Metabolic Inflexibility and Altered Substrate Utilization Drive Cardiac Remodeling in Metabolic Syndrome

Background and Hypothesis: Metabolic Syndrome (MetS) is a leading cause of heart failure; however, the underlying mechanisms remain unclear. We hypothesized that altered metabolic flux, particularly in long-chain fatty acids (LCFA) and glucose, and impaired mitochondrial function contributes to cardiac remodeling in MetS. Methods: Isolated hearts from Insulin2 mutant Akita mice were used as a model of MetS to investigate oxidative metabolism and substrate flux. Hearts from 14-week-old male Akita mice and their normoglycemic wild-type (WT) littermates (both n = 4) were studied using Langendorff perfusion with Krebs–Henseleit buffer containing 8 mM [1,6- 13 C]glucose, 1.2 mM [2- 13 C]lactate, 0.12 mM [2- 13 C]pyruvate, and 0.3 mM [U- 13 C]LCFA. Oxygen consumption (MVO 2 ) was measured using a blood gas analyzer and used to calculate absolute metabolic fluxes. 13 C-labeling patterns allowed differentiation of substrate-specific oxidation. Glycolytic flux was quantified by analyzing the effluent perfusate with 1 H-NMR spectroscopy. Coronary flow rates and heart weight-to-body weight ratios were recorded to assess cardiac perfusion and relative heart size. Results: The metabolic flux analysis revealed a marked shift toward fatty acid metabolism in the Akita heart, as evidenced by significantly increased LCFA oxidation (0.692 ± 0.013 vs. 0.473 ± 0.024 µmol/mg; p < 0.001). In contrast, glucose oxidation was severely impaired in Akita hearts (0.072 ± 0.012 vs. 0.199 ± 0.020 µmol/mg in WT; p < 0.0001), reflecting a substantial reduction in pyruvate dehydrogenase (PDH) flux (0.98 ± 0.18 vs. 2.16 ± 0.18 µmol/min/mg; p < 0.0001). A significantly lower oxygen consumption rates (7.61 ± 0.63 vs. 9.49 ± 0.52 µmol/min/mg; p < 0.01) and diminished TCA cycle flux (2.63 ± 0.22 vs. 3.25 ± 0.18 µmol/min/mg; p < 0.05) in the Akita heart demonstrate impaired mitochondrial function. Additionally, Akita hearts exhibited reduced production of labeled lactate and alanine from glucose, indicating impaired glycolytic oxidative fluxes. Coronary flow rates remained comparable between the groups, and heart weight-to-body weight ratios showed no significant differences. Conclusion: The Akita diabetic hearts demonstrate significant metabolic inflexibility, characterized by enhanced fatty acid oxidation, suppressed glucose utilization, and impaired mitochondrial function. These findings highlight the critical metabolic shifts associated with cardiac remodeling in MetS and underscore the need for therapeutic strategies targeting substrate utilization and mitochondrial function. This research was supported by AHA Grants 23SCEFIA1154964, 24IPA1272385, 24TPA1297929 (to G.S.); and NIH Grants R56HL156806, R01HL155618, 1P50AA030407 (to P.K.M.). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.