Paraventricular nucleus-locus coeruleus VGlut2 neural circuit regulates energy metabolism in mice.

The role of the central nervous system in energy homoeostasis remains unclear. This study examined the role of VGlut2-expressing neurons in the paraventricular nucleus of the hypothalamus (PVHVGlut2) and their downstream circuits in the regulation of energy homoeostasis. Long-term high-fat diet (HFD) disrupts energy balance and compensatorily activates PVHVGlut2 neurons that innervate interscapular brown adipose tissue (iBAT). These neurons are inhibited during food consumption, suggesting their involvement in feeding and energy metabolism regulation. Activation of PVHVGlut2 neurons reduces food intake and enhances iBAT thermogenesis. Further, optogenetic PVHVGlut2→ locus coeruleus (LC) circuit activation inhibited feeding and elevated iBAT temperature, which was blocked by sympathetic nerve denervation. Long-term chemogenetic PVHVGlut2 → LC neural circuit activation ameliorates HFD-induced obesity and insulin resistance. The PVHVGlut2 → LC circuit integrates feeding inhibition and peripheral thermogenesis signals to regulate energy metabolism, offering potential intervention targets for obesity and other energy homoeostasis disorders.