Inflammatory Pathways Regulated By Tumor-Necrosis Receptor Associated Factor 1 Protect From Metabolic Consequences In Diet-Induced Obesity
Rationale: The co-incidence of inflammation and metabolic derangements in obese adipose tissue has sparked the concept of met-inflammation. Previous observations, however, suggest that inflammatory pathways may not ultimately cause dysmetabolism.
Objective: We have revisited the relationship between inflammation and metabolism by testing the role of Tumor-Necrosis Receptor associated Factor (TRAF)-1, an inhibitory adapter of inflammatory signaling of TNFα, IL-1β, and TLRs.
Methods and Results: Mice deficient for TRAF-1, which is expressed in obese adipocytes and adipose tissue lymphocytes, caused an expected hyper-inflammatory phenotype in adipose tissue with enhanced adipokine and chemokine expression, increased leukocyte accumulation, and potentiated pro-inflammatory signaling in macrophages and adipocytes in a mouse model of diet-induced obesity (DIO). Unexpectedly, however, TRAF-1-/- mice were protected from metabolic derangements and adipocyte growth, failed to gain weight, and showed improved insulin resistance - an effect caused by increased lipid breakdown in adipocytes and UCP-1-enabled thermogenesis. TRAF-1-dependent catabolic and pro-inflammatory cues were synergistically driven by β3-adrenergic and inflammatory signaling, and required the presence of both, TRAF-1-deficient adipocytes and macrophages. In human obesity, TRAF-1-dependent genes were upregulated.
Conclusions: Enhancing TRAF-1 dependent inflammatory pathways in a gain-of-function approach protected from metabolic derangements in DIO. These findings identify TRAF-1 as a regulator of dysmetabolism in mice and humans and question the pathogenic role of chronic inflammation in metabolism.
- Received September 12, 2017.
- Revision received January 17, 2018.
- Accepted January 19, 2018.