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 (GH) exerts important biological effects primarily related to growth and metabolism. However, the role of GH signaling in the brain is still elusive. To better understand GH functions in the brain, we mapped the distribution of GH-responsive cells and identified the receptors involved in GH central effects. For this purpose, mice received an acute intraperitoneal challenge with specific ligands of the GH receptor (mouse GH), prolactin receptor (prolactin) or both receptors (human GH), and their brains were subsequently processed immunohistochemically to detect the phosphorylated form of STAT5 (pSTAT5). GH induced pSTAT5 immunoreactivity in neurons, but not in astroglial cells of numerous brain regions, including the cerebral cortex, nucleus accumbens, hippocampus, septum and amygdala. The most prominent populations of GH-responsive neurons were located in hypothalamic areas, including several preoptic divisions, and the supraoptic, paraventricular, suprachiasmatic, periventricular, arcuate, ventromedial, dorsomedial, tuberal, posterior and ventral premammillary nuclei. Interestingly, many brainstem structures also exhibited GH-responsive cells. Experiments combining immunohistochemistry for pSTAT5 and in situ hybridization for GH and prolactin receptors revealed that human GH induced pSTAT5 in most, but not all, brain regions through both prolactin and GH receptors. Additionally, males and females exhibited a similar number of GH-responsive cells in forebrain structures known to be sexually dimorphic. In summary, we found GH-responsive cells primarily distributed in brain regions implicated in neurovegetative, emotional/motivational and cognitive functions. Our findings deepen the understanding of GH signaling in the brain and suggest that central GH signaling is likely more ample and complex than formerly recognized.

Weight regain frequently follows interventions that reduce body weight, leading to a failure in long-term obesity treatment. Inhibitory proteins of the leptin signaling pathway, such as the suppressor of cytokine signaling 3 (SOCS3), have been studied in conditions that predispose animals to obesity. However, whether SOCS3 modulates postrestriction hyperphagia and weight regain remains unknown. Mice lacking SOCS3 protein specifically in leptin receptor (LepR)-expressing cells (LepR SOCS3 knockout [KO]) were generated and studied in fasting and refeeding conditions. LepR SOCS3 KO mice exhibited increased leptin sensitivity in the hypothalamus. Notably, LepR SOCS3 KO males and females showed attenuated food intake and weight regain after 48 hours of fasting. Postrestriction hyperleptinemia was also prevented in LepR SOCS3 KO mice. Next, we studied possible mechanisms and neural circuits involved in the SOCS3 effects. SOCS3 deletion did not prevent fasting- or refeeding-induced c-Fos expression in the arcuate nucleus of the hypothalamus (ARH) nor fasting-induced increased excitability of ARH LepR-expressing cells. On the other hand, SOCS3 ablation reduced the mRNA levels of hypothalamic orexigenic neuropeptides during fasting (neuropeptide Y, agouti-related protein, orexin, and melanin-concentrating hormone). In summary, our findings suggest that increased leptin sensitivity contributes to the maintenance of a reduced body weight after food deprivation. In addition, the attenuated postrestriction food intake observed in mutant mice was not explained by fasting-induced changes in the activity of ARH neurons but exclusively by a lower transcription of orexigenic neuropeptides during fasting. These results indicate a partial dissociation between the regulation of neuronal activity and gene expression in ARH LepR-expressing cells.

Growth hormone (GH) is secreted during hypoglycemia, and GH‐responsive neurons are found in brain areas containing glucose‐sensing neurons that regulate the counter‐regulatory response (CRR). However, whether GH modulates the CRR to hypoglycemia via specific neuronal populations is currently unknown. Mice carrying ablation of GH receptor (GHR) either in leptin receptor (LepR)‐ or steroidogenic factor‐1 (SF1)‐expressing cells were studied. We also investigated the importance of signal transducer and activator of transcription 5 (STAT5) signaling in SF1 cells for the CRR. GHR ablation in LepR cells led to impaired capacity to recover from insulin‐induced hypoglycemia and to a blunted CRR caused by 2‐deoxy‐d‐glucose (2DG) administration. GHR inactivation in SF1 cells, which include ventromedial hypothalamic neurons, also attenuated the CRR. The reduced CRR was prevented by parasympathetic blockers. Additionally, infusion of 2DG produced an abnormal hyperactivity of parasympathetic preganglionic neurons, whereas the 2DG‐induced activation of anterior bed nucleus of the stria terminalis neurons was reduced in mice without GHR in SF1 cells. Mice carrying ablation of Stat5a/b genes in SF1 cells showed no defects in the CRR. In summary, GHR expression in SF1 cells is required for a normal CRR, and these effects are largely independent of STAT5 pathway.—Furigo, I. C., de Souza, G. O., Teixeira, P. D. S., Guadagnini, D., Frazão, R., List, E. O., Kopchick, J. J., Prada, P. O., Donato, J., Jr. Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons. FASEB J. 33, 11909–11924 (2019). http://www.fasebj.org

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