title: Retinol-binding protein 4 inhibits insulin signaling in adipocytes by inducing proinflammatory cytokines in macrophages through a c-Jun N-terminal kinase- and toll-like receptor 4-dependent and retinol-independent mechanism.
abstract: Retinol-binding protein 4 (RBP4), the sole retinol transporter in blood, is secreted from adipocytes and liver. Serum RBP4 levels correlate highly with insulin resistance, other metabolic syndrome factors, and cardiovascular disease. Elevated serum RBP4 causes insulin resistance, but the molecular mechanisms are unknown. Here we show that RBP4 induces expression of proinflammatory cytokines in mouse and human macrophages and thereby indirectly inhibits insulin signaling in cocultured adipocytes. This occurs through activation of c-Jun N-terminal protein kinase (JNK) and Toll-like receptor 4 (TLR4) pathways independent of the RBP4 receptor, STRA6. RBP4 effects are markedly attenuated in JNK1-/- JNK2-/- macrophages and TLR4-/- macrophages. Because RBP4 is a retinol-binding protein, we investigated whether these effects are retinol dependent. Unexpectedly, retinol-free RBP4 (apo-RBP4) is as potent as retinol-bound RBP4 (holo-RBP4) in inducing proinflammatory cytokines in macrophages. Apo-RBP4 is likely to be physiologically significant since RBP4/retinol ratios are increased in serum of lean and obese insulin-resistant humans compared to ratios in insulin-sensitive humans, indicating that higher apo-RBP4 is associated with insulin resistance independent of obesity. Thus, RBP4 may cause insulin resistance by contributing to the development of an inflammatory state in adipose tissue through activation of proinflammatory cytokines in macrophages. This process reveals a novel JNK- and TLR4-dependent and retinol- and STRA6-independent mechanism of action for RBP4.
authors.affiliation: Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: Norseen
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hosooka
authors.forename: Ann
authors.initials: A
authors.lastname: Hammarstedt
authors.forename: Mark M
authors.initials: MM
authors.lastname: Yore
authors.forename: Shashi
authors.initials: S
authors.lastname: Kant
authors.forename: Pratik
authors.initials: P
authors.lastname: Aryal
authors.forename: Urban A
authors.initials: UA
authors.lastname: Kiernan
authors.forename: David A
authors.initials: DA
authors.lastname: Phillips
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Maruyama
authors.forename: Bettina J
authors.initials: BJ
authors.lastname: Kraus
authors.forename: Anny
authors.initials: A
authors.lastname: Usheva
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Davis
authors.forename: Ulf
authors.initials: U
authors.lastname: Smith
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002450:Cell Communication; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008262:Macrophage Activation; D008264:Macrophages / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D054839:Retinol-Binding Proteins, Plasma / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: D016207:Cytokines; D007328:Insulin; D008565:Membrane Proteins; C101326:RBP4 protein, human; C502487:Rbp4 protein, mouse; D054839:Retinol-Binding Proteins, Plasma; C519685:STRA6 protein, human; C108001:Stra6 protein, mouse; D051197:Toll-Like Receptor 4; D014801:Vitamin A; D048031:JNK Mitogen-Activated Protein Kinases