Introduction: Cardiovascular disease and its predisposing metabolic risk factors are accompanied by a chronic inflammatory response in the vasculature and adipose tissue. Tumor necrosis factor receptor-associated factor 5 (TRAF-5) is a potent modulator of anti-inflammatory signaling events that protect from atherosclerosis. Here, we aimed to interrogate whether TRAF-5 signaling has the potential to modulate cardiovascular inflammation already at the level of metabolic risk factors and adipose tissue in a murine model of diet-induced obesity (DIO).

Approach: Traf5-deficient (Traf5^−/−)and competent (Wt) mice were fed a high-fat diet (HFD) for 18 weeks to induce obesity. Metabolic and inflammatory phenotypes were characterized by insulin and glucose tolerance testing, plasma analysis, body MRI imaging, metabolic caging, western blotting, flow cytometry, FACS-Sorting, qPCR, ELISA, CBA and histology. A model of selective hematopoietic Traf5-deficiency was generated by bone marrow transplantation. To assess a potential significance of our findings for human disease, we studied TRAF5-expression in isolated adipocytes and blood samples of patients with or without a diagnosis of obesity or metabolic syndrome respectively as well as TRAF5-expression in abdominal subcutaneous adipose tissue of patients before and one year after undergoing bariatric surgery.

Results: Traf5^−/−mice on HFD gained significantly more weight compared to Wt mice and showed aggravated metabolic complications under a high-fat diet. The unproportioned weight gain in Traf5^-/-mice was caused by a selective expansion of adipose and liver tissue, while lean tissue mass and growth were not affected. Analysis of the visceral adipose tissue (VAT) revealed a pro-inflammatory milieu in Traf5^−/−mice with more macrophage-bearing crown-like-structures, increased JNK phosphorylation and amplified expression of inflammatory cytokines. We observed enhanced accumulation of pro-inflammatory leukocytes in visceral adipose tissue of Traf5^−/−mice. Surprisingly, selective hematopoietic Traf5-deficiency did not resemble the obese and inflammatory phenotype of global Traf5^−/−mice. Conversely, Traf5-deficient adipocytes, but not FACS-sorted leukocytes, expressed higher levels of TNFα and several chemokines. In obese mice, Traf5 was most downregulated in adipocytes, suggesting an adipocyte-dependent effect. In human disease, TRAF5 expression was decreased in blood and adipocytes from patients with a diagnosis of metabolic syndrome or obesity respectively, compared with controls. In addition, TRAF5 expression in abdominal subcutaneous adipose tissue increased one year after bariatric surgery, indicating that a higher TRAF5 expression associates with a more healthy adipose tissue status. 

Conclusion: We show that a genetic deficiency of Traf5 aggravates DIO and its metabolic consequences in mice. Enhanced accumulation of leukocytes in visceral adipose tissue caused by inflammation in adipocytes serves as the likely mechanism. Our data indicate that restoring TRAF5-signaling properties in adipocytes may favorably affect cardiometabolic disease.