Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons

Abstract

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

Effects of growth hormone in the central nervous system

“…In this sense, infusion of 2-deoxy-D-glucose produced abnormal hyperactivity in the parasympathetic preganglionic neurons in mice with GHR-ablated VMH neurons. In addition, pharmacological blockers of the parasympathetic nervous system prevent the counterregulatory defects caused by GHR ablation in the VMH (56). Unlike the effects induced by GHR depletion in the POMC neurons (54), GHR-ablated VMH neurons did not affect glucoprivically induced hyperphagia (56), demonstrating that GH action in each neuronal population induces very specific effects (Figure 3).…”

“…In a recent study (56), we showed that a large number of GH-responsive neurons are found in the ventromedial nucleus of the hypothalamus (VMH), a key relay station that regulates the counter-regulatory response to hypoglycemia (57). Although ablation of GHR in VMH neurons did not affect glucose tolerance or insulin sensitivity, the absence of GH action in the VMH neurons impaired the capacity of the mice to recover from insulininduced hypoglycemia and significantly decreased the counter-regulatory response induced by 2-deoxy-Dglucose injection (56). The effects of GH regulation on the counter-regulatory response are likely mediated by the parasympathetic nervous system.…”

Central Regulation of Metabolism by Growth Hormone

“…Since GH also regulates insulin sensitivity, part of this effect may be mediated by the brain as well. Previous studies investigated the physiological role of GH signaling in leptin receptor (LepR)-expressing cells [ 79 , 80 ]. Notably, GHR ablation in LepR-expressing cells led to impaired hepatic insulin sensitivity [ 79 , 80 ].…”

Growth hormone receptor (GHR)-expressing neurons in the hypothalamic arcuate nucleus regulate glucose metabolism and energy homeostasis

“…Evidence for the importance of GH-responsive neurons in the hypothalamus in modulating metabolism was reported in several studies (35)(36)(37)(38). We have recently identified a unique population of nutrient-sensing leptin receptor (LepRb)-GHR expressing neurons that regulate hepatic glucose production and lipid metabolism, suggesting that these neurons are crucial for the metabolic functions of GHR-neurocircuitry (18).…”