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Growth hormone receptor in VGLUT2 or Sim1 cells regulates glycemia and insulin sensitivity
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-12-19 , DOI: 10.1073/pnas.2407225121 Mariana R. Tavares, Willian O. dos Santos, Andressa G. Amaral, Edward O. List, John J. Kopchick, Guilherme A. Alves, Renata Frazao, Jessica D. M. dos Santos, Alessandra G. Cruz, João Paulo Camporez, Jose Donato
Proceedings of the National Academy of Sciences of the United States of America ( IF 9.4 ) Pub Date : 2024-12-19 , DOI: 10.1073/pnas.2407225121 Mariana R. Tavares, Willian O. dos Santos, Andressa G. Amaral, Edward O. List, John J. Kopchick, Guilherme A. Alves, Renata Frazao, Jessica D. M. dos Santos, Alessandra G. Cruz, João Paulo Camporez, Jose Donato
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 ∆GHR 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 ∆GHR mice. Furthermore, Sim1 ∆GHR mice exhibited reduced endogenous glucose production and improved hepatic insulin sensitivity without alterations in whole-body or muscle glucose uptake. Sim1 ∆GHR 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 ∆GHR 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 ∆GHR mice. The current findings uncover a mechanism involved in the effects of GHR signaling in regulating glucose homeostasis.
更新日期：2024-12-19
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