Integrative Mechanisms of Adipose Tissue Dysfunction In obesity

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DESCRIPTION (provided by applicant): Even after accounting for lack of physical activity and genetic susceptibility, excessive food energy intake remains, probably, the most common cause of overweight and obesity in western countries. Unfortunately, the expanding adipose tissue experiences an abnormal infiltration of circulating leukocytes, a phenomenon that occurs in the microcirculation and it is associated with adipose tissue inflammation and insulin resistance. The precise cellular and molecular mechanisms that initiate and govern leukocyte extravasation in the microcirculation of expanding adipose depots remain undefined. Consequently, whether leukocyte infiltration is the cause or the effect of adipocyte dysfunction remains largely unknown, which hinders therapeutic interventions in the ever-growing obese population of the USA. Emerging information in the literature and new preliminary data presented in this application demonstrate that nutrients overload causes a postprandial infiltration of neutrophils in visceral fat depots. Obviously, this acute response to dietary nutrients occurs well before weight gain and insulin resistance. Accordingly, we propose to test the hypothesis that nutrients overload acutely activates leukocyte-endothelium interactions in the microcirculation of the visceral fat and that this process initiates adipocyte dysfunction. The overall goals of this projet are to study: a) the mechanisms by which nutrients overload triggers this rapid activation of neutrophils in the adipose tissue microcirculation; b) the cellular and molecular determinants that make the microcirculation of visceral fat depots highly responsive to nutrients overload; c) the impact of this phenomenon on adipocyte homeostasis. To implement these studies, we will utilize knockout and transgenic mouse technology along with the following biochemistry and physiology techniques: western blot analysis, immunohistochemistry and immunofluorescence, cells and tissue isolation techniques, intravital microscopy, nitric oxide measurements. We hope that the results of this work will advance our understanding of the integrated mechanisms that initiate and maintain adipose tissue inflammation and related metabolic disorders.