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

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.obesity | insulin resistance | triglycerides | leptin

Tributyltin reduces the levels of serum adiponectin and activity of AKT and induces metabolic syndrome in male mice

“…Dyslipidemia is another hallmark of MS, which is characterized by high serum TG levels and a high LDL/HDL ratio . In this study, TBTCl exposure resulted in profound lipid‐elevating effects in mice.…”

“…To characterize the responsiveness of TBTCl‐exposed‐mice to insulin, we determined P‐AKT (Thr308 and S473) in liver tissue and skeletal muscle isolated from the mice at 8 min after insulin injection . The total AKT abundance was not different between the TBT groups and the control (Figure A‐C).…”

“…The liver and muscle were isolated from the mice 8 min after insulin injection (The time was performed according to the Ref. ), frozen in liquid nitrogen and stored at −80°C for Western blot analysis.…”

“…[19][20][21] Moreover, one recent study in vitro showed that TBT reduced adiponectin expression. 22 Adiponectin can counteract multiple manifestations of MS [23][24][25] and serve as a valuable biomarker for MS. 26,27 Therefore, these above-mentioned studies suggest that TBT exposure might be associated with the risk of developing MS. However, the adverse effects of TBT on metabolism are incompletely understood.…”

Glycogen synthase kinase-3 (GSK-3) activity regulates mRNA methylation in mouse embryonic stem cells

“…Gsk-3 is a major regulator of cellular metabolism, and has been linked to obesity via its role in regulating the insulin/PI3K pathway. Interestingly, it was recently found that transgenic mice expressing a form of Gsk-3 that is insensitive to inhibition by PI3K signaling were protected from developing metabolic syndrome, which includes obesity (75). While it is not yet known if the role of FTO in obesity is connected to Gsk-3 activity and mRNA methylation levels, it is a tantalizing possibility that should be explored further.…”