the hypothalamus, which could be mediated by suppressed microglial HIF‐1α signaling.