Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces non-alcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMP-activated protein kinase (AMPK) via the β1 subunit but whether salsalate requires AMPK β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK β1 knockout mice (AMPK β1KO) were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (∼1 mM). Salsalate treatment increased oxygen consumption, lowered fasting glucose, improved glucose tolerance and led to an ∼55% reduction in liver lipid content; effects observed in both WT and AMPK β1KO mice. To explain these AMPK-independent effects, it was found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial 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 UCP1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.
- Received May 2, 2016.
- Accepted August 16, 2016.
- © 2016 by the American Diabetes Association.