Department of Physiology and Biophysics, Instituto de Ciencias Biomedicas, Universidade de São Paulo, São Paulo, 05508-000, Brazil.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, 48109-5622, USA.
Endocrinology. 2022 Aug 1;163(8). doi: 10.1210/endocr/bqac103.
Growth hormone (GH) acts in several hypothalamic neuronal populations to modulate metabolism and the autoregulation of GH secretion via negative-feedback loops. However, few studies have investigated whether GH receptor (GHR) expression in specific neuronal populations is required for the homeostatic control of GH secretion and energy homeostasis. In the present study, we investigated the consequences of the specific GHR ablation in GABAergic (VGAT-expressing) or glutamatergic (VGLUT2-expressing) cells. GHR ablation in GABAergic neurons led to increased GH secretion, lean mass, and body growth in male and female mice. VGAT-specific GHR knockout (KO) male mice also showed increased serum insulin-like growth factor-1, hypothalamic Ghrh, and hepatic Igf1 messenger RNA levels. In contrast, normal GH secretion, but reduced lean body mass, was observed in mice carrying GHR ablation in glutamatergic neurons. GHR ablation in GABAergic cells increased weight loss and led to decreased blood glucose levels during food restriction, whereas VGLUT2-specific GHR KO mice showed blunted feeding response to 2-deoxy-D-glucose both in males and females, and increased relative food intake, oxygen consumption, and serum leptin levels in male mice. Of note, VGLUT2-cre female mice, independently of GHR ablation, exhibited a previously unreported phenotype of mild reduction in body weight without further metabolic alterations. The autoregulation of GH secretion via negative-feedback loops requires GHR expression in GABAergic cells. Furthermore, GHR ablation in GABAergic and glutamatergic neuronal populations leads to distinct metabolic alterations. These findings contribute to the understanding of the neuronal populations responsible for mediating the neuroendocrine and metabolic effects of GH.
生长激素 (GH) 作用于几个下丘脑神经元群体，通过负反馈环调节代谢和 GH 分泌的自身调节。然而，很少有研究调查特定神经元群体中的 GH 受体 (GHR) 表达是否是 GH 分泌和能量平衡的稳态控制所必需的。在本研究中，我们研究了特定 GHR 缺失在 GABA 能（VGAT 表达）或谷氨酸能（VGLUT2 表达）细胞中的后果。GHR 在 GABA 能神经元中的缺失导致雄性和雌性小鼠的 GH 分泌、瘦肉量和身体生长增加。VAT 特异性 GHR 敲除 (KO) 雄性小鼠还表现出血清胰岛素样生长因子-1、下丘脑 Ghrh 和肝 Igf1 信使 RNA 水平增加。相比之下，在谷氨酸能神经元中携带 GHR 缺失的小鼠表现出正常的 GH 分泌，但瘦肉量减少。GHR 在 GABA 能细胞中的缺失增加了体重减轻，并导致在食物限制期间血糖水平降低，而 VGLUT2 特异性 GHR KO 小鼠在雄性和雌性中对 2-脱氧-D-葡萄糖的进食反应均减弱，并且雄性小鼠的相对食物摄入量、耗氧量和血清瘦素水平增加。值得注意的是，VGLUT2-cre 雌性小鼠，独立于 GHR 缺失，表现出以前未报道的体重轻微减轻的表型，而没有进一步的代谢改变。通过负反馈环的 GH 分泌自身调节需要 GABA 能细胞中的 GHR 表达。此外，GHR 在 GABA 能和谷氨酸能神经元群体中的缺失导致不同的代谢改变。这些发现有助于理解介导 GH 的神经内分泌和代谢作用的神经元群体。
