title: Endothelin-1 stimulates resistin gene expression.
abstract: Resistin and endothelin (ET)-1 have been reported to inhibit adipogenesis and regulate adipocyte insulin resistance, respectively. Although both hormones interact with each other, the exact signaling pathway of ET-1 to act on resistin gene expression is still unknown. Using 3T3-L1 adipocytes, we investigated the signaling pathways involved in ET-1-stimulated resistin gene expression. The up-regulation of resistin mRNA expression by ET-1 depends on concentration and timing. The concentration of ET-1 that increased resistin mRNA levels by 100%-250% was approximately 100 nM for a range of 0.25-12 hours of treatment. Treatment with actinomycin D blocked ET-1-increased resistin mRNA levels, suggesting that the effect of ET-1 requires new mRNA synthesis. Treatment with an inhibitor of the ET type-A receptor, such as N-[1-Formyl-N-[N-[(hexahydro-1H-azepin-1-yl)carbonyl]-L-leucyl]-D-tryptophyl]-D-tryptophan (BQ610), but not with the ET type-B receptor antagonist N-[(cis-2,6-Dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-leucyl-1-(methoxycarbonyl)-D-tryptophyl-D-norleucine (BQ788), blocked ET-1, increased the levels of resistin mRNA, and phosphorylated levels of downstream signaling molecules, such as ERK1/2, c-Jun N-terminal kinases (JNKs), protein kinase B (AKT), and signal transducer and activator of transcription 3 (STAT3). Moreover, pretreatment of specific inhibitors of either ERK1/2 (1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene [U0126] and 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one [PD98059], two inhibitors of MEK1), JNKs (SP600125), phosphatidylinositol 3-kinase/AKT (LY294002 and Wortmannin), or Janus kinase 2 (JAK2)/STAT3 ((E)-2-Cyano-3-(3,4-dihydrophenyl)-N-(phenylmethyl)-2-propenamide, AG490) prevented ET-1-increased levels of resistin mRNA and reduced the ET-1-stimulated phosphorylation of ERK1/2, JNKs, AKT, and STAT3, respectively. However, the p38 kinase antagonist 4-[5-(4-Fluorophenyl)-2-[4-(methylsulfonyl)phenyl]-1H-imidazol-4-yl]pyridine (SB203580) did not alter the effect of ET-1. These results imply that ET type-A receptor, ERK1/2, JNKs, AKT, and JAK2, but not ET type-B receptor or p38, are necessary for the ET-1 stimulation of resistin gene expression. In vivo observations that ET-1 increased resistin mRNA and protein levels in sc and epididymal adipose tissues support the in vitro findings.
authors.affiliation: Department of Life Sciences (Y.-C.T., C.-W.L., H.-H.C., Y.-H.K.), National Central University, Jhongli, Taoyuan 32001, Taiwan; Department and Institute of Physiology (C.-C.J.), National Yang Ming University, Taipei 11221, Taiwan; Division of Gastroenterology (Y.-C.K.), Department of Internal Medicine, Taiwan Landseed Hospital, Taoyuan 32449, Taiwan; and Department of Emergency (C.-C.K., Y.-M.H.), Armed Forces Taoyuan General Hospital, Taoyuan 32551, Taiwan.
authors.forename: Ya-Chu
authors.initials: YC
authors.lastname: Tang
authors.forename: Chi-Wei
authors.initials: CW
authors.lastname: Liu
authors.forename: Hsin-Huei
authors.initials: HH
authors.lastname: Chang
authors.forename: Chi-Chang
authors.initials: CC
authors.lastname: Juan
authors.forename: Yow-Chii
authors.initials: YC
authors.lastname: Kuo
authors.forename: Chung-Cheng
authors.initials: CC
authors.lastname: Kao
authors.forename: Yao-Ming
authors.initials: YM
authors.lastname: Huang
authors.forename: Yung-Hsi
authors.initials: YH
authors.lastname: Kao
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000378:metabolism; D000730:Androstadienes / Q000737:chemistry; D000818:Animals; D000873:Anthracenes / Q000737:chemistry; D002070:Butadienes / Q000737:chemistry; D002867:Chromones / Q000737:chemistry; D003609:Dactinomycin / Q000378:metabolism; D019332:Endothelin-1 / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000737:chemistry; D009570:Nitriles / Q000737:chemistry; D009842:Oligopeptides / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D052243:Resistin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D020032:Tyrphostins / Q000737:chemistry; D000077191:Wortmannin
chemical_list: D000730:Androstadienes; D000873:Anthracenes; D002070:Butadienes; D002867:Chromones; D019332:Endothelin-1; D005419:Flavonoids; D009025:Morpholines; D009570:Nitriles; D009842:Oligopeptides; D010880:Piperidines; D052243:Resistin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D020032:Tyrphostins; C113580:U 0126; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D003609:Dactinomycin; C432165:pyrazolanthrone; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C086539:BQ 788; D051057:Proto-Oncogene Proteins c-akt; D048670:MAP Kinase Kinase 4; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin