Glycine N-methyltransferase deficiency in female mice impairs insulin signaling and promotes gluconeogenesis by modulating the PI3K/Akt pathway in the liver

Journal of Biomedical Science

Research

Tzong-Shyuan Lee¹  Shih-Ming Hsu²  Yuh-Ching Twu³  Ching-Ping Yang³  Chung-Kwe Wang⁴  Yi-Ming Arthur Chen⁵  Yu-Chih Liang⁶  Yi-Jen Liao⁶ 

[1] Department and Institute of Physiology, National Yang-Ming University, Taipei, Taiwan;Department of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan;Department of Biotechnology and Laboratory Science in Medicine, School of Biomedical Science and Engineering, National Yang-Ming University, Taipei, Taiwan;Department of International Medicine, Taipei City Hospital Ranai Branch, Taipei, Taiwan;Department of Microbiology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan;School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan;

关键词: Glycine N-methyltransferase;    Triglycerides;    Insulin signaling;    PI3K/Akt pathway;    Liver;   

DOI  :  10.1186/s12929-016-0278-8

 received in 2016-04-01, accepted in 2016-07-30,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundGlycine N-methyltransferase (GNMT) is abundantly expressed in the normal liver but is down-regulated in liver cancer tissues. GNMT knockout (Gnmt−/−) mice can spontaneously develop chronic hepatitis, fatty liver, and liver cancer. We previously demonstrated that hepatic GNMT is decreased in high-fat-diet-induced type 2 diabetes mellitus, but its contribution to metabolic syndrome is unclear. Here we show that GNMT modulates key aspects of metabolic syndrome in mice.MethodsEleven-week-old Gnmt−/− and wild-type (WT) mice with a C57BL/6 genetic background were used in this study. The metabolic defects of GNMT deficiency were measured by glucose and insulin tolerance tests, lipid homeostasis, gluconeogenesis, and insulin signaling.ResultsGnmt−/− mice, especially females, exhibited glucose intolerance and insulin resistance. However, their body fat and lean mass, food and water intakes, and energy expenditure did not differ from those of WT mice. In addition, glucose-stimulated insulin secretion and insulin-stimulated glucagon secretion were normal in the serum and pancreatic islets of Gnmt−/− mice. Importantly, we found that GNMT deficiency increased lipogenesis and triglycerides in the liver. The elevated triglycerides disrupted the ability of insulin to induce Akt and S6 ribosomal protein phosphorylation, and then triggered insulin resistance and gluconeogenesis in female Gnmt−/− mice.ConclusionsOur data indicate that hepatic GNMT regulates lipid and glucose homeostasis, and provide insight into the development of insulin resistance through modulating the PI3K/Akt pathway.

【 授权许可】

CC BY   
© The Author(s). 2016