Integrated Metabolomics Analysis Of The Effect Of Ppar Delta Agonist Gw501516 On Catabolism Of Bcaas And Carboxylic Acids In Diabetic Mice

The peroxisome proliferator-activated receptor (PPAR delta) agonists are reported to improve insulin sensitivity, reduce glucose levels, and alleviate dysfunctional lipid metabolism in animal models of type 2 diabetes mellitus. However, the underlying mechanisms remain incompletely understood. Metabolism plays an essential role in the biological system. Monitoring of metabolic changes in response to disease conditions or drug treatment is critical for better understanding of the pathophysiological mechanisms. In this study, metabolic profiling analysis by gas chromatography-mass spectrometry integrated with targeted analysis by liquid chromatography-mass spectrometry was carried out in plasma samples of db/db diabetic mice after six-week treatment of PPAR delta agonist GW501516. GW501516 treatment significantly altered levels of metabolites, such as branched-chain amino acids (BCAAs), BCAA metabolites (3-hydroxyisobutyric acid and 3-hydroxyisovaleric acid), long-chain fatty acids, uric acid and ketone bodies (3-hydroxybutyric acid and 2-hydroxybutyric acid) which are all associated with the impaired systemic insulin sensitivity. The present results indicate the beneficial effect of PPAR delta agonist in alleviating insulin resistance of diabetic mice by favorably modulating metabolic profile, thus providing valuable information in understanding the therapeutic potential of PPAR delta agonists in correcting metabolic dysfunction in diabetes. (C) 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.