Netrin-1 in obesity-associated inflammation and metabolic dysfunction

点击翻译按钮获取中文摘要

Obesity and its comorbidities, such as insulin resistance, type 2 diabetes and cardiovascular diseases, have dramatically increased over the past decades and are major threats to global health. Chronic inflammation in obesity is mediated by accumulation and retention of proinflammatory monocytes in the adipose tissue. While in lean mice and humans adipose tissue macrophages are mainly anti-inflammatory alternatively activated M2-macrophages, which maintain the insulin sensitivity of adipocytes by the secretion of IL-10, adipose tissue of obese is dominated by pro-inflammatory M1 macrophages contributing to the onset and the persistence of local and systemic chronic inflammation. These actively retained M1 macrophages are a key pathogenic link between obesity and its metabolic sequels. The neuronal guidance protein netrin-1 has dichotomous biological effects on the axonal growth cones in the developing central nervous development depending on the receptor it binds. In previous work we and others were able to demonstrate that netrin-1 impacts inflammatory processes in the periphery with divergent effects in acute and chronic inflammation. Recent work reported that netrin-1 blocks macrophage response to chemokines via Unc5b hindering macrophage egress from adipose tissue and enhancing macrophage survival in chronic inflammation in obesity. Therefore, I propose to identify the mechanisms causing netrin-1 and Unc5b induction on macrophages in obesity. Furthermore, I aim to understand the mechanisms by which netrin-1 and Unc5b sustain obesity related chronic inflammation and metabolic dysfunction. For this, I plan to test whether macrophage specific netrin-1 and/or Unc5b in obesity promote macrophage retention, alter macrophage polarization and metabolism and sustain metabolic dysfunction and systemic inflammation. Understanding mechanisms and identifying crucial pathways by which netrin-1 sustains obesity inflammation in obesity might open novel therapeutics options therapeutic which will be further tested by deleting macrophage specific netrin-1 in already obese mice with established chronic inflammation.