title: Receptor for advanced glycation end products regulates adipocyte hypertrophy and insulin sensitivity in mice: involvement of Toll-like receptor 2.
abstract: Receptor for advanced glycation end products (RAGE) has been shown to be involved in adiposity as well as atherosclerosis even in nondiabetic conditions. In this study, we examined mechanisms underlying how RAGE regulates adiposity and insulin sensitivity. RAGE overexpression in 3T3-L1 preadipocytes using adenoviral gene transfer accelerated adipocyte hypertrophy, whereas inhibitions of RAGE by small interfering RNA significantly decrease adipocyte hypertrophy. Furthermore, double knockdown of high mobility group box-1 and S100b, both of which are RAGE ligands endogenously expressed in 3T3-L1 cells, also canceled RAGE-medicated adipocyte hypertrophy, implicating a fundamental role of ligands-RAGE ligation. Adipocyte hypertrophy induced by RAGE overexpression is associated with suppression of glucose transporter type 4 and adiponectin mRNA expression, attenuated insulin-stimulated glucose uptake, and insulin-stimulated signaling. Toll-like receptor (Tlr)2 mRNA, but not Tlr4 mRNA, is rapidly upregulated by RAGE overexpression, and inhibition of Tlr2 almost completely abrogates RAGE-mediated adipocyte hypertrophy. Finally, RAGE(-/-) mice exhibited significantly less body weight, epididymal fat weight, epididymal adipocyte size, higher serum adiponectin levels, and higher insulin sensitivity than wild-type mice. RAGE deficiency is associated with early suppression of Tlr2 mRNA expression in adipose tissues. Thus, RAGE appears to be involved in mouse adipocyte hypertrophy and insulin sensitivity, whereas Tlr2 regulation may partly play a role.
authors.affiliation: Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masayo
authors.initials: M
authors.lastname: Monden
authors.forename: Hidenori
authors.initials: H
authors.lastname: Koyama
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Otsuka
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Morioka
authors.forename: Katsuhito
authors.initials: K
authors.lastname: Mori
authors.forename: Takuhito
authors.initials: T
authors.lastname: Shoji
authors.forename: Yohei
authors.initials: Y
authors.lastname: Mima
authors.forename: Koka
authors.initials: K
authors.lastname: Motoyama
authors.forename: Shinya
authors.initials: S
authors.lastname: Fukumoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shioi
authors.forename: Masanori
authors.initials: M
authors.lastname: Emoto
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Nishizawa
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kurajoh
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Inaba
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin / Q000096:biosynthesis / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001835:Body Weight; D049108:Cell Enlargement; D059305:Diet, High-Fat; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D020868:Gene Silencing; D018014:Gene Transfer Techniques; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000096:biosynthesis; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000235:genetics; D007328:Insulin / Q000494:pharmacology; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000235:genetics; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051195:Toll-Like Receptor 2 / Q000096:biosynthesis*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse; D051275:Glucose Transporter Type 4; D024243:HMGB1 Protein; D007328:Insulin; D009414:Nerve Growth Factors; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D064568:S100 Calcium Binding Protein beta Subunit; D009418:S100 Proteins; C579159:S100b protein, mouse; C495693:Slc2a4 protein, mouse; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D005947:Glucose