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FASEB J. 2019 Feb 19:fj201802328R. doi: 10.1096/fj.201802328R. [Epub ahead of print]

Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

Author information

1
University of Queensland Diamantina Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
2
Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.
3
Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Bonn, Germany.
4
Mater Research Institute, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
5
School of Biomedical Sciences, Institute of Health and Biomedical Innovation, The University of Queensland, Translational Research Institute, Brisbane, Queensland, Australia.
6
Department of Medicine, The University of Melbourne, Victoria, Australia.
7
Department of Biology and Bioinformatics Program, Boston University, Boston, Massachusetts, USA.

Abstract

Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 via the GHR ( Ghr-391 -/-) as for GHR-null ( GHR-/-) mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor β and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase ( Pck)- 1 expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin-2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up-regulation of IL-15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity.-Chhabra, Y., Nelson, C. N., Plescher, M., Barclay, J. L., Smith, A. G., Andrikopoulos, S., Mangiafico, S., Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

KEYWORDS:

gluconeogenesis; hepatic glucose output; metabolism

PMID:
30779881
DOI:
10.1096/fj.201802328R

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