Peroxisome Proliferator Activated Receptor γ2 Controls the Rate of Adipose Tissue Lipid Storage and Determines Metabolic Flexibility

One understudied function of white adipose tissue (AT) is its role in postprandial lipid buffering. In this study, we demonstrate that mice lacking the AT-specific transcription factor peroxisome proliferator activated receptor γ2 (PPARγ2) exhibit a defect in AT lipid storage rate. Impaired AT storage rate reduces metabolic flexibility, but does not compromise fasted glucose tolerance or insulin sensitivity, even after prolonged high-fat feeding. Mice eat many small meals throughout the day, limiting demands on AT storage rare. To challenge AT storage rate, we developed an acute overfeeding protocol. Overfeeding PPARγ2 KO mice caused a 10-fold increase in insulin and doubled FFA levels compared to controls. We next studied the long-term consequences of impaired AT storage rate and metabolic flexibility and showed that one year old PPARγ2 KO mice exhibited skeletal muscle insulin resistance. Our data suggest that failed AT storage may occur prior to defects in glucose handling and that overfeeding protocols may uncover genes controlling AT storage rate as opposed to capacity. Finally, our results suggest a hypercaloric mixed meal test may allow early diagnosis of humans with AT storage defects and diets that reduce demands on AT storage rate may be clinically beneficial for such individuals.