title: Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A.
abstract: Leptin, a circulating hormone secreted mainly from adipose tissues, is involved in the control of body weight. The plasma concentrations are correlated with body mass index, and are reported to be high in patients with insulin resistance, which is one of the major risk factors for cardiovascular disease. However, the direct effect of leptin on vascular wall cells is not fully understood. In this study, we investigated the effects of leptin on reactive oxygen species (ROS) generation and expression of monocyte chemoattractant protein-1 (MCP-1) in bovine aortic endothelial cells (BAEC). We found that leptin increases ROS generation in BAEC in a dose-dependent manner and that its effects are additive with those of glucose. Rotenone, thenoyltrifluoroacetone (TTFA), carbonyl cyanide m-chlorophenylhydrazone (CCCP), Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP), uncoupling protein-1 (UCP1) HVJ-liposomes, or manganese superoxide dismutase (MnSOD) HVJ-liposomes completely prevented the effect of leptin, suggesting that ROS arise from mitochondrial electron transport. Leptin increased fatty acid oxidation by stimulating the activity of carnitine palmitoyltransferase-1 (CPT-1) and inhibiting that of acetyl-CoA carboxylase (ACC), pace-setting enzymes for fatty acid oxidation and synthesis, respectively. Leptin-induced ROS generation, CPT-1 activation, ACC inhibition, and MCP-1 overproduction were found to be completely prevented by either genistein, a tyrosine kinase inhibitor, H-89, a protein kinase A (PKA) inhibitor, or tetradecylglycidate, a CPT-1 inhibitor. Leptin activated PKA, and the effects of leptin were inhibited by the cAMP antagonist Rp-cAMPS. These results suggest that leptin induces ROS generation by increasing fatty acid oxidation via PKA activation, which may play an important role in the progression of atherosclerosis in insulin-resistant obese diabetic patients.
authors.affiliation: Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Yamagishi
authors.forename: D
authors.initials: D
authors.lastname: Edelstein
authors.forename: X L
authors.initials: XL
authors.lastname: Du
authors.forename: Y
authors.initials: Y
authors.lastname: Kaneda
authors.forename: M
authors.initials: M
authors.lastname: Guzmán
authors.forename: M
authors.initials: M
authors.lastname: Brownlee
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors; D000818:Animals; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone / Q000494:pharmacology; D002352:Carrier Proteins / Q000494:pharmacology; D002417:Cattle; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000096:biosynthesis*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport; D004730:Endothelium, Vascular / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D019833:Genistein / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007473:Ion Channels; D007546:Isoquinolines / Q000494:pharmacology; D020738:Leptin / Q000008:administration & dosage / Q000494:pharmacology*; D008081:Liposomes; D008565:Membrane Proteins / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D024101:Mitochondrial Proteins; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D013449:Sulfonamides; D013482:Superoxide Dismutase / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism*; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology; D000071256:Uncoupling Protein 1
chemical_list: D002352:Carrier Proteins; D018932:Chemokine CCL2; D005227:Fatty Acids; D007473:Ion Channels; D007546:Isoquinolines; D020738:Leptin; D008081:Liposomes; D008565:Membrane Proteins; D008665:Metalloporphyrins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; D013449:Sulfonamides; C000604371:UCP1 protein, human; D000071256:Uncoupling Protein 1; C097284:manganese(III)-tetrakis(4-benzoic acid)porphyrin; D012402:Rotenone; D013481:Superoxides; D013804:Thenoyltrifluoroacetone; D002258:Carbonyl Cyanide m-Chlorophenyl Hydrazone; D019833:Genistein; D013482:Superoxide Dismutase; D017868:Cyclic AMP-Dependent Protein Kinases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide