Aging alters PPARgamma in rodent and human adipose tissue by modulating the balance in steroid receptor coactivator-1.

Abstract

Age is an important risk factor for the development of metabolic diseases (e.g. obesity, diabetes and atherosclerosis). Yet, little is known about the molecular mechanisms occurring upon aging that affect energy metabolism. Although visceral white adipose tissue (vWAT) is known for its key impact on metabolism, recent studies have indicated it could also be a key regulator of lifespan, suggesting that it can serve as a node for age-associated fat accretion. Here we show that aging triggers changes in the transcriptional milieu of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) in vWAT, which leads to a modified potential for transactivation of target genes upon ligand treatment. We found that in vWAT of mice, rats and men, aging induced a specific decrease in the expression of steroid receptor coactivator-1 (SRC-1), whose recruitment to PPARgamma is associated with improved insulin sensitivity and low adipogenic activity. In contrast, aging and oxidative stress did not impact on PPARgamma expression and PPARgamma ligand production. Age-induced loss of PPARgamma/SRC-1 interactions increased the binding of PPARgamma to the promoter of the adipogenic gene aP2. These findings suggest that strategies aimed at increasing SRC-1 expression and recruitment to PPARgamma upon aging might help improve age-associated metabolic disorders.