Hypoxia reduces the response of human adipocytes towards TNFα resulting in reduced NF-κB signaling and MCP-1 secretion

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 (TNF alpha)-induced nuclear factor-kappa B (NF-kappa B) signaling. RESULTS: Using cytokine array and ELISA analysis, we compared the secretion patterns of normoxic and hypoxic (1% O-2) 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-kappa B-related genes, such as growth-regulated oncogene-a, eotaxin and soluble TNF-Receptor1 (TNF-R1) under hypoxia. TNF alpha stimulation of hypoxic adipocytes resulted in a significantly reduced phosphorylation of NF-kappa B and its inhibitor I kappa B alpha compared with normoxic cells. Furthermore, chronic treatment of hypoxic adipocytes with TNF alpha 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 TNF alpha stimulation. CONCLUSION: In conclusion, human primary adipocytes show a basal and TNF alpha-induced reduction of MCP-1 release under hypoxia. This effect may be due to a reduced expression of TNF-R1 and therefore attenuated TNF alpha-induced NF-kappa B signaling. These observations demonstrate a reduced responsiveness of hypoxic adipocytes towards inflammatory stimuli like TNF alpha, which may represent an adaptation process to maintain adipose tissue function under hypoxia and inflammatory conditions.