In vitro hyperresponsiveness to tumor necrosis factor-alpha contributes to adipokine dysregulation in omental adipocytes of obese subjects.
BACKGROUND
In obesity, adipocyte hypertrophy and macrophage infiltration lead to overproduction of proinflammatory adipokines, which play a crucial role in the metabolic syndrome. The molecular mechanisms underlying this overproduction are still unsettled. The role of TNF-alpha also remains controversial in human obesity.


OBJECTIVE
We revisited the contribution of TNF-alpha to adipokine dysregulation in central obesity. We more particularly assessed the involvement of TNF-alpha vs. other stromal-vascular cell (SVC)-secreted factors and searched for potential differential responses to TNF-alpha between adipocytes of lean and obese individuals.


METHODS
Primary cultures of omental adipocytes from obese and nonobese age- and sex-matched subjects were used. For some experiments, we generated media previously conditioned by SVCs, which mimic adipocyte microenvironment.


RESULTS
Adipocytes of obese subjects mainly overexpressed adipokines, in comparison with those of lean ones, when cultured in SVC-conditioned media. This was abrogated by immunoneutralization of TNF-alpha, indicating that among the numerous factors secreted by SVCs, TNF-alpha is a crucial contributor to adipokine dysregulation. Accordingly, adipocytes of obese subjects overproduced adipokines in response to direct exposure of TNF-alpha. This hyperresponsiveness was mediated by TNF-alpha receptor 1 and hyperactivation of the nuclear factor-kappaB (NF-kappaB) pathway. Correspondingly, NF-kappaB activity was increased in adipocytes of obese subjects and correlated with adipocyte size, adipokine expression, and in vivo insulin resistance. Eventually adipokine overexpression in adipocytes of obese subjects was prevented by NF-kappaB inhibitors.


CONCLUSIONS
In obesity, TNF-alpha that is [corrected] over other SVC-secreted factors, a crucial determinant of adipokine dysregulation acts on enlarged adipocytes, which are hyperresponsive to this triggering signal [corrected]
Maury
Eléonore
E
Faculty of Medicine, University of Louvain, Brussels, Belgium.
Noël
Laurence
L
Detry
Roger
R
Brichard
Sonia M
SM
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D054392:Adipokines / Q000097:blood*; D052242:Adiponectin / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D002097:C-Reactive Protein / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D006801:Humans; D007328:Insulin / Q000097:blood; D020738:Leptin / Q000097:blood; D008297:Male; D009765:Obesity / Q000378:metabolism*; D009852:Omentum / Q000378:metabolism*; D012016:Reference Values; D013851:Thinness / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*
D054392:Adipokines; D052242:Adiponectin; D001786:Blood Glucose; D008078:Cholesterol, LDL; D007328:Insulin; D020738:Leptin; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein