Key result
Obese omental adipocytes overproduce adipokines in response to TNF-alpha vs lean controls via NF-kappaB hyperactivation.
Why the study?
The molecular mechanisms underlying proinflammatory adipokine overproduction in obesity and the role of TNF-alpha in human obesity remain unsettled.
In obesity, enlarged adipocytes are hyperresponsive to TNF-alpha, leading to adipokine dysregulation via the NF-kappaB pathway.
TNF-α hyperresponsiveness via NF-κB drives adipokine dysregulation in obese adipocytes; leaves open clinical translation and therapeutic targeting.
CONTEXT: 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. DESIGN AND PARTICIPANTS: 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]
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Maury et al. (2009) studied Obesity. TNF-alpha exposure vs. Adipocytes from lean subjects was evaluated on Adipokine expression and NF-kappaB pathway activation. Omental adipocytes from obese subjects overproduced adipokines in response to TNF-alpha compared to lean subjects, a process mediated by hyperactivation of the NF-kappaB pathway.
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