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 (PVH^VGlut2) and their downstream circuits in the regulation of energy homoeostasis. Long-term high-fat diet (HFD) disrupts energy balance and compensatorily activates PVH^VGlut2 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 PVH^VGlut2 neurons reduces food intake and enhances iBAT thermogenesis. Further, optogenetic PVH^VGlut2→ locus coeruleus (LC) circuit activation inhibited feeding and elevated iBAT temperature, which was blocked by sympathetic nerve denervation. Long-term chemogenetic PVH^VGlut2 → LC neural circuit activation ameliorates HFD-induced obesity and insulin resistance. The PVH^VGlut2 → LC circuit integrates feeding inhibition and peripheral thermogenesis signals to regulate energy metabolism, offering potential intervention targets for obesity and other energy homoeostasis disorders.