Exercise Resistance in Obese Male NZO Mice Manifests as Local Muscle Remodelling Without Glycaemic Improvements

AIMS: Exercise improves glycaemic control, yet some individuals show limited benefit, termed exercise resistance. We investigated tissue-specific adaptations to chronic exercise in a polygenic model of obesity-driven type 2 diabetes (T2D). MATERIALS AND METHODS: Male New Zealand Obese (NZO) mice were fed a high-fat diet and underwent 6 weeks of interval treadmill training. Physical capacity, body composition, glucose metabolism, skeletal muscle and liver glycogen and triglycerides, mitochondrial function, transcriptomics and systemic metabolites were assessed. RESULTS: The training regime had a positive impact on several physiological parameters, including increased physical capacity (18%, p < 0.01), skeletal muscle AMPK phosphorylation (25%, p < 0.05), complex I-linked respiration (67%, p < 0.05) and transcriptomic enrichment of muscle contraction pathways in trained versus sedentary NZO mice. However, body weight, fat mass, fasting glycaemia, insulin-stimulated glucose uptake, AKT phosphorylation and GLUT4 abundance remained unaltered. Plasma branched-chain amino acids (BCAAs) and ketone bodies (3.3-fold higher in trained, p < 0.05) increased, hepatic triglycerides rose (25%, p < 0.001) with hepatic glycogen depletion (37%, p < 0.05) and caloric intake was slightly higher. CONCLUSIONS: Interval training induced muscle-specific remodelling and enhanced physical capacity without improving systemic insulin sensitivity. Persistent adiposity, exacerbated hepatic steatosis and elevated circulating BCAAs may contribute to limited glycaemic improvement, with altered energy balance as a possible confounder. Consequently, the NZO model offers translational insight into tissue-uncoupled exercise resistance observed in human polygenic obesity and T2D heterogeneity.