2. Academic Validation
  3. Dapagliflozin and chiglitazar combination enhanced myocardial energy metabolism in high-fat diet-fed mice

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

  • Diabetes Obes Metab. 2025 Dec 17. doi: 10.1111/dom.70327.
Jieying Liu 1 2,  Jing Zhou 1,  Shunhua Li 1,  Ziyan Xie 1,  Mengyu He 1,  Jing Liu 1,  Xuemei Ma 1,  Miao Yu 1,  Dongmei Wang 3,  Xinhua Xiao 1
Affiliations

Affiliations

  • 1 Department of Endocrinology, Key Laboratory of Endocrinology of National Health Commission, Diabetes Research Center of Chinese Academy of Medical Sciences, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
  • 2 Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China.
  • 3 Department of Endocrinology, Genetics, Metabolism, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.
PMID: 41403279 DOI: 10.1111/dom.70327
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.

Keywords

chiglitazar; combination effect; dapagliflozin; energy metabolism; myocardial metabolism.

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