Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons

Abstract

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.

Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons

“…To evaluate whether GH signaling in SF1 cells is also necessary to maintain blood glucose levels during food deprivation, control and SF1 GHR KO mice were subjected to 5 d of 60% food restriction. Differently than that observed in mice carrying ablation of GHR in AgRP neurons (22), SF1 GHR KO mice exhibited a similar weight loss rate ( Fig. 7 A ) and glycemia (Fig.…”

“…Our group recently found that GHR ablation in AgRP neurons increases the weight loss and impairs the capacity of mice to maintain blood glucose levels during food deprivation (22). To evaluate whether GH signaling in SF1 cells is also necessary to maintain blood glucose levels during food deprivation, control and SF1 GHR KO mice were subjected to 5 d of 60% food restriction.…”

“…7 B ) during food restriction. We also assessed the 2DG‐induced hyperphagia because GHR ablation in AgRP neurons reduces this response (22). 2DG injection increased food intake similarly in control and SF1 GHR KO mice (Fig.…”

“…Food restriction or food deprivation also changes the pattern of GH secretion (26, 49, 50). Whereas food restriction suppresses GH pulsatility in mice (49, 50), baseline GH levels increase during prolonged food restriction (22, 26). The decreased GH pulsatility during food restriction is mediated by neuropeptide Y because KO mice for neuropeptide Y or Y1 receptor maintain the pulsatile secretion of GH (49).…”

“…GHR ablation in leptin receptor (LepR)‐expressing cells leads to hepatic insulin resistance and impaired peripheral lipid metabolism (21). Another study found that GH signaling in agouti‐related protein (AgRP) neurons represents a cue during food deprivation to trigger key adaptive responses to conserve limited fuel stores (22). Based on these findings, we hypothesized that the effects of GH on the CRR may require GH signaling in the brain as well.…”