Is leptin involved in phagocytic NADPH oxidase overactivity in obesity? Potential clinical implications.
OBJECTIVE
Hyperleptinemia and oxidative stress play a major role in the development of cardiovascular diseases in obesity. This study aimed to investigate whether there is a relationship between plasma levels of leptin and phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, and its potential relevance in the vascular remodeling in obese patients.


METHODS
The study was performed in 164 obese and 94 normal-weight individuals (controls). NADPH oxidase activity was evaluated by luminescence in phagocytic cells. Levels of leptin were quantified by ELISA in plasma samples. Carotid intima-media thickness (cIMT) was measured by ultrasonography. In addition, we performed in-vitro experiments in human peripheral blood mononuclear cells and murine macrophages.


RESULTS
Phagocytic NADPH oxidase activity and leptin levels were enhanced (P < 0.05) in obese patients compared with controls. NADPH oxidase activity positively correlated with leptin in obese patients. This association remained significant in a multivariate analysis. cIMT was higher (P < 0.05) in obese patients compared with controls. In addition, cIMT also correlated positively with leptin and NADPH oxidase activity in obese patients. In-vitro studies showed that leptin induced NADPH oxidase activation. Inhibition of the leptin-induced NADPH oxidase activity by wortmannin and bisindolyl maleimide suggested a direct involvement of the phosphatidylinositol 3-kinase and protein kinase C pathways, respectively. Finally, leptin-induced NADPH oxidase activation promoted macrophage proliferation.


CONCLUSIONS
These findings show that phagocytic NADPH oxidase activity is increased in obesity and is related to preclinical atherosclerosis in this condition. We also suggest that hyperleptinemia may contribute to phagocytic NADPH oxidase overactivity in obesity.
Fortuño
Ana
A
Division of Cardiovascular Sciences, Centre for Applied Medical Research, Pamplona, Spain. afortuno@unav.es
Bidegain
Julen
J
Baltanás
Ana
A
Moreno
María U
MU
Montero
Laura
L
Landecho
Manuel F
MF
Beloqui
Oscar
O
Díez
Javier
J
Zalba
Guillermo
G
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D016022:Case-Control Studies; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D020738:Leptin / Q000097:blood* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D008875:Middle Aged; D019255:NADPH Oxidases / Q000097:blood*; D009765:Obesity / Q000097:blood* / Q000150:complications / Q000201:enzymology* / Q000473:pathology; D018384:Oxidative Stress; D010586:Phagocytes / Q000201:enzymology; D013481:Superoxides / Q000097:blood; D017539:Tunica Intima / Q000473:pathology
D020738:Leptin; D013481:Superoxides; D019255:NADPH Oxidases