Weight Loss
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Abstract
of netrin-1 in and The increased accumulation of macrophages and lymphocytes in adipose tissue during propagates chronic inflammation, which is closely associated with systemic insulin resistance, and the development of metabolic syndrome and type 2 diabetes (T2D). Recent studies have explored the mechanisms by which these immune cells arerecruited. However, the signals that cause macrophages to persist in adipose, promoting chronic inflammation, are not understood. We recently uncovered a novel role for the neuronal guidance cue, Netrin-1, in inducing macrophage (Mø) chemostasis and thus blocking their emigration from atherosclerotic plaques. Our preliminary data indicate that Netrin-1 is also increased in adipose tissue from obese mice and humans compared to lean controls. Lethally irradiated wild-type mice reconstituted with Ntn1 null bone marrow display protection against diet-induced adipose inflammation and insulin resistance compared to mice with wild-typemarrow. Based on these data we hypothesize that Netrin-1 critically regulates immune cell trafficking and accumulation in WAT and metabolic dysfunction in HFD feeding, thereby leading to insulin resistance and diabetes. To test this hypothesis, we will determine (1) the mechanisms of Netrin-1 regulation in WAT, (2) the contribution of Mø and Treg derived netrin-1 on WAT inflammation in mouse models of tissue-specific or conditional deletion of netrin1, and (3) whether Netrin-1 targeting using a nanoparticle delivery system improves metabolic parameters in obese mice. model diffusion-weighted in judiciously formalisms anisotropy. analysis workflow to diagnostic specificity in complex pathologies microstructure,