Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis in aged mice in a sex-specific manner

Evidence for hypothalamic regulation of energy homeostasis and thermoregulation in brown adipose tissue (BAT) during aging has been well recognized, yet the central molecular mediators involved in this process are poorly understood. The arcuate hypothalamus (ARC), orexigenic agouti-related peptide (AgRP) neurons control nutrient intake, energy homeostasis, and BAT thermogenesis. To determine the roles of growth hormone receptor (GHR) signaling in the AgRP neurons we used mice with the AgRP-specific GHR deletion (AgRP ΔGHR ). We found that female AgRP ΔGHR mice were resistant to temperature adaptation, and their body core temperature remained significantly lower when held at 10°C, 22°C, or 30°C, compared to control mice. Low body core temperature in female AgRP ΔGHR mice has been associated with significant reductions in Ucp1 and Pgc1α expression in the BAT. Further, neuronal activity in AgRP in response to cold exposure was blunted in AgRP ΔGHR females, while the number of Fos + AgRP neurons was increased in control females exposed to cold. Global transcriptome from BAT identified increased expression of genes related to immune responses and chemokine activity and decreased expression of genes involved in triglycerides synthesis and metabolic pathways in AgRP ΔGHR females. Importantly, these were the same genes that are downregulated by thermoneutrality in control mice but not in the AgRP ΔGHR animals. Collectively, these data demonstrate a novel circuit of thermal regulation between the hypothalamic AgRP-GHR and BAT and provide insight into the brain systems that are critical for the thermogenic vitality of the elderly.