Long-term voluntary exercise partially reverses obesity-associated transcriptomic remodeling in brown adipose tissue.

Background: Although exercise may counteract some changes caused by obesity-induced functional and molecular remodeling of brown adipose tissue (BAT), the extent to which long-term voluntary exercise reverses obesity-associated BAT transcriptional changes remains unclear. Methods: Male C57BL/6J mice were assigned to the control, high-fat diet (HFD), or HFD plus voluntary exercise (HFD + VE) groups for four months (n = 4 per group). Interscapular BAT transcriptomic profiles were analyzed using the Clariom S Mouse Array. Differential expression was explored using eBayes ANOVA, and transcript clusters with an absolute fold change >2, a nominal P value < 0.05, and a mean log2 signal intensity ≥8 in the group with higher expression were selected for exploratory analyses. FDR-adjusted P values were additionally examined to account for multiple testing. Gene Ontology enrichment analysis was performed using DAVID. Results: Using the prespecified exploratory criteria (absolute fold change >2, nominal P < 0.05, and mean log2 signal intensity ≥8 in the group with higher expression), 579 transcript clusters differed between the control and HFD groups. In the HFD versus HFD + VE comparison, 89 transcript clusters met these exploratory criteria; 74 showed lower expression and 15 showed higher expression with VE. None of the 89 transcript clusters remained significant at FDR <0.05 after genome-wide multiple-testing correction. GO enrichment analysis nevertheless identified coordinated immune/inflammatory and muscle contraction-related biological processes, several of which remained significant after FDR correction for GO-term testing. Conclusions: Long-term voluntary exercise was associated with transcriptomic changes that opposed a subset of HFD-associated alterations, particularly immune and inflammatory signatures. A restricted contractile/Ca2+-related transcriptional signature was also identified, although the transcriptomic data alone do not establish altered Ca2+ signaling. These exploratory findings highlight the need for further investigation of the cellular and signaling mechanisms underlying exercise-associated BAT remodeling.