| First Author | van Dierendonck XAMH | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 51 | Pages | 17535-17548 |
| PubMed ID | 33453996 | Mgi Jnum | J:305115 |
| Mgi Id | MGI:6693969 | Doi | 10.1074/jbc.RA120.014868 |
| Citation | van Dierendonck XAMH, et al. (2020) The role of uncoupling protein 2 in macrophages and its impact on obesity-induced adipose tissue inflammation and insulin resistance. J Biol Chem 295(51):17535-17548 |
| abstractText | The development of a chronic, low-grade inflammation originating from adipose tissue in obese subjects is widely recognized to induce insulin resistance, leading to the development of type 2 diabetes. The adipose tissue microenvironment drives specific metabolic reprogramming of adipose tissue macrophages, contributing to the induction of tissue inflammation. Uncoupling protein 2 (UCP2), a mitochondrial anion carrier, is thought to separately modulate inflammatory and metabolic processes in macrophages and is up-regulated in macrophages in the context of obesity and diabetes. Here, we investigate the role of UCP2 in macrophage activation in the context of obesity-induced adipose tissue inflammation and insulin resistance. Using a myeloid-specific knockout of UCP2 (Ucp2(DeltaLysM)), we found that UCP2 deficiency significantly increases glycolysis and oxidative respiration, both unstimulated and after inflammatory conditions. Strikingly, fatty acid loading abolished the metabolic differences between Ucp2(DeltaLysM) macrophages and their floxed controls. Furthermore, Ucp2(DeltaLysM) macrophages show attenuated pro-inflammatory responses toward Toll-like receptor-2 and -4 stimulation. To test the relevance of macrophage-specific Ucp2 deletion in vivo, Ucp2(DeltaLysM) and Ucp2(fl/fl) mice were rendered obese and insulin resistant through high-fat feeding. Although no differences in adipose tissue inflammation or insulin resistance was found between the two genotypes, adipose tissue macrophages isolated from diet-induced obese Ucp2(DeltaLysM) mice showed decreased TNFalpha secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2(fl/fl) littermates. Together, these results demonstrate that although UCP2 regulates both metabolism and the inflammatory response of macrophages, its activity is not crucial in shaping macrophage activation in the adipose tissue during obesity-induced insulin resistance. |
