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(Circulation Research. 2009;105:25.)
© 2009 American Heart Association, Inc.

Molecular Medicine

Activating Transcription Factor 3 Constitutes a Negative Feedback Mechanism That Attenuates Saturated Fatty Acid/Toll-Like Receptor 4 Signaling and Macrophage Activation in Obese Adipose Tissue

Takayoshi Suganami, Xunmei Yuan, Yuri Shimoda, Kozue Uchio-Yamada, Nobutaka Nakagawa, Ibuki Shirakawa, Takako Usami, Takamitsu Tsukahara, Keizo Nakayama, Yoshihiro Miyamoto, Kazuki Yasuda, Junichiro Matsuda, Yasutomi Kamei, Shigetaka Kitajima, Yoshihiro Ogawa

From the Department of Molecular Medicine and Metabolism (T.S., X.Y., Y.S., N.N., I.S., Y.K., Y.O.), Department of Biochemical Genetics (S.K.), Global Center of Excellence Program (Y.O.); and International Research Center for Molecular Science in Tooth and Bone Diseases, Laboratory of Recombinant Animals (T.U.), Medical Research Institute, Tokyo Medical and Dental University, Tokyo; Division of Biomedical Research Resources (K.U.-Y., J.M.), National Institute of Biomedical Innovation, Osaka; Kyoto Institute of Nutrition and Pathology (T.T., K.N.); Department of Medicine (Y.M.), Division of Atherosclerosis and Diabetes, National Cardiovascular Center Hospital, Osaka; and Department of Metabolic Disorder (K.Y.), Research Institute, International Medical Center of Japan, Tokyo, Japan.

Correspondence to Yoshihiro Ogawa, Department of Molecular Medicine and Metabolism, Medical Research Institute, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan. E-mail ogawa.mmm{at}mri.tmd.ac.jp

Obese adipose tissue is markedly infiltrated by macrophages, suggesting that they may participate in the inflammatory pathways that are activated in obese adipose tissue. Evidence has suggested that saturated fatty acids released via adipocyte lipolysis serve as a naturally occurring ligand that stimulates Toll-like receptor (TLR)4 signaling, thereby inducing the inflammatory responses in macrophages in obese adipose tissue. Through a combination of cDNA microarray analyses of saturated fatty acid-stimulated macrophages in vitro and obese adipose tissue in vivo, here we identified activating transcription factor (ATF)3, a member of the ATF/cAMP response element-binding protein family of basic leucine zipper-type transcription factors, as a target gene of saturated fatty acids/TLR4 signaling in macrophages in obese adipose tissue. Importantly, ATF3, when induced by saturated fatty acids, can transcriptionally repress tumor necrosis factor- production in macrophages in vitro. Chromatin immunoprecipitation assay revealed that ATF3 is recruited to the region containing the activator protein-1 site of the endogenous tumor necrosis factor- promoter. Furthermore, transgenic overexpression of ATF3 specifically in macrophages results in the marked attenuation of proinflammatory M1 macrophage activation in the adipose tissue from genetically obese KKA^y mice fed high-fat diet. This study provides evidence that ATF3, which is induced in obese adipose tissue, acts as a transcriptional repressor of saturated fatty acids/TLR4 signaling, thereby revealing the negative feedback mechanism that attenuates obesity-induced macrophage activation. Our data also suggest that activation of ATF3 in macrophages offers a novel therapeutic strategy to prevent or treat obesity-induced adipose tissue inflammation.

Key Words: adipocytes • ATF3 • fatty acids • inflammation • macrophages • TLR4