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Diabetes 54:3358-3370, 2005
© 2005 by the American Diabetes Association, Inc.

Peroxisome Proliferator–Activated Receptor (PPAR){alpha} Activation Increases Adiponectin Receptors and Reduces Obesity-Related Inflammation in Adipose Tissue

Comparison of Activation of PPAR{alpha}, PPAR{gamma}, and Their Combination

Atsushi Tsuchida1, Toshimasa Yamauchi1,2, Sato Takekawa1, Yusuke Hada1, Yusuke Ito1, Toshiyuki Maki1, and Takashi Kadowaki1,2,3

1 Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
2 Core Research for Evolutional Science and Technology of Japan Science and Technology Agency, Kawaguchi, Japan
3 National Institute of Health and Nutrition, Tokyo, Japan

We examined the effects of activation of peroxisome proliferator–activated receptor (PPAR){alpha}, PPAR{gamma}, and both of them in combination in obese diabetic KKAy mice and investigated the mechanisms by which they improve insulin sensitivity. PPAR{alpha} activation by its agonist, Wy-14,643, as well as PPAR{gamma} activation by its agonist, rosiglitazone, markedly improved insulin sensitivity. Interestingly, dual activation of PPAR{alpha} and -{gamma} by a combination of Wy-14,643 and rosiglitazone showed increased efficacy. Adipocyte size in Wy-14,643–treated KKAy mice was much smaller than that of vehicle- or rosiglitazone-treated mice, suggesting that activation of PPAR{alpha} prevents adipocyte hypertrophy. Moreover, Wy-14,643 treatment reduced inflammation and the expression of macrophage-specific genes in white adipose tissue (WAT). Importantly, Wy-14,643 treatment upregulated expression of the adiponectin receptor (AdipoR)-1 and AdipoR2 in WAT, which was decreased in WAT of KKAy mice compared with that in nondiabetic control mice. Furthermore, Wy-14,643 directly increased expression of AdipoRs and decreased monocyte chemoattractant protein-1 expression in adipocytes and macrophages. Rosiglitazone increased serum adiponectin concentrations and the ratio of high molecular weight multimers of adiponectin to total adiponectin. A combination of rosiglitazone and Wy-14,643 increased both serum adiponectin concentrations and AdipoR expression in WAT. These data suggest that PPAR{alpha} activation prevents inflammation in WAT and that dual activation of PPAR{alpha} and -{gamma} enhances the action of adiponectin by increasing both adiponectin and AdipoRs, which can result in the amelioration of obesity-induced insulin resistance.

Address correspondence and reprint requests to Takashi Kadowaki, MD, PhD, Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp

Abbreviations: AdipoR, adiponectin receptor; BAT, brown adipose tissue; DMEMH, Dulbecco’s modified high-glucose Eagle’s medium; HMW, high molecular weight; MCP, monocyte chemotactic protein; PDK4, pyruvate dehydrogenase kinase isozyme 4; PPAR, peroxisome proliferator–activated receptor; TNF, tumor necrosis factor; TZD, thiazolidinedione; UCP, uncoupling protein; WAT, white adipose tissue


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