TNF-α represses β-Klotho expression and impairs FGF21 action in adipose cells: involvement of JNK1 in the FGF21 pathway.
Fibroblast growth factor 21 (FGF21) is a member of the FGF family that reduces glycemia and ameliorates insulin resistance. Adipose tissue is a main target of FGF21 action. Obesity is associated with a chronic proinflammatory state. Here, we analyzed the role of proinflammatory signals in the FGF21 pathway in adipocytes, evaluating the effects of TNF-α on β-Klotho and FGF receptor-1 expression and FGF21 action in adipocytes. We also determined the effects of rosiglitazone on β-Klotho and FGF receptor-1 expression in models of proinflammatory signal induction in vitro and in vivo (high-fat diet-induced obesity). Because c-Jun NH(2)-terminal kinase 1 (JNK1) serves as a sensing juncture for inflammatory status, we also evaluated the involvement of JNK1 in the FGF21 pathway. TNF-α repressed β-Klotho expression and impaired FGF21 action in adipocytes. Rosiglitazone prevented the reduction in β-Klotho expression elicited by TNF-α. Moreover, β-Klotho levels were reduced in adipose tissue from high-fat diet-induced obese mice, whereas rosiglitazone restored β-Klotho to near-normal levels. β-Klotho expression was increased in white fat from JNK1(-/-) mice. The absence of JNK1 increased the responsiveness of mouse embryonic fibroblast-derived adipocytes and brown adipocytes to FGF21. In conclusion, we show that proinflammatory signaling impairs β-Klotho expression and FGF21 responsiveness in adipocytes. We also show that JNK1 activity is involved in modulating FGF21 effects in adipocytes. The impairment in the FGF21 response machinery in adipocytes and the reduction in FGF21 action in response to proinflammatory signals may play important roles in metabolic alterations in obesity and other diseases associated with enhanced inflammation.
Department of Biochemistry and Molecular Biology, University of Barcelona, Avda Diagonal 643, 08028-Barcelona, Spain. diazdelfin_j@yahoo.com
Julieta
J
Díaz-Delfín
Elayne
E
Hondares
Roser
R
Iglesias
Marta
M
Giralt
Carme
C
Caelles
Francesc
F
Villarroya
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D000090265:Klotho Proteins; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
C538995:KLB protein, human; C418622:Klb protein, mouse; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D048055:Mitogen-Activated Protein Kinase 8; D000090265:Klotho Proteins