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

Adilson Guilherme,Gregory J Tesz,Kalyani V.P Guntur,Michael P Czech

doi:10.1074/jbc.m809042200

Adilson Guilherme, Gregory J Tesz + Show 2 more

Open Access

https://doi.org/10.1074/jbc.m809042200

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Abstract

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

Highlights

A large body of work has identified transcriptional regulators that participate in the control of adipocyte differentiation as Grants DK30898 and DK030638
TNF␣ Decreases PPAR␥ Protein Levels, while Increasing the Formation of a 45-kDa Immunoreactive PPAR␥ Fragment—It has been previously shown that TNF␣ treatment of cultured adipocytes reduced PPAR␥ protein levels, presumably through suppression of Ppar␥ gene transcription via the NF␬B signaling pathway [30, 31, 41]
We conducted experiments to determine whether activation of TNF␣ receptors in 3T3-L1 adipocytes could lead to PPAR␥ protein degradation

Summary

Introduction

A large body of work has identified transcriptional regulators that participate in the control of adipocyte differentiation as Grants DK30898 and DK030638 We present evidence that TNF␣ triggers a caspase-dependent cleavage of PPAR␥ proteins in cultured adipocytes, which disrupts its nuclear localization. We postulate that a caspase-3/caspase-6-dependent pathway contributes to the mechanisms whereby TNF␣ suppresses PPAR␥ protein levels and its function in adipose cells.

Results

Conclusion