Adipose tissue inflammation and estrogen synthesis

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Obesity is now recognized as a risk factor for several types of cancer, including postmenopausal breast and endometrial cancer. Both have been linked to an increased synthesis of estrogens in obese women. Although it is known that extragonadal aromatization of androgens to estrogens after menopause occurs largely in adipose tissue, the mechanisms linking excess adiposity to increased estrogen synthesis are not clear. Specifically, it is unclear which cells synthesize estrogen, and whether specific changes in adipose tissue biology in obesity contribute to the increased estrogen synthesis. Of particular interest, obesity is now known to be associated with adipose tissue infiltration of immune cells such as macrophages, T-cells, and dendritic cells. Experiments largely done in mouse models of obesity have shown that this inflammation of adipose tissue is the primary mechanism by which obesity causes systemic inflammation and insulin resistance. It has remained largely unclear, however, whether the obesity-associated increase in serum estrogen is also caused by adipose tissue inflammation. The hypothesis underlying this proposal is that immune cells infiltrating adipose tissue as part of the obesity-associated inflammation of that tissue express the estrogen- synthesizing hormone aromatase, and/or stimulate aromatase expression in resident cells. We will obtain omental and subcutaneous abdominal adipose tissue from 16 morbidly obese postmenopausal women undergoing bariatric surgery, and by subcutaneous biopsy following weight loss 12 months later. Baseline samples will be compared to those obtained from 16 leaner postmenopausal women free of chronic metabolic and inflammatory disease who undergo elective surgery such as cholecystectomy or hernia repair. Cells present in the stromavascular fraction of adipose tissue will be characterized by flow cytometry, and the different immune cell populations will be collected by fluorescence-activated cell sorting. Gene expression of aromatase as well as mediators of inflammation such as tumor necrosis factor a (TNFa) will be measured in sorted cells, adipocytes, and whole adipose tissue. The concentrations of androgens and estrogens will be measured in adipose tissue and serum samples. We hypothesize that aromatase as well as mediators of inflammation such as TNFa will be expressed in immune cells present in adipose tissue, that the numbers of these cells will be higher in adipose tissue samples of morbidly obese women, and that the number of those cells as well as their inflammatory activity will be reduced by weight loss. This reduction in adipose tissue inflammation will be associated with a reduced expression of aromatase and lower adipose tissue and serum concentrations of estrogens. Identifying the cell types expressing aromatase in adipose tissue, the differences between different fat tissue depots, as well as the link between estrogen synthesis and obesity- associated inflammation will be an important first step in furthering our understanding of the metabolic and cellular mechanisms linking obesity to postmenopausal breast and endometrial cancer. PUBLIC HEALTH RELEVANCE: After menopause, obese women have a higher risk of certain types of cancer, including breast and endometrial cancer. It is thought that increased estrogen synthesis in the expanded fat tissue largely causes this increased risk. We propose a study in lean to morbidly obese postmenopausal women to investigate why fat tissue in obese women produces more estrogen, and which cell types in fat tissue are involved in this process.