Leptin induces tissue factor expression in human peripheral blood mononuclear cells: a possible link between obesity and cardiovascular risk?
BACKGROUND
Obesity is a major modifiable risk factor for cardiovascular disease. Leptin, the hormone synthesized and released primarily by adipose tissue and found increased in obese individuals, has been implicated in the regulation of inflammation and arterial and venous thrombosis.


OBJECTIVE
To investigate the role of tissue factor (TF), the pivotal agonist of the clotting cascade, as a link between obesity and cardiovascular disease.


RESULTS
In 15 obese patients, plasma levels of leptin and TF as well as TF expression in resting and endotoxin-stimulated mononuclear leukocytes (MN) were increased when compared with healthy donors. In a selected sample of obese patients, loss of body weight led to decreased circulating leptin levels, accompanied by a reduction in plasma TF as well as in TF expression, both in resting and endotoxin-stimulated MN. In subsequent in vitro experiments, leptin was incubated with MN from healthy subjects. Leptin induced TF activity and antigen in a dose-dependent fashion, as assessed by clotting assay and ELISA, respectively. Increased migration of c-Rel/p65 into the nucleus, as determined by EMSA, and development of TF mRNA in monocytes, as assessed by RT-PCR, were observed. Experiments with mitogen-activated protein kinase (MAPK) inhibitors, indicated the involvement of p38 and ERK1/2 pathways.


CONCLUSIONS
The presence of TF-expressing MN in blood from obese subjects and the in vitro induction of TF by pharmacologic concentrations of leptin in MN from healthy subjects suggest that TF expression by leptin-stimulated monocytes may contribute to the cardiovascular risk associated with obesity.
Napoleone
E
E
Centro Giovanni Paolo II di Ricerche e Formazione ad Alta Tecnologia nelle Scienze Biomediche, Università Cattolica, Campobasso, Italy.
DI Santo
A
A
Amore
C
C
Baccante
G
G
di Febbo
C
C
Porreca
E
E
de Gaetano
G
G
Donati
M B
MB
Lorenzet
R
R
D002318:Cardiovascular Diseases / Q000097:blood / Q000209:etiology* / Q000378:metabolism*; D019281:Dimerization; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D020738:Leptin / Q000378:metabolism / Q000502:physiology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D009765:Obesity / Q000097:blood / Q000150:complications* / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000737:chemistry / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D051996:Transcription Factor RelA / Q000737:chemistry / Q000378:metabolism
D020738:Leptin; D020569:Proto-Oncogene Proteins c-rel; C498143:RELA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D013925:Thromboplastin