Abstract
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 (Ucp2ΔLysM), 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 Ucp2ΔLysM macrophages and their floxed controls. Furthermore, Ucp2ΔLysM 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, Ucp2ΔLysM and Ucp2fl/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 Ucp2ΔLysM mice showed decreased TNFα secretion after ex vivo lipopolysaccharide stimulation compared with their Ucp2fl/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.
Highlights
The occurrence of obesity and related metabolic disturbances, including insulin resistance and development of type 2 diabetes, has risen to epidemic proportions [1, 2]
We compared the regulation of Uncoupling protein 2 (UCP2) in three adipose tissue macrophage models: ATMs isolated from mice fed a high-fat diet (HFD) versus a low-fat diet (LFD) [10]; bone marrow– derived macrophages (BMDMs) co-cultured with obese versus lean adipose tissue; and human adipose tissue macrophages isolated from obese diabetic patients versus obese nondiabetic patients [33] (Fig. 1A and Fig. S1)
These levels likely correspond with the influx of immune cells into the adipose tissue, because increased Ucp2 expression in the adipose tissue of HFD-fed versus LFD-fed (Ctrl) mice is mainly attributable to the stromal vascular fraction, including ATMs, and not to adipocytes (Fig. 1C)
Summary
The occurrence of obesity and related metabolic disturbances, including insulin resistance and development of type 2 diabetes, has risen to epidemic proportions [1, 2]. UCP2 mRNA is widely expressed throughout different tissues in mice, UCP2 protein can only be detected in spleen, lung, stomach, adipose tissue, and isolated immune cells, including macrophages [13,14,15]. Because of its involvement in both immune cell functioning and defining cellular metabolism of glucose versus fatty acids, UCP2 potentially provides an interesting target in elucidating the molecular mechanisms underlying immunometabolic reprogramming and activation of macrophages in the context of obesity-induced adipose tissue inflammation and insulin resistance.
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