Abstract
Objective:
Obesity is associated with adipose tissue hypoxia, and is thought to be linked to the chronic low-grade inflammation of adipose tissue, although the precise mechanism has remained unclear. In this study, we investigated the effect of a prominent hypoxia on human primary adipocyte secretion and tumor necrosis factor alpha (TNFα)-induced nuclear factor-κB (NF-κB) signaling.
Results:
Using cytokine array and ELISA analysis, we compared the secretion patterns of normoxic and hypoxic (1% O2) adipocytes and observed various alterations in adipokine release. We could reproduce known alterations like an induction of interleukin (IL)-6, vascular endothelial growth factor, leptin and a reduction in adiponectin release under hypoxia. Interestingly, we observed a significant reduction in the secretion of macrophage chemotactic protein (MCP)-1 and other NF-κB-related genes, such as growth-regulated oncogene-α, eotaxin and soluble TNF-Receptor1 (TNF-R1) under hypoxia. TNFα stimulation of hypoxic adipocytes resulted in a significantly reduced phosphorylation of NF-κB and its inhibitor IκBα compared with normoxic cells. Furthermore, chronic treatment of hypoxic adipocytes with TNFα resulted in an expected higher secretion of the chemokines MCP-1 and IL-8, but under hypoxia, the secretion level was substantially lower than that under normoxia. This reduction in protein release was accompanied by a reduced mRNA expression of MCP-1, whereas IL-8 mRNA expression was not altered. Additionally, we observed a significantly reduced expression of the TNF-receptor TNF-R1, possibly being one cause for the reduced responsiveness of hypoxic adipocytes towards TNFα stimulation.
Conclusion:
In conclusion, human primary adipocytes show a basal and TNFα-induced reduction of MCP-1 release under hypoxia. This effect may be due to a reduced expression of TNF-R1 and therefore attenuated TNFα-induced NF-κB signaling. These observations demonstrate a reduced responsiveness of hypoxic adipocytes towards inflammatory stimuli like TNFα, which may represent an adaptation process to maintain adipose tissue function under hypoxia and inflammatory conditions.
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Acknowledgements
This work was supported by the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen, the Bundesministerium für Gesundheit, the Deutsche Forschungsgemeinschaft (SE 1922/2-1), the Commission of the European Communities (Collaborative Project ADAPT, contract number HEALTH-F2-2008–201100) and EU COST Action BM0602. We thank Prof Liebau and her team, Department of Plastic Surgery, Florence-Nightingale-Hospital Düsseldorf, and PD Dr Andree and his team, Department of Plastic Surgery and Breast Reconstruction, Sana Hospital Düsseldorf-Gerresheim, for support in obtaining adipose tissue samples. The secretarial assistance of Birgit Hurow is gratefully acknowledged.
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Famulla, S., Horrighs, A., Cramer, A. et al. Hypoxia reduces the response of human adipocytes towards TNFα resulting in reduced NF-κB signaling and MCP-1 secretion. Int J Obes 36, 986–992 (2012). https://doi.org/10.1038/ijo.2011.200
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DOI: https://doi.org/10.1038/ijo.2011.200
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