Theranostics 2021; 11(17):8283-8300. doi:10.7150/thno.61192

Research Paper

Growth hormone receptor disrupts glucose homeostasis via promoting and stabilizing retinol binding protein 4

Jinxin Liu1, Chenzhipeng Nie1, Lamei Xue1, Ying Yan2, Shengnan Liu2, Juan Sun1, Mingcong Fan1, Haifeng Qian1, Hao Ying2, Li Wang1✉, Yan Li1✉

1. State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi 214122, China;
2. Chinese Academy of Sciences Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031 Shanghai, China.

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Citation:
Liu J, Nie C, Xue L, Yan Y, Liu S, Sun J, Fan M, Qian H, Ying H, Wang L, Li Y. Growth hormone receptor disrupts glucose homeostasis via promoting and stabilizing retinol binding protein 4. Theranostics 2021; 11(17):8283-8300. doi:10.7150/thno.61192. Available from https://www.thno.org/v11p8283.htm

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Abstract

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.

Method: 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.

Results: 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.

Conclusions: 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.

Keywords: GHR, RBP4, systemic insulin resistance, glucose homeostasis, hepatokine