Rationale: The molecular mechanisms underlying the pathogenesis of systemic insulin resistance in type 2 diabetes remain elusive. Growth hormone receptor (GHR) deficiency has long been known to improved insulin sensitivity. However, whether hepatic GHR overexpression or activation is a cause of insulin resistance is still unknown. The aim of this study was to identify the new role of GHR in systemic insulin resistance and explore the underlying mechanism./nMethod: Different samples obtained from obese humans, ob/ob mice, db/db mice, high-fat diet (HFD)-fed mice and primary mouse hepatocytes were used to evaluate the correlations between GHR and metabolic disorders. Recombinant adeno-associated viruses encoding GHR and STAT5 and GHR knockout mice were used to investigate the roles of hepatic GHR in glucose homeostasis. Tissue H&E, Oil Red O and PAS staining were performed for histomorphological analysis. Gel filtration chromatography was employed for the separation of serum RBP4-TTR complexes. Plasmids (related to GHR, STAT5 and HIF1α), siRNA oligos (siGHR and siSTAT5), luciferase activity and ChIP assays were used to explore the potential mechanism of hepatic GHR./nResults: Here, we found that hepatic GHR expression was elevated during metabolic disorder. Accordingly, hepatic GHR overexpression disrupted systemic glucose homeostasis by promoting gluconeogenesis and disturbing insulin responsiveness in the liver. Meanwhile, hepatic GHR overexpression promoted lipolysis in white adipose tissue and repressed glucose utilization in skeletal muscle by promoting the circulating level of RBP4, which contributed to impaired systemic insulin action. A mechanistic study revealed that hepatic GHR disrupted systemic insulin sensitivity by increasing RBP4 transcription by activating STAT5. Additionally, overexpression of hepatic GHR promoted TTR transcriptional levels by enhancing the expression of HIF1α, which not only increased the protein stability of RBP4 but also inhibited renal clearance of RBP4 in serum./nConclusions: Hepatic GHR overexpression and activation accelerated systemic insulin resistance by increasing hepatic RBP4 production and maintaining circulating RBP4 homeostasis. Our current study provides novel insights into the pathogenesis of type 2 diabetes and its associated metabolic complications.

中文翻译：

---

生长激素受体通过促进和稳定视黄醇结合蛋白 4 来破坏葡萄糖稳态

基本原理： 2 型糖尿病全身性胰岛素抵抗发病机制的分子机制仍然难以捉摸。众所周知，生长激素受体 (GHR) 缺乏会改善胰岛素敏感性。然而，肝脏 GHR 过度表达或激活是否是胰岛素抵抗的原因仍然未知。本研究的目的是确定 GHR 在全身性胰岛素抵抗中的新作用并探索其潜在机制。/n 方法：从肥胖人、ob/ob小鼠、db/db获得的不同样本小鼠、高脂饮食 (HFD) 喂养的小鼠和原代小鼠肝细胞用于评估 GHR 与代谢紊乱之间的相关性。使用编码 GHR 和 STAT5 的重组腺相关病毒和 GHR 敲除小鼠研究肝 GHR 在葡萄糖稳态中的作用。组织 H&E、油红 O 和 PAS 染色用于组织形态学分析。凝胶过滤色谱法用于血清 RBP4-TTR 复合物的分离。使用质粒（与 GHR、STAT5 和 HIF1α 相关）、siRNA 寡核苷酸（siGHR 和 siSTAT5）、荧光素酶活性和 ChIP 检测来探索肝脏 GHR 的潜在机制。/n结果：在这里，我们发现肝脏 GHR 表达在代谢紊乱期间升高。因此，肝脏 GHR 过表达通过促进糖异生和扰乱肝脏中的胰岛素反应来破坏全身葡萄糖稳态。同时，肝脏 GHR 过表达促进了白色脂肪组织中的脂肪分解，并通过促进 RBP4 的循环水平来抑制骨骼肌中的葡萄糖利用，这导致全身胰岛素作用受损。一项机制研究表明，肝脏 GHR 通过激活 STAT5 增加 RBP4 转录来破坏全身胰岛素敏感性。此外，肝脏 GHR 的过表达通过增强 HIF1α 的表达来促进 TTR 转录水平，这不仅增加了 RBP4 的蛋白质稳定性，而且抑制了血清中 RBP4 的肾清除。/n结论：肝脏 GHR 过表达和激活通过增加肝脏 RBP4 的产生和维持循环 RBP4 稳态来加速全身胰岛素抵抗。我们目前的研究为 2 型糖尿病的发病机制及其相关代谢并发症提供了新的见解。