Dapagliflozin and chiglitazar combination enhanced myocardial energy metabolism in high‐fat diet‐fed mice

Abstract Aims Oral antidiabetic drugs dapagliflozin and chiglitazar have shown potential effects in improving myocardial metabolism. This study aimed to investigate their combined impacts on cardiac energy metabolism in high‐fat diet (HFD)‐induced obesity mice. Methods Male C57BL/6N mice were randomized into seven groups: (1) normal chow control, (2) high‐fat diet (HFD) control, (3) dapagliflozin monotherapy, (4) low dose of chiglitazar monotherapy, (5) high dose of chiglitazar monotherapy and (6, 7) combination therapy groups with dapagliflozin and varying doses of chiglitazar. Myocardial tissues were subjected to targeted metabolomic analysis for free fatty acids (FFAs) species and key intermediates in central carbon metabolism pathways. Results The combination therapy significantly improved overall metabolic phenotypes and reduced cardiac lipid droplet size in HFD mice. FFAs profile analysis showed an increased proportion of unsaturated FFAs and a decreased proportion of saturated FFAs. The central carbon metabolism analysis demonstrated alterations in energy metabolic pathways, including glycolysis, purine and pyrimidine metabolism, amino acid metabolism, and the tricarboxylic acid (TCA) cycle. Combined analysis of FFAs and central carbon showed that the TCA cycle was accelerated and ATP production was increased compared with monotherapy. Decreased expression of acetyl‐CoA carboxylase 1, increased expression of carnitine palmitoyltransferase 1, as well as elevated levels of citrate synthase and isocitrate dehydrogenase, were validated by Western blot. Conclusions The combination of dapagliflozin and chiglitazar improved cardiac fatty acid and central carbon metabolism, among which acceleration of metabolic flux through the TCA cycle, increased ATP production, and upregulation of key enzyme expression might represent the key beneficial mechanisms.