Adipose tissue lymphatic vessel functions in obesity
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abstract
The obesity epidemic and its associated cardiovascular complications has made understanding adipose tissue physiology of paramount importance. Adipose tissue is an endocrine tissue that, when healthy, hormonally regulates energy balance and serves as a benign caloric store. In pathological obesity, however, adipose tissue inflammation - characterized by immune cell infiltration and fibrosis - is the primary driver of obesity's systemic consequences. During inflammation, adipocytes fail to sequester lipids properly and the obese adipose secretome drives further inflammation leading to whole body dyslipidemia and insulin resistance. A common hallmark of inflammation is lymphangiogenesis, the growth and expansion of the lymphatic vasculature. Studies augmenting or blocking lymphangiogenic pathways have demonstrated that inflammation-associated lymphangiogenesis is necessary to resolve inflammation by transporting fluid, macromolecules, and immune cells from the periphery. Lymphatic morphology is altered in obese adipose and these structural changes appear to be detrimental. A model is needed to determine how adipose tissue lymphatic density and function regulate adipose homeostasis and could potentially ameliorate obesity-induced inflammation. To address this timely question, we have generated Adipo-VD mice (AdipoQ-rtTA x TRE-VEGF-D) that inducibly express potently lymphangiogenic murine VEGF-D protein in adipose tissue when given doxycycline. These mice demonstrate marked lymphatic expansion in white and brown adipose depots and make murine adipose, which is relatively alymphatic compared to human fat, more human-relevant, and allow control of lymphatic density in a doxycycline-concentration manner. We have characterized lymphangiogenesis in this model and preliminary data suggest increased lymphatic density may protect adipose tissue from obesity-associated inflammation. The proposed studies will identify how lymphatic density and function impact adipose tissue inflammation and metabolite transport and how obesity impacts this new vasculature. This innovative Grant-in-Aid proposal thus addresses novel regulation of adipose tissue physiology in a model and environment that uniquely positions us to achieve the Aims. In essence, whether and how adipose lymphangiogenesis potentially addresses the "cause" of the metabolic syndrome will be identified and provide a future therapeutic target for obesity driven co-pathologies. (AHA Program: Grant-in-Aid)
