Tumor necrosis factor-α induces caspase-mediated cleavage of peroxisome proliferator-activated receptor γ in adipocytes

Abstract

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) 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 (TNFα) in adipose tissue of obese subjects potently suppresses the expression of PPARγ and attenuates adipocyte functions. Here we show that PPARα is a substrate of caspase-3 and caspase-6 during TNFα receptor signaling in adipocytes, and the consequent PPARγ cleavage disrupts its nuclear localization.TNFα treatment of 3T3-L1 adipocytes decreases full-length PPARγ while increasing the level of a 45-kDa immunoreactive PPARγ fragment. Specific inhibitors of caspase-3 and caspase-6 attenuate the cleavage of PPARγ protein in response to TNFα in cultured adipocytes. Incubation of nuclear fractions with recombinant caspase-3 and caspase-6 also generates a 45-kDa PPARγ cleavage product. Dispersion of nuclearPPARγ to the cytoplasm in response toTNFα treatment occurs in parallel with detection of activated caspase-3. We suggest that activation of the caspase cascade by TNFα down-regulates PPARγ protein and PPARγ-mediated metabolic processes in adipose cells. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.