Hypothalamic mTORC1 signaling is involved in nutrient sensing. Neurons that express the agouti-related protein (AgRP) are activated by food restriction and integrate interoceptive and exteroceptive signals to control food intake, energy expenditure, and other metabolic responses. To determine whether mTORC1 signaling in AgRP neurons is necessary for regulating energy and glucose homeostasis, especially in situations of negative energy balance, mice carrying ablation of the Raptor gene exclusively in AgRP-expressing cells were generated. AgRPΔRaptor mice showed no differences in body weight, fat mass, food intake, or energy expenditure; however, a slight improvement in glucose homeostasis was observed compared to the control group. When subjected to 5 days of food restriction (40% basal intake), AgRPΔRaptor female mice lost less lean body mass and showed a blunted reduction in energy expenditure, whereas AgRPΔRaptor male mice maintained a higher energy expenditure compared to control mice during the food restriction and 5 days of refeeding period. AgRPΔRaptor female mice did not exhibit the food restriction-induced increase in serum corticosterone levels. Finally, although hypothalamic fasting- or refeeding-induced Fos expression showed no differences between the groups, AgRPΔRaptor mice displayed increased hyperphagia during refeeding. Thus, some metabolic and neuroendocrine responses to food restriction are disturbed in AgRPΔRaptor mice.

Weight loss triggers important metabolic responses to conserve energy, especially via the fall in leptin levels. Consequently, weight loss becomes increasingly difficult with weight regain commonly occurring in most dieters. Here we show that central growth hormone (GH) signaling also promotes neuroendocrine adaptations during food deprivation. GH activates agouti-related protein (AgRP) neurons and GH receptor (GHR) ablation in AgRP cells mitigates highly characteristic hypothalamic and metabolic adaptations induced by weight loss. Thus, the capacity of mice carrying an AgRP-specific GHR ablation to save energy during food deprivation is impaired, leading to increased fat loss. Additionally, administration of a clinically available GHR antagonist (pegvisomant) attenuates the fall of whole-body energy expenditure of food-deprived mice, similarly as seen by leptin treatment. Our findings indicate GH as a starvation signal that alerts the brain about energy deficiency, triggering key adaptive responses to conserve limited fuel stores.

The maternal organism undergoes numerous metabolic adaptations to become prepared for the demands associated with the coming offspring. These metabolic adaptations involve changes induced by several hormones that act at multiple levels, ultimately influencing energy and glucose homeostasis during pregnancy and lactation. Previous studies have shown that central growth hormone (GH) action modulates glucose and energy homeostasis. However, whether central GH action regulates metabolism during pregnancy and lactation is still unknown. In the present study, we generated mice carrying ablation of GH receptor (GHR) in agouti-related protein (AgRP)-expressing neurons, in leptin receptor (LepR)-expressing cells or in the entire brain to investigate the role played by central GH action during pregnancy and lactation. AgRP-specific GHR ablation led to minor metabolic changes during pregnancy and lactation. However, while brain-specific GHR ablation reduced food intake and body adiposity during gestation, LepR GHR knockout (KO) mice exhibited increased leptin responsiveness in the ventromedial nucleus of the hypothalamus during late pregnancy, although their offspring showed reduced growth rate. Additionally, both Brain GHR KO and LepR GHR KO mice had lower glucose tolerance and glucose-stimulated insulin secretion during pregnancy, despite presenting increased insulin sensitivity, compared with control pregnant animals. Our findings revealed that during pregnancy central GH action regulates food intake, fat retention, as well as the sensitivity to insulin and leptin in a cell-specific manner. Together, the results suggest that GH acts in concert with other "gestational hormones" to prepare the maternal organism for the metabolic demands of the offspring.