DNA Debris From Dying Fat Cells Causes Chronic Inflammation

We examined the association between obesity and the release of cfDNA, and investigated the role of cfDNA in macrophage activation and in the development of adipose tissue inflammation and insulin resistance by using a diet-induced obesity model, a bone marrow transplantation (BMT) model, and an in vivo TLR9 inhibition study involving wild-type and TLR9-deficient (Tlr9−/−) mice. Furthermore, we examined cfDNA level in human plasma to show clinically translatable evidence. Our study may provide a novel mechanism for the development of adipose tissue inflammation and a potential therapeutic target for insulin resistance. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9−/−) macrophages. Fat-fed Tlr9−/− mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9−/− mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plas...
Source: Fight Aging! - Category: Research Authors: Tags: Medicine, Biotech, Research Source Type: blogs