DNASE1L3 role in obesity-mediated inflammation and metabolic syndrome – DOMINOS

Obesity is a global health problem affecting 13% of the world population. There are multiple complications associated with obesity, including metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, atherosclerosis and ischemic cardiovascular disease. These complications account for most of the morbidity caused by obesity, severely impact obese patients’ quality of life and represent a major economic burden on health care systems. The development of metabolic syndrome and complications associated with obesity is attributed to the resulting chronic low-grade inflammation in metabolic tissues such as the liver and the white adipose tissue. In recent years, obesity was reported to induce a systemic accumulation of cell-free self-DNA that positively correlates with disease severity. This cell-free self-DNA aberrantly activates innate immune responses by stimulating DNA sensing pathways and thus contributes to metabolic tissue inflammation and ultimately to the development of obesity-associated metabolic syndrome. However, the form and the source of this accumulating cell-free self-DNA and how its abundance and immunogenicity is regulated during obesity remains unknown.
We previously characterized a nuclease called DNASE1L3, which primarily functions to digest various sources of extracellular cell-free self-DNA, particularly DNA associated to microparticles released by dying cells. Consequently, DNASE1L3 restricts self-DNA accumulation, its ability to aberrantly activate immune responses, and thus prevents the development of systemic autoimmunity. Given the function of DNASE1L3 in mediating tolerance to self-DNA, we investigated its role in the development of metabolic syndrome induced by obesity. Our preliminary results suggest that deficiency in DNASE1L3 exacerbates weight gain, glucose intolerance and insulin resistance in mice that were fed a high-fat diet. These observations position DNASE1L3 as an important player in the regulation of obesity-mediated metabolic syndrome, and thus further investigation of its function in this pathological context is warranted. We propose to first confirm and expand the study of the impact of DNASE1L3 deficiency on obesity-mediated pathogenesis and to address DNASE1L3 function in the regulation of metabolic tissue inflammation and cell-free self-DNA distribution during obesity. In parallel, we will evaluate the relevance of DNASE1L3 in obese patients, by quantifying its activity in the circulation and dissecting the impact of DNASE1L3 modulations on cell-free self-DNA levels and obese patients’ clinical outcomes. Finally, we will define the cellular and molecular mechanisms of DNASE1L3 in the regulation of cell-free self-DNA availability and immunogenicity during obesity and address the therapeutic impact of DNASE1L3 supplementation on the development of metabolic syndrome induced by obesity. Therefore, the proposed work may lead to the identification of an entirely novel pathogenic loop at play in obesity-mediated metabolic syndrome and contribute to the development of much needed novel therapeutic avenues for obese patients, based on “boosting” DNASE1L3 potential to limit the detrimental accumulation and immunogenicity of self-DNA.