318-OR: Targeting PPARγ Phosphorylation Prevents Obesity by Inducing a Brown-Like Healthy Remodeling of Adipose Tissue

The prevalence of obesity—and thus the incidence of metabolic diseases, including type 2 diabetes and cardiovascular disease—is dramatically increasing worldwide. Despite the critical role of adipose tissues in nutrient metabolism, there are surprisingly few clinically-approved medications targeting adipose tissue. Thiazolidinediones (TZDs), PPARγ agonists are exceptions that act in adipose tissue, but they are associated with adverse effects such as weight gain, and heart failure. An exciting series of studies demonstrate that posttranslational modifications can selectively enhance the insulin sensitizing activity of PPARγ. Our laboratory previously showed that roscovitine (RS), a CDK inhibitor, prevents diet-induced obesity by blocking PPARγ S273 phosphorylation, which promotes formation of UCP1+ (brite) adipocytes in WAT. RNA profiling reveals that brite adipocytes are distinct from beige adipocytes, which arise through catecholamine signaling suggesting that brown-like adipocytes in WAT may arise from multiple origins. Using adipocytes and progenitor’s lineage tracing mice, we demonstrate that brite adipocytes originate from mature white adipocytes through trans-differentiation. Inhibition of S273 phosphorylation of PPARγ in obese mice prevents weight gain, restores insulin and glucose sensitivity and a normal pancreatic β-cells response to glucose as well as prevents liver steatosis and adipocytes formation in bone. Moreover, mass spectrometry analysis of extracellular matrix proteins showed a reduced adipose tissues fibrosis following RS treatment. Mechanistically, inhibition of PPARγ phosphorylation shifts its interaction with cofactors favoring a brown-like healthy remodeling of adipose tissue, which includes suppression of genes associated with inflammation and fibrosis. Overall, we demonstrate targeting PPARγ phosphorylation using RS can constitute a new therapy for obesity and its metabolic complications.