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In Vitro Hyperresponsiveness to Tumor Necrosis Factor- Contributes to Adipokine Dysregulation in Omental Adipocytes of Obese Subjects

Endocrinology and Metabolism (E.M., L.N., S.M.B.) and Surgery Units (R.D.), Faculty of Medicine, University of Louvain, B-1200 Brussels, Belgium

Address all correspondence and requests for reprints to: S. M. Brichard, Unité d’Endocrinologie et Métabolisme, Université Catholique de Louvain/Unité d’Endocrinologie et Metabolisme 5530 Avenue Hippocrate 55, B-1200 Brussels, Belgium. E-mail: sonia.brichard{at}uclouvain.be.

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- also remains controversial in human obesity.

Objective: We revisited the contribution of TNF- to adipokine dysregulation in central obesity. We more particularly assessed the involvement of TNF- vs. other stromal-vascular cell (SVC)-secreted factors and searched for potential differential responses to TNF- 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-, indicating that among the numerous factors secreted by SVCs, TNF- is a crucial contributor to adipokine dysregulation. Accordingly, adipocytes of obese subjects overproduced adipokines in response to direct exposure of TNF-. This hyperresponsiveness was mediated by TNF- receptor 1 and hyperactivation of the nuclear factor-B (NF-B) pathway. Correspondingly, NF-B 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-B inhibitors.

Conclusions: In obesity, TNF-, i.e. over other SVC-secreted factors, a crucial determinant of adipokine dysregulation acts on enlarged adipocytes, which are hyperresponsive to this triggering signal. This ultimately exacerbates adipokine production, inflammation, and the metabolic syndrome.