Endocrine Abstracts

Growth hormone (GH) responsive cells are extensively distributed in the brain, including in neurons of the arcuate nucleus (ARH) and ventromedial nucleus (VMH) of the hypothalamus, areas that control food intake, energy expenditure and blood glucose levels. However, the functional role of central GH signaling for energy and glucose homeostasis has not been unveiled yet. We generated mice lacking GH receptor (GHR) in multiple neuronal populations to investigate whether central GHR signaling modulates energy and glucose homeostasis during normal conditions or during situations of metabolic stress. GHR ablation in AgRP neurons did not affect the body weight, food intake, energy expenditure, glucose tolerance and leptin sensitivity, compared to control animals. However, fasting induced a lower c-Fos expression, a marker of neuronal activation, in the ARH of AgRP GHR KO, suggesting that AgRP neurons are unable to appropriately sense food deprivation without GH signaling. Remarkably, GHR ablation in AgRP cells mitigated highly characteristic hypothalamic and neuroendocrine adaptations induced by weight loss. Thus, while control mice adapted to a 60% food deprivation by progressively saving energy, AgRP GHR KO mice exhibited a higher T4 and testosterone concentrations as well as an increased energy expenditure and UCP-1 mRNA expression in the brown adipose tissue, compared to control animals. These effects led to a higher rate of weight loss, which was predominantly due to fat. In contrast, GHR ablation in steroidogenic factor-1 (SF1) cells, which include VMH neurons, did not affect the responses to food restriction in comparison with control group. However, a blunted counter-regulatory response to hypoglycemia was observed in SF1 GHR KO mice, indicating that GH signaling in VMH neurons helps the organism to recover from hypoglycemia. These findings indicate a previously unidentified function of GH to induce appropriate metabolic responses that ensure survival via its action on specific neuronal populations.