Obesity is a major global health challenge driven by profound metabolic dysregulation. Hypothalamic pro-opiomelanocortin (POMC) neurons are indispensable for whole-body metabolic homeostasis, and transient receptor potential vanilloid 4 (TRPV4) channels have emerged as regulators of metabolic control. However, the cell-type-specific function of TRPV4 in POMC neurons remains poorly defined. Herein, we demonstrate a vital role of TRPV4 in regulating POMC neuronal activity. We found that hypothalamic TRPV4 was selectively upregulated in diet-induced obese mice, but remained unchanged in genetically obese mice. TRPV4 expression levels were influenced by nutritional status and exhibited co-localization with POMC. Mice lacking TRPV4 specifically in POMC neurons showed no alterations in systemic energy metabolism under chow diet conditions. However, under high-fat diet feeding, these mice exhibited exacerbated obesity and hyperphagia. In vitro assays revealed that TRPV4 activation impaired POMC neurons by promoting mitophagy. In contrast, TRPV4 inhibition restored POMC neuronal function. Mechanistically, TRPV4 compromised POMC neuronal activity by triggering Ca2+-dependent PGAM5 activation and enhancing PINK1/PARKIN-mediated mitophagy. These findings provide comprehensive insights into TRPV4 as a critical regulator of hypothalamic energy balance circuits and highlight its potential as a therapeutic target for metabolic disorders.
