PMID- 11342529
OWN - NLM
STAT- MEDLINE
DCOM- 20010809
LR  - 20220408
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 276
IP  - 27
DP  - 2001 Jul 6
TI  - Leptin induces mitochondrial superoxide production and monocyte chemoattractant 
      protein-1 expression in aortic endothelial cells by increasing fatty acid 
      oxidation via protein kinase A.
PG  - 25096-100
AB  - 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.
FAU - Yamagishi, S I
AU  - Yamagishi SI
AD  - Department of Medicine, Diabetes Research Center, Albert Einstein College of 
      Medicine, Bronx, NY 10461, USA.
FAU - Edelstein, D
AU  - Edelstein D
FAU - Du, X L
AU  - Du XL
FAU - Kaneda, Y
AU  - Kaneda Y
FAU - Guzman, M
AU  - Guzman M
FAU - Brownlee, M
AU  - Brownlee M
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, P.H.S.
DEP - 20010507
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (Carrier Proteins)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Fatty Acids)
RN  - 0 (Ion Channels)
RN  - 0 (Isoquinolines)
RN  - 0 (Leptin)
RN  - 0 (Liposomes)
RN  - 0 (Membrane Proteins)
RN  - 0 (Metalloporphyrins)
RN  - 0 (Mitochondrial Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Sulfonamides)
RN  - 0 (UCP1 protein, human)
RN  - 0 (Uncoupling Protein 1)
RN  - 0 (manganese(III)-tetrakis(4-benzoic acid)porphyrin)
RN  - 03L9OT429T (Rotenone)
RN  - 11062-77-4 (Superoxides)
RN  - 326-91-0 (Thenoyltrifluoroacetone)
RN  - 555-60-2 (Carbonyl Cyanide m-Chlorophenyl Hydrazone)
RN  - DH2M523P0H (Genistein)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 2.7.11.11 (Cyclic AMP-Dependent Protein Kinases)
RN  - EC 6.4.1.2 (Acetyl-CoA Carboxylase)
RN  - IY9XDZ35W2 (Glucose)
RN  - M876330O56 (N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide)
SB  - IM
MH  - Acetyl-CoA Carboxylase/antagonists & inhibitors
MH  - Animals
MH  - Carbonyl Cyanide m-Chlorophenyl Hydrazone/pharmacology
MH  - Carrier Proteins/pharmacology
MH  - Cattle
MH  - Cells, Cultured
MH  - Chemokine CCL2/*biosynthesis
MH  - Cyclic AMP-Dependent Protein Kinases/*metabolism
MH  - Dose-Response Relationship, Drug
MH  - Electron Transport
MH  - Endothelium, Vascular/*metabolism
MH  - Fatty Acids/*metabolism
MH  - Genistein/pharmacology
MH  - Glucose/pharmacology
MH  - Humans
MH  - Ion Channels
MH  - Isoquinolines/pharmacology
MH  - Leptin/administration & dosage/*pharmacology
MH  - Liposomes
MH  - Membrane Proteins/pharmacology
MH  - Metalloporphyrins/pharmacology
MH  - Mitochondria/drug effects/*metabolism
MH  - Mitochondrial Proteins
MH  - Oxidation-Reduction
MH  - Reactive Oxygen Species/metabolism
MH  - Rotenone/pharmacology
MH  - *Sulfonamides
MH  - Superoxide Dismutase/metabolism
MH  - Superoxides/*metabolism
MH  - Thenoyltrifluoroacetone/pharmacology
MH  - Uncoupling Protein 1
EDAT- 2001/05/09 10:00
MHDA- 2001/08/10 10:01
CRDT- 2001/05/09 10:00
PHST- 2001/05/09 10:00 [pubmed]
PHST- 2001/08/10 10:01 [medline]
PHST- 2001/05/09 10:00 [entrez]
AID - S0021-9258(20)79589-X [pii]
AID - 10.1074/jbc.M007383200 [doi]
PST - ppublish
SO  - J Biol Chem. 2001 Jul 6;276(27):25096-100. doi: 10.1074/jbc.M007383200. Epub 2001 
      May 7.