Sci. Signal., 27 July 2010
Metabolism A Phosphorylation Target for Diabetes Therapy
Science Signaling, AAAS, Washington, DC 20005, USA
Stimulation of the nuclear receptor PPAR (peroxisome proliferator–activated receptor ) leads to the transcription of genes that promote adipogenesis and glucose uptake. PPAR is targeted by the thiazolidinedione class of antidiabetic drugs, which includes rosiglitazone. However, efficacy of thiazolidinediones and other antidiabetic drugs cannot always be predicted from the degree of PPAR agonism. Choi et al. found that cyclin-dependent kinase 5 (Cdk5)–mediated phosphorylation of Ser273 in PPAR increased in 3T3-L1 adipocytes exposed to free fatty acids or inflammatory cytokines such as TNF- and IL-6. Wild-type PPAR (PPARWT) and a mutant form of PPAR that could not be phosphorylated (Ser273Ala; PPARS273A) showed similar activity in transcriptional and adipogenesis assays. However, cells expressing PPARS273A showed increased abundance of the transcripts encoding the fatty acid transporter CD36 and the adipokines adiponectin, adipsin, and leptin, and fat pads expressing PPARS273A showed higher abundance of the transcripts for adiponectin and adipsin. Mice on a high-fat and high-sugar diet showed increased phosphorylation of PPAR at Ser273 in fat and increased activation of Cdk5 compared with mice on a normal diet. Rosiglitazone inhibited TNF-–induced Ser273 phosphorylation of PPAR, an effect that was blocked by the PPAR antagonist GW9662. Analysis of several antidiabetic drugs indicated that antidiabetic activity appeared to correlate better with the ability to reduce Cdk5-mediated phosphorylation of PPAR than with PPAR agonism. Treatment with rosiglitazone or MRL24 (which is a more potent antidiabetic drug but a poorer PPAR agonist than rosiglitazone) reduced expression of the same set of genes as did expression of PPARS273A. Hydrogen/deuterium exchange and mass spectrometry revealed that rosiglitazone and MRL24 induced a conformational change in PPAR that the authors speculated was less favorable for phosphorylation by Cdk5. Treating mice on a high-fat diet with rosiglitazone or MRL24 improved glucose tolerance, reduced fasting insulin concentrations, decreased Cdk5-mediated phosphorylation of PPAR, and altered gene expression patterns. Furthermore, phosphorylation of PPAR at Ser273 in subcutaneous fat was reduced in individuals receiving rosiglitazone therapy. In the associated commentary, Houtkooper and Auwerx note that the results of Choi et al. may help in the design of antidiabetic drugs targeting PPAR that are more effective and have fewer side effects.
J. H. Choi, A. S. Banks, J. L. Estall, S. Kajimura, P. Boström, D. Laznik, J. L. Ruas, M. J. Chalmers, T. M. Kamenecka, M. Blüher, P. R. Griffin, B. M. Spiegelman, Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPAR by Cdk5. Nature 466, 451–456 (2010). [PubMedl]
R. H. Houtkooper, J. Auwerx, New life for antidiabetic drugs. Nature 466, 443–444 (2010). [PubMed]
Citation: W. Wong, A Phosphorylation Target for Diabetes Therapy. Sci. Signal. 3, ec227 (2010).
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