Hong Chen, Abul Fajol, Miriam Hoene, Bingbing Zhang, Erwin D. Schleicher, Yun Lin, Carsten Calaminus, Bernd J. Pichler, Cora Weigert, Hans U. Häring, Florian Lang, and Michael Föller

Significance

The PI3 kinase-dependent inactivation of glycogen synthase kinase (GSK) 3 is an important aspect of normal insulin signaling. Surprisingly, transgenic mice expressing PI3 kinase-resistant GSK3 (gsk3^KI) have been found not to be insulin-resistant. We show that gsk3^KI mice are even protected from the development of metabolic syndrome characterized by insulin resistance, obesity, and dyslipidemia, which all could readily be induced by a high-fat diet in gsk3^WT mice. The metabolic syndrome affects millions of patients and is associated with a high prevalence of cardiovascular disease and a significant reduction of life span. Exploring the underlying mechanism, we found that the production of the hormone adiponectin, which provides protection from metabolic syndrome, is controlled by a GSK3-dependent pathway.

 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.

See http://www.pnas.org/content/113/20/5754.full

PNAS May 17 2016; vol.113; no.20: 5754–5759

Fig. 1. High-fat-diet–induced obesity and fat accumulation in gsk3^WT mice but not in gsk3^KI mice. Body weight (A; n = 9) in dependence on the duration of high-fat-diet feeding (HFD), relative weight gain after 11 wk of high-fat-diet feeding (B; n = 9), the mass of different fat depots of 6-mo-old mice on control diet (C; n = 5) and of 6-mo-old mice after 4 mo of high-fat-diet feeding (D, n = 4), and the serum leptin concentration (E; n = 5–6) before (control) and after 10 wk of high-fat-diet feeding. All parameters were determined in gsk3^WT mice (white bars) and gsk3^KI mice (black bars) and are given as arithmetic means ± SEM. (F and G) High-fat-diet feeding induced fatty liver in gsk3^WT mice but not in gsk3^KI mice. Shown is the abdominal situs of mice (F) on control diet (Upper panels) and high-fat diet (Lower panels); in addition, the livers and a microphotograph (G) of Oil Red O staining to visualize lipid droplets of hepatic sections is demonstrated. (Magnification: ×200.) (Left panels) gsk3^WT mice. (Right panels) gsk3^KI mice. *P < 0.05, **P < 0.01, and ***P < 0.001 indicate significant difference between the genotypes; ^#P < 0.05 indicates significant difference from the absence of HFD treatment.