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
Authors
Norseen, JulieHosooka, Tetsuya
Hammarstedt, Ann
Yore, Mark M.
Kant, Shashi
Aryal, Pratik
Kiernan, Urban A.
Phillips, David A.
Maruyama, Hiroshi
Kraus, Bettina J.
Usheva, Anny
Davis, Roger J.
Smith, Ulf
Kahn, Barbara B.
UMass Chan Affiliations
Program in Molecular MedicineDocument Type
Journal ArticlePublication Date
2012-05-01Keywords
3T3 CellsAdipocytes
Animals
Cell Communication
Coculture Techniques
Cytokines
Humans
Insulin
Insulin Resistance
JNK Mitogen-Activated Protein Kinases
Macrophage Activation
Macrophages
Membrane Proteins
Mice
Retinol-Binding Proteins, Plasma
Signal Transduction
Toll-Like Receptor 4
Vitamin A
Biochemistry
Cell Biology
Cellular and Molecular Physiology
Molecular Biology
Metadata
Show full item recordAbstract
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.Source
Mol Cell Biol. 2012 May;32(10):2010-9. doi: 10.1128/MCB.06193-11. Epub 2012 Mar 19. Link to article on publisher's siteDOI
10.1128/MCB.06193-11Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28314PubMed ID
22431523Related Resources
Link to Article in PubMedRights
Copyright © American Society for Microbiology. Publisher PDF posted as allowed by publisher's author rights policy at http://journals.asm.org/site/misc/ASM_Author_Statement.xhtml.
ae974a485f413a2113503eed53cd6c53
10.1128/MCB.06193-11