Growth hormone receptor regulates β cell hyperplasia and glucose-stimulated insulin secretion in obese mice
Yingjie Wu, Chengyu Liu, Hui Sun, Archana Vijayakumar, Pejman Raeisi Giglou, Ruifang Qiao, Joshua Oppenheimer, Shoshana Yakar, Derek LeRoith
Yingjie Wu, Chengyu Liu, Hui Sun, Archana Vijayakumar, Pejman Raeisi Giglou, Ruifang Qiao, Joshua Oppenheimer, Shoshana Yakar, Derek LeRoith
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Brief Report Metabolism

Growth hormone receptor regulates β cell hyperplasia and glucose-stimulated insulin secretion in obese mice

Abstract

Insulin, growth hormone (GH), and insulin-like growth factor–1 (IGF-1) play key roles in the regulation of β cell growth and function. Although β cells express the GH receptor, the direct effects of GH on β cells remain largely unknown. Here we have employed a rat insulin II promoter–driven (RIP-driven) Cre recombinase to disrupt the GH receptor in β cells (βGHRKO). βGHRKO mice fed a standard chow diet exhibited impaired glucose-stimulated insulin secretion but had no changes in β cell mass. When challenged with a high-fat diet, βGHRKO mice showed evidence of a β cell secretory defect, with further deterioration of glucose homeostasis indicated by their altered glucose tolerance and blunted glucose-stimulated insulin secretion. Interestingly, βGHRKO mice were impaired in β cell hyperplasia in response to a high-fat diet, with decreased β cell proliferation and overall reduced β cell mass. Therefore, GH receptor plays critical roles in glucose-stimulated insulin secretion and β cell compensation in response to a high-fat diet.

Authors

Yingjie Wu, Chengyu Liu, Hui Sun, Archana Vijayakumar, Pejman Raeisi Giglou, Ruifang Qiao, Joshua Oppenheimer, Shoshana Yakar, Derek LeRoith

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Figure 1

Assessment of Ghr excision and expression in βGHRKO mice.

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Assessment of Ghr excision and expression in βGHRKO mice. (A) Isolat...
(A) Isolation of the islets from pancreas by laser capture microdissection. Original magnification, ×10. (B) PCR analysis of GHR excision in different tissues of βGHRKO mice using primers S6 and R2 (see Supplemental Figure 1A). LL, mice homozygous for the floxed Ghr allele; LLc, βGHRKO mice; WWc, RIP-Cre transgenic mice; I, islet; Exo, exocrine; P, pancreas; H, hypothalamus; S, spleen; L, liver. “L” arrowhead indicates the floxed allele, “W” indicates the wild-type allele, and “–” indicates the recombinant allele. (C) Immunofluorescence analysis of GHR protein (red) and insulin (green) in pancreatic sections. (D) Immunofluorecence analysis of Cre (red) and insulin (green) in pancreatic sections. (E) Gene expression of Ghr and the Cre transgene in islets analyzed by real-time PCR. *P < 0.05. (F) Phosphorylation of STAT5 in liver upon intravenous injection of GH to obese control and βGHRKO mice, as assessed by Western immunoblotting. (G) Immunofluorecence analysis of phosphorylated STAT5 protein in pancreatic sections from obese mice (insulin [INS], red; pSTAT5, green; and nucleus, blue). Scale bars: 200 μm (C, D, and G).