The expanding fat depots of overweight and obese individuals experience pathologic leukocyte infiltration, a process that takes place in the microcirculation of organ tissue. Thus, the visceral adipose depots become inflamed, dysfunctional and contributes to insulin resistance, cardiovascular disease, cancer and arthritis, whose incidence is gaining in the ever-growing obese population of the USA. The precise time-course and mechanisms by which excessive calorie intake instigates leukocyte infiltration in expanding adipose depots remain undefined, which limits therapeutic interventions in obese humans. Published work, along with new preliminary data presented here, uncover a novel role for the endothelium of the adipose tissue microcirculation in these processes. Our preliminary data demonstrate a mechanistic role for the calcium- dependent cysteine protease calpain in post-prandial infiltration of circulating leukocytes into visceral fat depots. Our working hypothesis is that lipids overload causes post-prandial activation of endothelial-expressed calpain via transactivation of the EGF receptor, with subsequent upregulation of leukocyte-endothelium interactions in the microcirculation of the visceral fat depots. As a result, adipose tissue is subjected to the inflammatory action of infiltrating leukocytes. The long-term goals of this project are: 1) to understand the molecular and cellular determinants that makes the microcirculation of visceral fat highly responsive to post-prandial absorption of macronutrients; 2) to investigate the signaling pathways responsible for post-prandial activation of endothelial calpain; 3) to study the impact of these processes on the postprandial and chronic inflammatory responses of the adipose tissue. Toward these goals, we will utilize knockout and transgenic mouse technology along with the following physiology and biochemistry techniques: intravital microscopy, cells and tissue isolation procedures, western blot analysis, immunohistochemistry and immunofluorescence, interfering RNA technology. 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 disorders in the overweight/obese organism.
Obesity is a major health challenge facing the US population. Research has now shown that as weight increase to reach the levels referred as ?overweight? and ?obesity? incidence of and mortality from diabetes, cardiovascular disease and cancer increase. These complications of obesity have been widely linked to adipose tissue inflammation. In fact, the number of inflammatory cells is almost invariably elevated in the adipose tissue of obese individual and experimental animal models. What drives infiltration of inflammatory cells in fat depots, especially the visceral ones, remains largely unexplained. The vascular endothelium of the microcirculation is the physiological gatekeeper of leukocyte infiltration in inflammatory states. Thus, primary endothelial dysfunction could be, in theory, the initial, critical event in adipose tissue inflammation. Accordingly, the long-term goal of this project is to test the hypothesis that post-prandial processing of lipids initiates infiltration of inflammatory cells in visceral adipose depots via activation of signaling pathways in the vascular endothelium of the microcirculation. Overall, this research will uncover novel mechanisms of adipose tissue inflammation in obesity, and it will provide a framework for developing new therapeutic strategies to avert complications in the overweigh, obese population of the USA.
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