期刊
DIABETES
卷 65, 期 11, 页码 3352-3361出版社
AMER DIABETES ASSOC
DOI: 10.2337/db16-0564
关键词
-
资金
- Canadian Institutes of Health Research (CIHR) Postdoctoral Fellowship
- Michael G. DeGroote Postdoctoral Fellowship
- Ontario Graduate Scholarship
- Queen Elizabeth II Graduate Scholarship in Science and Technology
- Canadian Graduate Scholarship from CIHR/MitoCanada
- Australian Research Council
- National Health and Medical Research Council
- Victorian Government's Operational Infrastructure
- Canadian Diabetes Association
- CIHR
- Natural Sciences and Engineering Research Council of Canada
Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the beta 1 subunit, but whether salsalate requires AMPK-beta 1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-beta 1-knockout (AMPK-beta 1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (similar to 1 mmol/L). Salsalate treatment increased VO2, lowered fasting glucose, improved glucose tolerance, and led to an similar to 55% reduction in liver lipid content. These effects were observed in both WT and AMPK-beta 1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondria! proton conductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondria! uncoupling.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据