title: Androgen-androgen receptor system improves chronic inflammatory conditions by suppressing monocyte chemoattractant protein-1 gene expression in adipocytes via transcriptional regulation.
abstract: Age-related decreases in sex hormones are closely related to chronic inflammation in obesity and metabolic diseases. Particularly, the molecular basis of androgen activity in regulating inflammation and controlling metabolism remains largely unknown. Obese adipocytes secrete monocyte chemoattractant protein-1 (MCP-1), a key chemokine that promotes the infiltration of monocytes/macrophages into adipose tissue, thereby leading to metabolic disorders. Here, we studied the role of androgen-androgen receptor (AR) action in regulating MCP-1 expression in adipose tissue. We observed the induction of Mcp-1 expression in 3T3-L1 adipocytes co-cultured with RAW264.7 macrophages. Additionally, Mcp-1 expression was upregulated by culturing in conditioned medium derived from inflammatory macrophages (M1-Mφ) containing tumor necrosis factor-alpha (TNF-α). We found that sex hormones downregulated TNF-α-induced Mcp-1 and interleukin (Il)-6 expression in 3T3-L1 adipocytes. Furthermore, luciferase-reporter analysis indicated that MCP-1 promoter activity was predominantly suppressed by dihydrotestosterone (DHT)-AR interactions through functional canonical nuclear factor-kappa B (NF-κB) sites, whereas non-canonical NF-κB site containing important flanking sequences exhibited minor contributions to DHT-AR transcriptional repression. These findings suggested that androgen-AR suppressed obesity-induced chronic inflammation in adipose tissue.
authors.affiliation: Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512, Japan. Electronic address: amorooka@gunma-u.ac.jp.
authors.forename: Nobukatsu
authors.initials: N
authors.lastname: Morooka
authors.affiliation: Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Ueguri
authors.affiliation: Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512, Japan; Human Resources Cultivation Center, Gunma University, 1-5-1 Tenjin-cho, Kiryushi, Gunma, 376-8515, Japan.
authors.forename: Karen Kar Lye
authors.initials: KKL
authors.lastname: Yee
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, Jonan-ku, Fukuoka, 814-0180, Japan.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
authors.affiliation: Institute for Molecular and Cellular Regulation, Gunma University, 3-39-15 Showa-machi, Maebashi, Gunma, 371-8512, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Sato
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000728:Androgens / Q000378:metabolism*; D000818:Animals; D018932:Chemokine CCL2 / Q000378:metabolism*; D002908:Chronic Disease; D005786:Gene Expression Regulation; D007249:Inflammation / Q000378:metabolism*; D051379:Mice; D000067996:RAW 264.7 Cells; D011944:Receptors, Androgen / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C000607144:AR protein, mouse; D000728:Androgens; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D011944:Receptors, Androgen
keywords: Adipocyte; Androgen; Androgen receptor, AR; Chronic inflammation; MCP-1; Macrophage