Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity

Abstract

R, Rui L. Myeloid cell TRAF3 promotes metabolic inflammation, insulin resistance, and hepatic steatosis in obesity. Am J Physiol Endocrinol Metab 308: E460 -E469, 2015. First published January 27, 2015; doi:10.1152/ajpendo.00470.2014.-Myeloid cells, particularly macrophages, mediate metabolic inflammation, thus promoting insulin resistance and metabolic disease progression in obesity. Numerous cytokines, toxic metabolites, damage-associated molecular patterns, and pathogen-associated molecular patterns are involved in activating macrophages via their cognate receptors in obesity. TRAF3 (TNF receptor-associated factor 3) is a common signaling molecule for these ligands/receptors and negatively regulates the proinflammatory NF-B and MAPK pathways, but its metabolic activity is unknown. We here show that myeloid cell TRAF3 is required for metabolic inflammation and metabolic disease progression in obesity. Myeloid cell-specific deletion of TRAF3 significantly attenuated insulin resistance, hyperglycemia, hyperinsulinemia, glucose intolerance, and hepatic steatosis in mice with either genetic (ob/ob) or high-fat diet (HFD)-induced obesity. Myeloid cell-specific deletion of TRAF3 had the opposite effects on metabolic inflammation between obese and lean mice. It decreased the expression of proinflammatory cytokines in the liver and adipose tissue of obese mice and largely prevented HFD-induced inflammation in these metabolic tissues; by contrast, in lean mice, it increased the expression of proinflammatory cytokines in the liver and adipose tissue. These data suggest that, in obesity progression, myeloid TRAF3 functionally switches its activity from anti-inflammatory to proinflammatory modes, thereby coupling overnutrition to metabolic inflammation, insulin resistance, and metabolic disease. metabolic inflammation; TRAF3; obesity; insulin resistance; steatosis

TRAF3 deficiency promotes metabolic reprogramming in B cells

“…More recent work showed that hepatocyte-specific TRAF3 deletion protects mice from insulin resistance and hepatic steatosis3738. Interestingly, analogous results were found with myeloid-specific TRAF3 deletion39. B cells have also been shown to promote inflammation in obesity-induced Type 2 diabetes40.…”

Interferon Regulatory Factor Signalings in Cardiometabolic Diseases

“…198 Previous investigations have indicated that liver-specific TRAF2-KO mice exhibited attenuated diet-induced hyperglycemia compared with controls through the inactivation of glucagon signaling; however, the deficiency of TRAF2 in the liver was not sufficient to significantly influence the HFD-induced inflammatory response or insulin sensitivity. 199 Most recently, Chen et al 200 reported that TRAF3 in myeloid cells is essential for the development of metabolic disorders, as evidenced by the finding that the myeloid cell-specific deficiency of TRAF3 dramatically reduced genetic (ob/ob) or HFD-induced insulin resistance, glucose intolerance, hepatic steatosis, and obesity resulting from its powerful capacity to regulate inflammatory responses. Although TRAFs are positive regulators of IRF activation, to the best of our knowledge, there is no evidence about the involvement of IRFs in TRAF-regulated metabolic dysfunction.…”

Neuron-Specific Tumor Necrosis Factor Receptor–Associated Factor 3 Is a Central Regulator of Neuronal Death in Acute Ischemic Stroke

“…10 Until recently, TRAF3 was thought to be involved mainly in the regulation of the alternative, but not the canonical, NF-κB pathway; However, Perez de Diego et al 5,8 recently showed that R118W-mutant TRAF3 was responsible for the impaired TLR-induced nuclear translocation of the NF-κB p65 subunit in-transformed human fibroblasts. More recently, Chen et al 31 reported that myeloid TRAF3 promotes metabolic inflammation by switching from an anti-inflammatory factor to a proinflammatory one. The underlying mechanism and functional significance of TRAF3-mediated canonical NF-κB signaling, however, remain largely unknown.…”