Abstract / Summary
Background/Objectives: Obesity is linked to hepatic metabolic dysfunction and inflammation. Combined aerobic and resistance exercise is associated with improved body composition, but its effects on liver metabolomics remain unclear. This study examined an 8-week combined exercise intervention in high-fat diet (HFD)-induced obese mice. Methods: A subset of 18 male C57BL/6J mice from a larger well-characterized cohort was divided into three groups (n = 6/group): standard diet control (C), HFD model (HF), and HFD with combined exercise (HFAR). The intervention comprised treadmill running (12–15 m/min, 30–60 min/day) and weighted ladder climbing (10–70% body weight load), 6 days/week. Hepatic steatosis was assessed using H&E and Oil Red O staining. Hepatic lipids, transaminases (ALT/AST), and cytokines (IL-1β, IL-6, TNF-α) were measured by ELISA. Liver metabolomics was performed via LC-MS-based untargeted profiling. Results: Despite no significant reductions in terminal body weight, fat mass, or fat percentage, HFAR mice exhibited markedly attenuated hepatic steatosis. Biochemically, exercise significantly lowered hepatic TC, TG, LDL-C, ALT, and AST (all p < 0.01), elevated HDL-C (p < 0.01), and suppressed pro-inflammatory cytokines (all p < 0.05). Six core metabolites (MSI Level 1a/1b) were identified based on authentic standards, highlighting histidine and pyrimidine metabolism as key hubs. Conclusions: Combined exercise was associated with attenuated hepatic pathology independent of weight loss. Integrated metabolomics revealed a signature of six core metabolites associated with this benefit, suggesting coordinated shifts across histidine, pyrimidine, purine, tryptophan, and cysteine and methionine metabolism. These findings offer valuable insights into weight-loss-independent hepatoprotection in MASLD.