Voluntary Exercise Differentially Affects High-Fat Induced Metabolic Phenotypes Across BXD Mouse Strains
- 1University of Luxembourg
Abstract
Obesity and metabolic diseases such as diabetes reflect long-term interactions between diet, lifestyle, and genetics, variables that are hard to control in humans but can be systematically varied in mice, though behavioral variables like long-term exercise remain harder to model. Having previously phenotyped ~50 BXD strains, we identified BXD40, BXD43, and BXD100 as predisposed to voluntary wheel-running (~6 km/day at 24 weeks) with variable susceptibility to diet-induced obesity and diabetes. We followed these strains from 8-32 weeks on a 60% kcal/fat high-fat (HF) diet, with or without access to running wheels. Wheel usage declined from ~9 km/day in the first two weeks to a steady ~5 km/day thereafter yet still improved oral glucose tolerance by 35% over sedentary controls by 24 weeks. Despite equivalent body weight, runners ate 20% more relative to body weight, indicating the glucose benefit was independent of caloric intake. We next asked whether the gut microbiome contributes to this benefit. Long-term exercise produced only modest, cohort-dependent shifts in cecal microbial composition, though functional profiling revealed exercise-associated differences in carbohydrate- and glucose-metabolism pathways. Reciprocal bedding exchange between sedentary and running BXD43 cages reduced microbial differentiation in a taxon-specific manner and coincided with marked attenuation of the glucose phenotype, despite unchanged running behavior. Together, these findings validate BXD40, BXD43, and BXD100, alongside the canonical C57BL/6, as a model for studying diet, exercise, and genetics in metabolic disease, and implicate gut microbial taxa in shaping exercise's metabolic effects during HF feeding.
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BibTeX
@misc{lamanna2026voluntary,
title = {{Voluntary Exercise Differentially Affects High-Fat Induced Metabolic Phenotypes Across BXD Mouse Strains}},
author = {A. Lamanna and Z. Zhou and B. Boussoufa and E. Pansart and M. Buttini and T. Heurtaux and P. Garcia and G. Marcon and D. Coowar and E. G. Williams},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.28.752290},
url = {https://www.biorxiv.org/content/10.64898/2026.09.28.752290v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Voluntary Exercise Differentially Affects High-Fat Induced Metabolic Phenotypes Across BXD Mouse Strains
AU - A. Lamanna
AU - Z. Zhou
AU - B. Boussoufa
AU - E. Pansart
AU - M. Buttini
AU - T. Heurtaux
AU - P. Garcia
AU - G. Marcon
AU - D. Coowar
AU - E. G. Williams
PY - 2026
DA - 2026/09/28
PB - bioRxiv
DO - 10.64898/2026.09.28.752290
UR - https://www.biorxiv.org/content/10.64898/2026.09.28.752290v1
AB - Obesity and metabolic diseases such as diabetes reflect long-term interactions between diet, lifestyle, and genetics, variables that are hard to control in humans but can be systematically varied in mice, though behavioral variables like long-term exercise remain harder to model. Having previously phenotyped ~50 BXD strains, we identified BXD40, BXD43, and BXD100 as predisposed to voluntary wheel-running (~6 km/day at 24 weeks) with variable susceptibility to diet-induced obesity and diabetes. We followed these strains from 8-32 weeks on a 60% kcal/fat high-fat (HF) diet, with or without access to running wheels. Wheel usage declined from ~9 km/day in the first two weeks to a steady ~5 km/day thereafter yet still improved oral glucose tolerance by 35% over sedentary controls by 24 weeks. Despite equivalent body weight, runners ate 20% more relative to body weight, indicating the glucose benefit was independent of caloric intake. We next asked whether the gut microbiome contributes to this benefit. Long-term exercise produced only modest, cohort-dependent shifts in cecal microbial composition, though functional profiling revealed exercise-associated differences in carbohydrate- and glucose-metabolism pathways. Reciprocal bedding exchange between sedentary and running BXD43 cages reduced microbial differentiation in a taxon-specific manner and coincided with marked attenuation of the glucose phenotype, despite unchanged running behavior. Together, these findings validate BXD40, BXD43, and BXD100, alongside the canonical C57BL/6, as a model for studying diet, exercise, and genetics in metabolic disease, and implicate gut microbial taxa in shaping exercise's metabolic effects during HF feeding.
ER -