Growth hormone receptor (GHR) in AgRP neurons regulates thermogenesis 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 brown adipose tissue (BAT) thermogenesis. To determine the roles of growth hormone receptor (GHR) signaling in the AgRP neurons we used the AgRP(delta)GHR mice. We found that female AgRP(delta)GHR mice were resistant to temperature adaptation, and their body core temperature remained significantly lower under 10C, 22C, and 30C, compared to control mice. Low body core temperature in female AgRP(delta)GHR mice has been associated with significant reductions in Ucp1 and Pgc1a expression in the BAT. Further, neuronal activity in AgRP in response to cold exposure was blunted in females AgRP(delta)GHR, while the number of Fos+ AgRP neurons was increased in control females exposed to cold. Global transcriptome from BAT identified increased expression of genes involved in biological processes related to immune responses, chemokine activity, and decreased expression of genes involved in triglycerides synthesis, and metabolic pathways in females AgRP(delta)GHR. Moreover, these were the same genes downregulated by thermoneutrality in control mice but not in theAgRP(delta)GHR 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.