Adipose tissue inflammation and estrogen synthesis

描述（由申请人提供）：肥胖现在被认为是几种癌症的危险因素，包括绝经后乳腺癌和子宫内膜癌。两者都与肥胖女性体内雌激素合成的增加有关。虽然已知绝经后雄激素到雌激素的角外芳构化主要发生在脂肪组织中，但过多脂肪与雌激素合成增加之间的联系机制尚不清楚。具体来说，目前尚不清楚哪些细胞合成雌激素，以及肥胖中脂肪组织生物学的特异性变化是否有助于雌激素合成的增加。特别有趣的是，现在已知肥胖与免疫细胞（如巨噬细胞、t细胞和树突状细胞）的脂肪组织浸润有关。在肥胖小鼠模型中进行的大量实验表明，脂肪组织的炎症是肥胖引起全身炎症和胰岛素抵抗的主要机制。然而，与肥胖相关的血清雌激素的增加是否也是由脂肪组织炎症引起的，这在很大程度上仍不清楚。这一假说的基础是，浸润脂肪组织的免疫细胞作为肥胖相关炎症的一部分，表达雌激素合成激素芳香酶，和/或刺激常驻细胞中芳香酶的表达。我们将从16名接受减肥手术的病态肥胖绝经后妇女中获得网膜和皮下腹部脂肪组织，并在体重减轻12个月后进行皮下活检。基线样本将与16名接受选择性手术（如胆囊切除术或疝修补术）、无慢性代谢和炎症性疾病的较瘦的绝经后妇女的样本进行比较。存在于脂肪组织的基质血管部分的细胞将通过流式细胞术进行表征，不同的免疫细胞群将通过荧光激活细胞分选收集。芳香化酶的基因表达以及炎症介质如肿瘤坏死因子a （TNFa）将在分选细胞、脂肪细胞和整个脂肪组织中被测量。将测量脂肪组织和血清样本中雄激素和雌激素的浓度。我们假设芳香化酶和炎症介质如TNFa将在脂肪组织中存在的免疫细胞中表达，这些细胞的数量将在病态肥胖女性的脂肪组织样本中更高，并且这些细胞的数量及其炎症活性将因体重减轻而减少。脂肪组织炎症的减少将与芳香化酶表达的减少以及脂肪组织和血清雌激素浓度的降低有关。确定脂肪组织中表达芳香化酶的细胞类型，不同脂肪组织库之间的差异，以及雌激素合成与肥胖相关炎症之间的联系，将是进一步了解肥胖与绝经后乳腺癌和子宫内膜癌之间的代谢和细胞机制的重要第一步。

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.