title: The Dietary Isoflavone Daidzein Reduces Expression of Pro-Inflammatory Genes through PPARα/γ and JNK Pathways in Adipocyte and Macrophage Co-Cultures.
abstract: Obesity-induced inflammation caused by adipocyte-macrophage interactions plays a critical role in developing insulin resistance, and peroxisome proliferator-activated receptors (PPARs) regulate inflammatory gene expression in these cells. Recently, the soy isoflavone daidzein was reported to act as a PPAR activator. We examined whether daidzein affected adipocyte-macrophage crosstalk via the regulation of PPARs. Co-cultures of 3T3-L1 adipocytes and RAW264 macrophages, or palmitate-stimulated RAW264 macrophages were treated with daidzein in the presence or absence of specific inhibitors for PPARs: GW6471 (a PPARα antagonist), and GW9662 (a PPARγ antagonist). Inflammatory gene expression was then determined. Daidzein significantly decreased chemokine (C-C motif) ligand 2 (Ccl2, known in humans as monocyte chemo-attractant protein 1 (MCP1)) and interleukin 6 (Il6) mRNA levels induced by co-culture. In 3T3-L1 adipocytes, daidzein inversed the attenuation of adiponectin gene expression by co-culture, and these effects were inhibited by the PPAR-γ specific inhibitor. Daidzein also decreased Ccl2 and Il6 mRNA levels in RAW264 macrophages stimulated with palmitate or conditioned medium (CM) from hypertrophied 3T3-L1 adipocytes. This inhibitory effect on Il6 expression was abrogated by a PPAR-α inhibitor. Additionally, we examined the activation of nuclear factor-kappa B (NF-κB) and c-Jun N-terminal kinase (JNK) pathways and found that daidzein significantly inhibited palmitate-induced phosphorylation of JNK. Our data suggest that daidzein regulates pro-inflammatory gene expression by activating PPAR-α and -γ and inhibiting the JNK pathway in adipocyte and macrophage co-cultures. These effects might be favorable in improving adipose inflammation, thus, treatment of daidzein may be a therapeutic strategy for chronic inflammation in obese adipose tissue.
authors.affiliation: Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Sakamoto
authors.affiliation: Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Kanatsu
authors.affiliation: Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Toh
authors.affiliation: Laboratory of Applied Nutrition, Faculty of Human Life and Environmental Sciences, Ochanomizu University, Tokyo, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Naka
authors.affiliation: Endowed Research Department "Food for Health", Ochanomizu University, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kondo
authors.affiliation: Department of Nutrition and Food Science, Graduate School of Humanities and Sciences, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo, Japan.
authors.forename: Kaoruko
authors.initials: K
authors.lastname: Iida
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D007529:Isoflavones / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D047493:PPAR alpha / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D018836:Inflammation Mediators; D007529:Isoflavones; D047493:PPAR alpha; D047495:PPAR gamma; C004742:daidzein; D048031:JNK Mitogen-Activated Protein Kinases