The combination of dapagliflozin and chiglitazar improved cardiac fatty acid and central carbon metabolism, accelerated the TCA cycle, and increased ATP production compared with monotherapy.
RCT
randomized
Does combination therapy with dapagliflozin and chiglitazar improve cardiac energy metabolism in high-fat diet-induced obesity mice?
The combination of dapagliflozin and chiglitazar synergistically improves cardiac fatty acid and central carbon metabolism in a mouse model of diet-induced obesity.
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.
Liu et al. (Wed,) conducted a rct in High-fat diet (HFD)-induced obesity. Dapagliflozin and chiglitazar combination vs. Normal chow control, HFD control, and monotherapies was evaluated on Cardiac energy metabolism (free fatty acids and central carbon metabolism pathways). The combination of dapagliflozin and chiglitazar improved cardiac fatty acid and central carbon metabolism, accelerated the TCA cycle, and increased ATP production compared with monotherapy.