Growing evidence indicates that visceral adiposity is particularly detrimental to health, due to associations with insulin resistance, dyslipidemia, Type 2 diabetes and CVD. Rapid expansion of visceral adipose tissue in obesity is accompanied by insufficient vascular growth leading to hypoxia and inflammation that are closely linked to development of insulin resistance in obesity. As a compensatory mechanism to counteract hypoxia, formation of new blood vessels- angiogenesis is triggered. Interestingly, in subcutaneous adipose tissue, angiogenic responses are adequate, balancing hypoxia. However, in visceral adipose tissue, angiogenesis is not adequately compensating tissue growth leading to persistence of tissue hypoxia and exacerbation of inflammation. The mechanisms responsible for this depot specific effect are incompletely understood but may explain in part why associations of cardio- metabolic complications of obesity were linked mostly to visceral adipose tissue. The lipoxygenase pathway is a key player in adipose tissue inflammation in animal models of obesity and insulin resistance. 12/15 lipoxygenases are required for development of insulin resistance and their targeted genetic deletion prevents insulin resistance in obesity. However, functional roles of lipoxygenase enzymes in human adipose tissue are not known. We have shown previously that 12/15 lipoxygenase isoforms have a distinct pattern of expression in subcutaneous and omental (visceral) adipose tissue in humans and are mostly expressed by non-adipose cells. In this proposal we aim to investigate in detail enzymes expression and activity in different cells component of human AT and to determine modulation by hypoxia. Further, we want to investigate the role of 12/15 lipoxygenase pathway in endothelial cells angiogenic response to hypoxia and establish differences between different depots. We also aim to determine the role of 12/15 lipoxygenase pathway in adipose tissue macrophage inflammation in response to hypoxia and identify key genes responsible for production of inflammatory mediators. In humans with obesity and diabetes, weight loss following bariatric surgery leads to improved insulin sensitivity and resolution of diabetes. However, the contribution of adipose tissue inflammation to this clinical outcome is not known. In this proposal we will examine correlations between changes in 12/15 lipoxygenases expression and activity and changes in body weight and insulin resistance in subjects undergoing bariatric surgery. We will study correlations both longitudinally and cross-sectionally in subjects with or without diabetes. Understanding of the functions of 12/15 ALOX isoforms in different cells component of human AT and the depot- specific pathway modulation in obesity and insulin resistance may lead to targeted innovative therapy to treat diabetes and to prevent CVD mortality. This project also provides excellent opportunities for training of undergraduate, graduate and medical students in a variety of biochemical, cellular and molecular biology techniques.
This will be the first study to investigate the functional and pathological roles of the pro-inflammatory lipoxygenase pathway in visceral fat in human obesity. The completed project could greatly improve the public health of millions of Americans with obesity by identifying novel treatment targets to improve blood sugar and cardiovascular risk.
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