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

SUBMITTER: Wu Y

PROVIDER: S-EPMC3104750 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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

Wu Yingjie Y Liu Chengyu C Sun Hui H Vijayakumar Archana A Giglou Pejman Raeisi PR Qiao Ruifang R Oppenheimer Joshua J Yakar Shoshana S LeRoith Derek D

The Journal of clinical investigation 20110509 6

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. Whe ...[more]

PMID: 21555853

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Project description:ObjectiveIL-6 is an important contributor to glucose and energy homeostasis through changes in whole-body glucose disposal, insulin sensitivity, food intake and energy expenditure. However, the relative contributions of peripheral versus central IL-6 signaling to these metabolic actions are presently unclear. A conditional mouse model with reduced brain IL-6Ra expression was used to explore how blunted central IL-6 signaling alters metabolic status in lean and obese mice.MethodsTransgenic mice with reduced levels of central IL-6 receptor alpha (IL-6Ra) (IL-6Ra KD mice) and Nestin Cre controls (Cre+/- mice) were fed standard chow or high-fat diet for 20 weeks. Obese and lean mouse cohorts underwent metabolic phenotyping with various measures of energy and glucose homeostasis determined. Glucose-stimulated insulin secretion was assessed in vivo and ex vivo in both mouse groups.ResultsIL-6Ra KD mice exhibited altered body fat mass, liver steatosis, plasma insulin, IL-6 and NEFA levels versus Cre+/- mice in a diet-dependent manner. IL-6Ra KD mice had increased food intake, higher RER, decreased energy expenditure with diminished cold tolerance compared to Cre+/- controls. Standard chow-fed IL-6Ra KD mice displayed reduced plasma insulin and glucose-stimulated insulin secretion with impaired glucose disposal and unchanged insulin sensitivity. Isolated pancreatic islets from standard chow-fed IL-6Ra KD mice showed comparable morphology and glucose-stimulated insulin secretion to Cre+/- controls. The diminished in vivo insulin secretion exhibited by IL-6Ra KD mice was recovered by blockade of autonomic ganglia.ConclusionsThis study shows that central IL-6Ra signaling contributes to glucose and energy control mechanisms by regulating food intake, energy expenditure, fuel flexibility and insulin secretion. A plausible mechanism linking central IL-6Ra signaling and pancreatic insulin secretion is through the modulation of autonomic output activity. Thus, brain IL-6 signaling may contribute to the central adaptive mechanisms engaged in response to metabolic stress.

Dataset Information

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

Publications

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

Similar Datasets

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