title: Inhibitory effect on protein kinase Ctheta by Crocetin attenuates palmitate-induced insulin insensitivity in 3T3-L1 adipocytes.
abstract: Epidemiologic and experimental studies have pointed to an etiologic role of elevated plasma free fatty acids in insulin resistance, which is frequently associated with a state of low-grade inflammation. In this study, we investigated the effects of Crocetin, a unique carotenoid, on insulin resistance induced by palmitate in 3T3-L1 adipocytes. Exposure of palmitate led to an increase in insulin receptor substrate-1 (IRS-1) serine(307) phosphorylation as well as activation of c-Jun NH(2)-terminal kinase (JNK) and inhibitor kappaB kinase beta (IKKbeta), concomitantly with reductions of IRS-1 function and glucose metabolism. Interestingly, pretreatment with Crocetin almost reversed all of these abnormalities in a dose-dependent manner. IRS-1 serine(307) phosphorylation was significantly reduced by JNK or IKKbeta inhibitor, especially by combination of these two inhibitors. Moreover, palmitate treatment induced activation of protein kinase Ctheta (PKCtheta) while blocking PKCtheta significantly inhibited JNK and IKKbeta activation induced by palmitate or phorbol 12-myristate 13-acetate (PKC activator, PMA), and attenuated the palmitate-induced defects in insulin action. Crocetin demonstrated an impressive suppression in the activation of PKCtheta induced not only by palmitate but also by PMA in a dose-dependent manner. Taken together, Crocetin inhibited JNK and IKKbeta activation via suppression of PKCtheta phosphorylation, attenuating insulin insensitivity induced by palmitate in 3T3-L1 adipocytes.
authors.affiliation: Department of Pharmacology, China Pharmaceutical University, 24 Tongjia Xiang, Nanjing 210009, PR China.
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Qian
authors.forename: Hui
authors.initials: H
authors.lastname: Ji
authors.forename: Ruhui
authors.initials: R
authors.lastname: Yang
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Wang
authors.forename: Liang
authors.initials: L
authors.lastname: Xi
authors.forename: Liang
authors.initials: L
authors.lastname: Sheng
authors.forename: Bohua
authors.initials: B
authors.lastname: Zhao
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002338:Carotenoids / Q000494:pharmacology*; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins / Q000737:chemistry / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D051379:Mice; D010168:Palmitates / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D000074121:Protein Kinase C-theta; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014801:Vitamin A / Q000031:analogs & derivatives
chemical_list: D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007527:Isoenzymes; D010168:Palmitates; D047428:Protein Kinase Inhibitors; C487773:trans-sodium crocetinate; D014801:Vitamin A; D002338:Carotenoids; D012694:Serine; D003847:Deoxyglucose; D051550:I-kappa B Kinase; C489593:Prkcq protein, mouse; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; D048031:JNK Mitogen-Activated Protein Kinases; D005947:Glucose