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 adipose tissue-specific transcription factor peroxisome proliferator-activated receptor gamma 2 (PPAR gamma 2) exhibit a defect in their rate of adipose tissue lipid storage. Impaired adipose tissue storage rate reduces metabolic flexibility, without compromising fasted glucose tolerance or insulin sensitivity, even following prolonged high-fat feeding. However, acutely overfeeding PPAR gamma 2-KO mice caused a 10-fold increase in insulin levels compared with controls. Although impaired adipose tissue storage rate did not result in insulin resistance in young mice, 1-year-old PPAR gamma 2-KO mice developed skeletal muscle insulin resistance. Our data indicate that failed adipose tissue storage may occur prior to defects in glucose handling and that overfeeding protocols may uncover genes controlling adipose tissue storage rate, as opposed to capacity, and act as a diagnostic test for early-stage human metabolic disease.