R-spondin 1 restores hypothalamic glucose-sensing and systemic glucose homeostasis via Wnt signaling in diet-induced obese mice

Summary High-fat diet (HFD) feeding disrupts systemic glucose metabolism, yet the underlying neural mechanisms remain incompletely understood. Here, we demonstrate that glucose-excited (GE) neurons in the ventromedial hypothalamus (VMH GE ) are essential for acute glucose regulation and that their function is compromised by HFD via structural synaptic remodeling. We found that HFD feeding suppresses canonical Wnt signaling and downregulates R-spondin 1 (RSPO1), a Wnt enhancer, in the VMH. This Wnt inhibition leads to a loss of dendritic spines and blunted glucose-sensing in VMH GE neurons. Conversely, central administration of RSPO1 restores Wnt/β-catenin signaling, promotes synaptogenesis, and recovers neuronal glucose responsiveness. Consequently, RSPO1 treatment ameliorates HFD-induced glucose intolerance by enhancing peripheral glucose utilization. These findings identify the RSPO1-Wnt signaling axis as a critical regulator of VMH neuronal plasticity and metabolic homeostasis, providing a mechanistic link between diet-induced synaptic pathology and systemic metabolic dysfunction. Highlights - Glucose-excited neurons in VMH were labeled with TRAP - VMH glucose-excited neurons regulates systemic glucose metabolism - Wnt signaling regulates synaptogenesis in VMH and maintain neuronal glucose-sensitivity - R-spondin1 recovers VMH neuronal glucose sensitivity in HFD fed obese mice