Abstract 18139: Genetic Deficiency of Traf-1 Attenuates Diet-Induced Adipose Tissue Inflammation by Limiting the Pool of Circulating and Splenic Monocytes in Mice
Background: Accumulation of inflammatory leukocytes, such as of macrophages, is a prerequisite of adipose tissue inflammation during the metabolic syndrome. We recently reported that genetic deficiency of Tumor necrosis factor receptor-associated factor (TRAF) -1 attenuated inflammatory cell recruitment in atherosclerosis. Here, we tested the hypothesis that TRAF-1 deficiency modulates adipose tissue inflammation in a model of diet-induced obesity (DIO) in mice.
Methods and Results: To test the association of TRAFs and adipose tissue inflammation we screened for expression of different TRAFs in mouse adipose tissue after 20 weeks of feeding with a high fat (HFD) or a control diet. HFD induced up-regulation of TRAF-1, -3, -5, -6, and -7 mRNA. Interestingly, the amplitude of gene regulation was highest for TRAF-1 (4.9-fold, n=8 per group, p=0.002). Also, in human subcutaneous tissue TRAF-1 gene expression correlated with body mass index of donors (r=0.94, p=0.019). To test functional relevance of our findings, WT or TRAF-1-/- mice consumed HFD for 12 weeks (n ≥ 10 mice per group). Interestingly, TRAF-1-/- mice gained less weight during DIO (119 ± 7.5 % vs. 41 ± 3.7 % of starting body weight for WT and TRAF-1-/-, respectively). Accordingly, total body weight, weight of visceral and cardiac fat pads was decreased in TRAF-1-/- mice. Moreover, TRAF-1-/- mice demonstrated lower glucose levels after starving and during weight-adapted intraperitoneal glucose and insulin tolerance tests, suggesting functional involvement of TRAF-1 in insulin and glucose signaling. Finally, inflammatory cell recruitment was impaired in TRAF-1-/- mice with reduced numbers of adipose tissue macrophages. Functionally, circulating and splenic, but not bone marrow monocytes were lowered in TRAF-1-/- mice, proposing that TRAF-1 modulates monocyte mobilization during inflammation.
Conclusion: We present the novel finding that TRAF-1 is regulated in obese murine and human adipose tissue. Genetic deficiency of TRAF-1 attenuates adipose tissue inflammation in mice by limiting monocyte recruitment. These findings identify TRAF-1 as a potent mediator at the interface of cardiovascular and metabolic disease.
- © 2013 by American Heart Association, Inc.