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

Authors

Christian Springer, Sebastian Sill, Christian Binsch, Taylor Schoen, Laura Toska, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Diran Herebian, D Margriet Ouwens, Delsi Altenhofen, Angelika Horrighs, Birgit Knebel, Regina Ensenauer, Dominik Pesta, Michael Roden, Alexandra Chadt, Hadi Al-Hasani

Published in

Diabetes, obesity & metabolism. Jul 06, 2026. Epub Jul 06, 2026.

Abstract

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).
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.
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.
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.

PMID:
42410330
Bibliographic data and abstract were imported from PubMed on 07 Jul 2026.

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