Tavares Mariana R, Dos Santos Willian O, Amaral Andressa G, List Edward O, Kopchick John J, Alves Guilherme A, Frazao Renata, Dos Santos Jessica D M, Cruz Alessandra G, Camporez João Paulo, Donato Jose
Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo 05508-000, Brazil.
Edison Biotechnology Institute and Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701.
Proc Natl Acad Sci U S A. 2024 Dec 24;121(52):e2407225121. doi: 10.1073/pnas.2407225121. Epub 2024 Dec 19.
Growth hormone (GH) has several metabolic effects, including a profound impact on glucose homeostasis. For example, GH oversecretion induces insulin resistance and increases the risk of developing diabetes mellitus. Here, we show that GH receptor (GHR) ablation in vesicular glutamate transporter 2 (VGLUT2)-expressing cells, which comprise a subgroup of glutamatergic neurons, led to a slight decrease in lean body mass without inducing changes in body adiposity. VGLUT2 mice exhibited reduced glycemia and improved glucose tolerance and insulin sensitivity. Among different glutamatergic neuronal populations, we found that GHR inactivation in Sim1-expressing cells recapitulated the phenotype observed in VGLUT2 mice. Furthermore, Sim1 mice exhibited reduced endogenous glucose production and improved hepatic insulin sensitivity without alterations in whole-body or muscle glucose uptake. Sim1 mice were protected against acute but not chronic diabetogenic effects of exogenous GH administration. Pharmacological activation of ATP-sensitive potassium channels in the brain normalized blood glucose levels in Sim1 mice. In conclusion, the absence of GHR signaling in VGLUT2/Sim1-expressing cells causes a persistent reduction in glycemia and improves hepatic insulin sensitivity. Central glucose-sensing mechanisms are likely involved in the reduced glycemia exhibited by Sim1 mice. The current findings uncover a mechanism involved in the effects of GHR signaling in regulating glucose homeostasis.
生长激素（GH）具有多种代谢作用，包括对葡萄糖稳态产生深远影响。例如，GH分泌过多会诱导胰岛素抵抗并增加患糖尿病的风险。在此，我们表明，在表达囊泡谷氨酸转运体2（VGLUT2）的细胞（构成谷氨酸能神经元的一个亚组）中消融生长激素受体（GHR），会导致瘦体重略有下降，但不会引起身体脂肪量的变化。VGLUT2小鼠表现出血糖降低、葡萄糖耐量改善和胰岛素敏感性提高。在不同的谷氨酸能神经元群体中，我们发现，在表达Sim1的细胞中使GHR失活可重现VGLUT2小鼠中观察到的表型。此外，Sim1小鼠的内源性葡萄糖生成减少，肝脏胰岛素敏感性提高，而全身或肌肉的葡萄糖摄取没有改变。Sim1小鼠对外源性GH给药的急性致糖尿病作用具有抵抗力，但对慢性作用没有抵抗力。在大脑中对ATP敏感性钾通道进行药理激活可使Sim1小鼠的血糖水平恢复正常。总之，在表达VGLUT2/Sim1的细胞中缺乏GHR信号会导致血糖持续降低，并改善肝脏胰岛素敏感性。中枢葡萄糖感知机制可能与Sim1小鼠表现出的血糖降低有关。目前的研究结果揭示了GHR信号在调节葡萄糖稳态中的作用机制。
