Exercise rescues obesity-induced adipose tissue premature aging and restores cardio-metabolic homeostasis

Abstract

Modifiable lifestyle choices, such as physical activity, can favor metabolic health in aging and obesity. We demonstrated that endocardial fibrosis and cardiovascular dysfunction decrease in response to exercise in aged mice. Recent evidence suggests exercise may prevent high fat diet (HFD)-induced adipose tissue premature senescence and rescue cardio-metabolic function. Our aim was to understand the role of white adipose tissue (WAT) bioenergetics in the accumulation of senescent cells during HFD and exercise. Thirty-two WT male mice (5 months old) were subjected to high-fat diet (HFD: 60% fat) and chow diet (CD: 13% fat). After 5 weeks on diets, animals were randomized to 4 weeks of sedentary or exercise protocol ( n = 8/group). Exercise consisted in forced swimming for 90 min/day for 5 days/week. Before and after the 4-week exercise/sedentary protocol, mice were evaluated for the cardio-metabolic profile. Histological, molecular and bioenergetic features of inguinal and epidydimal WAT (iWAT and eWAT, respectively) were evaluated. Short-term exercise is sufficient to attenuate obesity-induced cardiac interstitial fibrosis and dysfunction, WAT alterations and glucose intolerance, before major body weight reduction. Cardiac functional improvement was associated with decreased plasma leptin levels in HFD trained mice. Both fat depots, iWAT and eWAT, showed premature senescence in response to HFD, at time when inflammation and fibrosis were not in place yet, and exercise reversed it. Iterative testing in a supervised predictive model on the transcriptional profile of WAT under HFD confirmed differences in the depot response to diet and exercise. We provide evidence that attenuation of cardiac dysfunction is associated with the response of WAT to exercise. Strategies targeting senescence could be of primary relevance to restore cardio-metabolic health in different pathophysiological conditions.