Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance
Year: 2016
Type: article
Abstract: Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. 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, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.
Source: Science Advances
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,500
Awards: The Role and the Molecular Mechanisms of Homeostatic Inflammation in the Pathophysiology of Cardiac Hypertrophy, Establishment of research fundation of IRF7 on the treatment of obesity and metabolic syndrome, G288563529, G3026919343, Elucidation of molecular mechanism of plaque destabilization and identification of predictable factors for acute coronary syndrome, G3612747087, A novel strategy using radical scavengers against intermittent hypoxia-induced oxidative stress in heart, kidney, and brain, Role of ectopic fat in the mechanism of cardiovascular diseases, A study to elucidate the mechanism by which sterile chronic inflammation occurs in arterial wall and perivascular adipose tissue, The role of TLR9 in the development of insulin resistance, Development of a novel revascularization method to treat diffuse coronary artery diseases with transplantation of artery and adipose tissues, Elucidation of concept of ectopic fat consortium of cardiac fat, ectopic fat and sarcopenia and life-style diseases, G5603067476, Development of therapies for severe ischemic cardiomyopathy to substute heart transplantation, Molecular genetic analysis of atherosclerosis and atrial thrombosis rat model spontaneously induced by hypoactivity, G6192415659, G6351372631, Establishment of a novel therapeutic strategy for atherosclerosis utilizing a focal adhesion adaptor molecule, G7137751853, G7660166471, Visualization of chronic inflammation in arterial wall and perivascular adipose tissue, G8262597823, G8336438666
OpenAlex ID: W2309306045