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The Adipogenic Acetyltransferase Tip60 Targets Activation Function 1 of Peroxisome Proliferator-Activated Receptor

Department of Metabolic and Endocrine Diseases (O.v.B., N.H., R.B., E.K.), University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands; Department of Physiological Chemistry (A.B.B., N.J.F.v.d.B.), University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands; and Department of Biochemistry and Molecular Biology (L.G., S.M.), University of Southern Denmark, 5230 Odense M, Denmark

Address all correspondence and requests for reprints to: Eric Kalkhoven, Department of Metabolic and Endocrine Diseases, University Medical Center Utrecht, Room KE.03.139.2, Lundlaan 6, 3584 EA Utrecht, The Netherlands. E-mail: e.kalkhoven{at}umcutrecht.nl.

The transcription factor peroxisome proliferator-activated receptor (PPAR) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPAR is dictated by the set of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPAR transcriptional activity. Using tandem mass spectrometry, we found that PPAR and the acetyltransferase Tip60 interact in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPAR, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip60 protein is recruited to PPAR target genes in mature 3T3-L1 adipocytes but not in preadipocytes, indicating that Tip60 requires PPAR for its recruitment to PPAR target genes. Importantly, we show that in common with disruption of PPAR function, small interfering RNA-mediated reduction of Tip60 protein impairs differentiation of 3T3-L1 preadipocytes. Taken together, these findings qualify the acetyltransferase Tip60 as a novel adipogenic factor.