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Proc Natl Acad Sci U S A. 2016 May 17;113(20):5754-9. doi: 10.1073/pnas.1601355113. Epub 2016 May 2.

PI3K-resistant GSK3 controls adiponectin formation and protects from metabolic syndrome.

Author information

1
Department of Physiology, University of Tübingen, 72076 Tuebingen, Germany;
2
Division of Clinical Chemistry and Pathobiochemistry, Department of Internal Medicine IV, University Hospital Tübingen, 72076 Tuebingen, Germany;
3
Division of Clinical Chemistry and Pathobiochemistry, Department of Internal Medicine IV, University Hospital Tübingen, 72076 Tuebingen, Germany; Institute for Diabetes Research and Metabolic Diseases of the Helmholtz-Zentrum München, University of Tübingen, 72076 Tuebingen, Germany; German Center for Diabetes Research, 85764 Neuherberg, Germany;
4
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, University of Tübingen, 72076 Tuebingen, Germany;
5
Department of Physiology, University of Tübingen, 72076 Tuebingen, Germany; Department of Internal Medicine III, University Hospital Tübingen, 72076 Tuebingen, Germany;
6
Department of Physiology, University of Tübingen, 72076 Tuebingen, Germany; Institute of Agricultural and Nutritional Sciences, Martin-Luther University Halle-Wittenberg, D-06120 Halle (Saale), Germany michael.foeller@landw.uni-halle.de.

Abstract

Metabolic syndrome is characterized by insulin resistance, obesity, and dyslipidemia. It is the consequence of an imbalance between caloric intake and energy consumption. Adiponectin protects against metabolic syndrome. Insulin-induced signaling includes activation of PI3 kinase and protein kinase B (PKB)/Akt. PKB/Akt in turn inactivates glycogen synthase kinase (GSK) 3, a major regulator of metabolism. Here, we studied the significance of PI3K-dependent GSK3 inactivation for adiponectin formation in diet-induced metabolic syndrome. Mice expressing PI3K-insensitive GSK3 (gsk3(KI)) and wild-type mice (gsk3(WT)) were fed a high-fat diet. Compared with gsk3(WT) mice, gsk3(KI) mice were protected against the development of metabolic syndrome as evident from a markedly lower weight gain, lower total body and liver fat accumulation, better glucose tolerance, stronger hepatic insulin-dependent PKB/Akt phosphorylation, lower serum insulin, cholesterol, and triglyceride levels, as well as higher energy expenditure. Serum adiponectin concentration and the activity of transcription factor C/EBPα controlling the expression of adiponectin in adipose tissue was significantly higher in gsk3(KI) mice than in gsk3(WT) mice. Treatment with GSK3 inhibitor lithium significantly decreased the serum adiponectin concentration of gsk3(KI) mice and abrogated the difference in C/EBPα activity between the genotypes. Taken together, our data demonstrate that the expression of PI3K-insensitive GSK3 stimulates the production of adiponectin and protects from diet-induced metabolic syndrome.

KEYWORDS:

insulin resistance; leptin; obesity; triglycerides

PMID:
27140617
PMCID:
PMC4878493
DOI:
10.1073/pnas.1601355113
[Indexed for MEDLINE]
Free PMC Article

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