Tumor Necrosis Factor-α Induces Caspase-mediated Cleavage of Peroxisome Proliferator-activated Receptor γ in Adipocytes

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) is a ligand-dependent transcription factor that acts as a primary regulator of adipogenesis and controls adipocyte metabolism and insulin action. Increased expression of tumor necrosis factor (TNF alpha) in adipose tissue of obese subjects potently suppresses the expression of PPAR gamma and attenuates adipocyte functions. Here we show that PPAR gamma is a substrate of caspase-3 and caspase-6 during TNF alpha receptor signaling in adipocytes, and the consequent PPAR gamma cleavage disrupts its nuclear localization. TNF alpha treatment of 3T3-L1 adipocytes decreases full-length PPAR gamma while increasing the level of a 45-kDa immunoreactive PPAR gamma fragment. Specific inhibitors of caspase-3 and caspase-6 attenuate the cleavage of PPAR gamma protein in response to TNF alpha in cultured adipocytes. Incubation of nuclear fractions with recombinant caspase-3 and caspase-6 also generates a 45-kDa PPAR gamma cleavage product. Dispersion of nuclear PPAR gamma to the cytoplasm in response to TNF alpha treatment occurs in parallel with detection of activated caspase-3. We suggest that activation of the caspase cascade by TNF alpha down-regulates PPAR gamma protein and PPAR gamma-mediated metabolic processes in adipose cells.