Housing temperature influences metabolic phenotype of heart failure with preserved ejection fraction in J vs N strain C57BL/6 mice.

Preclinical heart failure studies rely heavily on mouse models despite their higher metabolic and heart rates compared to humans. This study examines how mouse strain (C57BL/6J vs. C57BL/6N) and housing temperature (23 °C vs. 30 °C) affect a well-established two-hit HFpEF model using high-fat diet with L-NAME treatment in male C57BL/6 mouse. Metabolic parameters and cardiac function were assessed at baseline, week 5, and week 15. Thermoneutral housing (30 °C) reduced early diastolic dysfunction in the J strain and altered metabolic profiles in both strains, decreasing energy expenditure and fat oxidation. The J strain specifically showed reduced respiratory exchange ratio and glucose oxidation at 30 °C. While physical activity remained constant across groups, both strains exhibited increased cardiac fibrosis and inflammatory gene expression under HFD + L-NAME, independent of housing temperature. These findings reveal strain-specific physiological adaptations to housing temperature, emphasizing the need to consider environmental conditions in heart failure research carefully.