Department of Biological Sciences, Integrative Biosciences Center (IBio), Wayne State University, Detroit, MI 48202, USA.
Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Cells. 2021 May 3;10(5):1093. doi: 10.3390/cells10051093.
The growth hormone receptor (GHR) is expressed in brain regions that are known to participate in the regulation of energy homeostasis and glucose metabolism. We generated a novel transgenic mouse line (GHR) to characterize GHR-expressing neurons specifically in the arcuate nucleus of the hypothalamus (ARC). Here, we demonstrate that ARC neurons are co-localized with agouti-related peptide (AgRP), growth hormone releasing hormone (GHRH), and somatostatin neurons, which are activated by GH stimulation. Using the designer receptors exclusively activated by designer drugs (DREADD) technique to control the ARC neuronal activity, we demonstrate that the activation of ARC neurons elevates a respiratory exchange ratio (RER) under both fed and fasted conditions. However, while the activation of ARC promotes feeding, under fasting conditions, the activation of ARC neurons promotes glucose over fat utilization in the body. This effect was accompanied by significant improvements in glucose tolerance, and was specific to GHR versus GHRH neurons. The activation of ARC neurons increased glucose turnover and whole-body glycolysis, as revealed by hyperinsulinemic-euglycemic clamp studies. Remarkably, the increased insulin sensitivity upon the activation of ARC neurons was tissue-specific, as the insulin-stimulated glucose uptake was specifically elevated in the skeletal muscle, in parallel with the increased expression of muscle glycolytic genes. Overall, our results identify the GHR-expressing neuronal population in the ARC as a major regulator of glycolysis and muscle insulin sensitivity in vivo.
生长激素受体 (GHR) 在已知参与调节能量平衡和葡萄糖代谢的脑区表达。我们生成了一种新型转基因小鼠系 (GHR)，以专门研究下丘脑弓状核 (ARC) 中表达 GHR 的神经元。在这里，我们证明 ARC 神经元与刺鼠相关肽 (AgRP)、生长激素释放激素 (GHRH) 和生长抑素神经元共定位，这些神经元被 GH 刺激激活。使用专门被设计药物激活的 Designer Receptors (DREADD) 技术来控制 ARC 神经元活性，我们证明 ARC 神经元的激活在进食和禁食条件下都会升高呼吸交换率 (RER)。然而，虽然 ARC 的激活促进了进食，但在禁食条件下，ARC 神经元的激活促进了体内葡萄糖而不是脂肪的利用。这种作用伴随着葡萄糖耐量的显著改善，并且与 GHR 而不是 GHRH 神经元特异性相关。ARC 神经元的激活通过高胰岛素-正常血糖钳夹研究揭示了葡萄糖周转率和全身糖酵解的增加。值得注意的是，ARC 神经元激活后胰岛素敏感性的增加是组织特异性的，因为肌肉葡萄糖摄取在骨骼肌中特异性升高，与肌肉糖酵解基因的表达增加平行。总的来说，我们的结果确定了 ARC 中表达 GHR 的神经元群体是体内糖酵解和肌肉胰岛素敏感性的主要调节者。
