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.
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http://dx.doi.org/10.1126/sciadv.1501332 | DOI Listing |
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John Ochsner Heart and Vascular Institute, Ochsner Clinical School University of Queensland School of Medicine, New Orleans, LA, USA.
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View Article and Find Full Text PDFJ Mol Model
January 2025
Department of Biochemistry, Faculty of Basic Medical Science, Olabisi Onabanjo University, Sagamu Campus, Ago Iwoye, Ogun State, Nigeria.
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View Article and Find Full Text PDFNaunyn Schmiedebergs Arch Pharmacol
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Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan.
This study aimed to evaluate the comparative efficacy of Myo-inositol (MI) and D-chiro-inositol (DCI) with metformin in enhancing ovarian function, promoting ovulation, and reducing perceived stress in patients with polycystic ovary syndrome (PCOS). Women with PCOS were identified using the Androgen Excess Society's criteria, and 60 participants were enrolled and divided equally into two groups. One group received a 40:1 ratio of MI plus DCI, while the other received metformin for a 12-week period.
View Article and Find Full Text PDFTransl Behav Med
January 2025
University of Pittsburgh School of Public Health, Department of Epidemiology, Pittsburgh, PA, USA.
Background: In previous efforts, health-related quality of life (HRQoL) improved for individuals at high risk of type 2 diabetes and cardiovascular disease after participation in community-based lifestyle interventions (LI) with a moderate-to-vigorous physical activity (MVPA) movement goal.
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Pathophysiology
January 2025
Department of Biochemistry, Osmania University, Hyderabad 500007, India.
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