Upregulation of hypothalamic TRPV4 via S100a4/AMPKα signaling pathway promotes the development of diet-induced obesity.

Obesity is associated with abnormal regulation of energy metabolism in the hypothalamus. Transient receptor potential vanilloid 4 (TRPV4) is involved in regulating osmotic pressure, temperature and mechanical force transmission, but little is known about its role in obesity. Herein, the present study aimed to elucidate the effect of hypothalamic TRPV4 on high-fat diet-induced obesity (DIO) and evaluate its potential for regulating energy metabolism. Here we show that hypothalamic TRPV4 content is increased in DIO rats. Central administration of adeno-associated virus expressing TRPV4 in these animals remarkably increased body weight and fat mass by activating the S100a4/AMPKα signaling pathway, thereby promoting positive energy metabolism. Overexpressed hypothalamic TRPV4 impaired glucose tolerance, while promoting the accumulation of fat in liver cells, resulting in hepatic steatosis. In addition, the upregulation of hypothalamic TRPV4 reduces high-fat induced central inflammation. This study provides evidence that hypothalamic TRPV4 plays a significant role in regulating homeostasis. Hypothalamic TRPV4 emerges as a target for therapeutic intervention against obesity.