Metformin Protects Endothelial Function in Diet-Induced Obese Mice by Inhibition of Endoplasmic Reticulum Stress Through 5' Adenosine Monophosphate-Activated Protein Kinase-Peroxisome Proliferator-Activated Receptor δ Pathway

Objective 5 Adenosine monophosphate-activated protein kinase (AMPK) interacts with peroxisome proliferator-activated receptor (PPAR) to induce gene expression synergistically, whereas the activation of AMPK inhibits endoplasmic reticulum (ER) stress. Whether the vascular benefits of antidiabetic drug metformin (AMPK activator) in diabetes mellitus and obesity is mediated by PPAR remains unknown. We aim to investigate whether PPAR is crucial for metformin in ameliorating ER stress and endothelial dysfunction induced by high-fat diet. Approach and Results Acetylcholine-induced endothelium-dependent relaxation in aortae was measured on wire myograph. ER stress markers were determined by Western blotting. Superoxide production in mouse aortae and NO generation in mouse aortic endothelial cells were assessed by fluorescence imaging. Endothelium-dependent relaxation was impaired and ER stress markers and superoxide level were elevated in aortae from high-fat diet-induced obese mice compared with lean mice. These effects of high-fat diet were reversed by oral treatment with metformin in diet-induced obese PPAR wild-type mice but not in diet-induced obese PPAR knockout littermates. Metformin and PPAR agonist GW1516 reversed tunicamycin (ER stress inducer)-induced ER stress, oxidative stress, and impairment of endothelium-dependent relaxation in mouse aortae as well as NO production in mouse aortic endothelial cells. Effects of metformin were abolished by cotreatment of GSK0660 (PPAR antagonist), whereas effects of GW1516 were unaffected by compound C (AMPK inhibitor). Conclusions Metformin restores endothelial function through inhibiting ER stress and oxidative stress and increasing NO bioavailability on activation of AMPK/PPAR pathway in obese diabetic mice.