Sedentariness disrupts, while exercise restores, thermogenic and metabolic plasticity in inguinal adipose tissue of mice.

Inguinal WAT (IngWAT) quickly adapts its metabolism to body energy status variations, including uncoupling protein 1 (UCP1) expression. However, its long-term metabolic response to long-term sedentary and exercise training has not been fully characterized. This study investigated IngWAT's long-term response to sedentary (SED, restricted cage) vs. exercise (EXER, treadmill running with a defined protocol) conditions in mice. EXER mice showed increased expression of Sarcoendoplasmic Reticulum Calcium ATPase (SERCA)2b and UCP1, along with a reduction in adipocyte size, indicating activation of thermogenesis. Fascinatingly, exercise elevated the expression of CIDEA in tiny adipocytes and promoted a beiging effect in mice. Elevated OXPHOS complex proteins expression and NMR-based metabolite profiling in IngWAT revealed that exercise profoundly reprogrammed energy metabolism by strengthening phosphocreatine-creatine buffering, regulating TCA cycle metabolite cycling (citrate and succinate), and increasing ketone body formation (3-hydroxybutyrate and acetone). Elevated glycerol level, a higher glycerol-lactate ratio, and reduced carnitine in IngWAT of EXER mice reflected improved fatty acid uptake and β-oxidation, in contrast to the metabolic inefficiency observed during sedentariness. Moreover, increased vascularization was accomplished by upregulated expression of vascular endothelial growth factor 1a (VEGF1a), angiopoietins (ANG)1&2, supports elevated metabolic state in exercise. Conversely, SED mice showed larger adipocytes with uniform CIDEA expression, but a downregulation of thermogenic proteins. Interestingly, a significant downregulation of mitochondrial complex III was also observed, which indicates altered mitochondrial physiology in SED mice. Data presented here suggest that IngWAT is metabolically flexible and can undergo both structural and metabolic adaptations in accordance with physical activity level.