Ovarian hormone suppression and regulation of adipogenesis in women

卵巢激素抑制和女性脂肪生成的调节

• 批准号: 8164784
• 负责人: Wendy M Kohrt
• 金额: $ 22.95万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8164784
• 关键词: Abdomen; Adipocytes; Adipose tissue; Agonist; Atrophic; Attenuated; Back; Bioenergetics; Bone Marrow; CCAAT-Enhancer-Binding Proteins; CD36 gene; Cell Count; Cell Fraction; Cell Proliferation; Cell Size; Cell surface; Cells; Chronic Disease; Clinical; Coronary Arteriosclerosis; Coronary heart disease; DNA; Detection; Deuterium; Energy Intake; Energy Metabolism; Estradiol; Estrogens; Fatty acid glycerol esters; Flow Cytometry; Gene Expression; Gonadotropin Hormone Releasing Hormone; Human; Hypertension; Infiltration; Inflammation; Integrins; Interleukin-6; Label; Lead; Leptin; Measures; Mediating; Menopause; Metabolic; Metabolic syndrome; Methodology; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovarian hormone; Phenotype; Placebos; Platelet-Derived Growth Factor Receptor; Postmenopause; Premenopause; Production; Randomized; Regulation; Research Personnel; Reverse Transcriptase Polymerase Chain Reaction; Risk; Rodent; Role; Stem cells; TNF gene; Testing; Time; Weight Gain; Withdrawal; Woman; abdominal fat; base; cytokine; hormone therapy; hypertensive heart disease; in vivo; lipid biosynthesis; mRNA Expression; macrophage; notch protein; novel; open label; prevent; progenitor; programs; response; subcutaneous; treatment duration

DESCRIPTION (provided by applicant): Estradiol (E2) deficiency triggers weight gain, and specifically abdominal fat gain, in women. The shift toward central adiposity after menopause likely contributes to increased risk for the metabolic syndrome and associated chronic diseases (i.e., type 2 diabetes, coronary artery disease, hypertension). The long-term aim is to understand the mechanisms by which E2 deficiency mediates increases in abdominal adiposity. The primary aim (PA1) of the R21 is to determine whether ovarian hormone suppression in premenopausal women, which is known to cause fat gain, triggers an increase in adipogenesis (i.e., increase in cell number) in abdominal adipose tissue. This will be assessed by measuring the changes in cell size distribution and the incorporation of deuterium (2H) into DNA of cells in the non-stromal (i.e., mature adipocyte) fraction. Secondary aims are to determine: SA2) effects of ovarian hormone suppression on mRNA expression of factors involved in adipogenesis (C/EBP1, PPAR3) and markers of macrophage infiltration (CD68, Emr-1) and inflammation (IL-6, TNF-1); and SA3) whether new adipocytes arise from non-resident bone marrow progenitor (BMP) cells using cell surface markers (Notch 4, Platelet-derived Growth Factor Receptor (PDGFR) 2, Integrin 15, CD36) that enable detection by flow cytometry. To achieve these aims, 24 premenopausal women will be studied before and after 30 and 60 days of ovarian hormone suppression via gonadotropin releasing hormone agonist therapy with add-back of placebo (GnRHAG+PL) or estradiol (GnRHAG+E2). Hypotheses are: H1a) GnRHAG+PL for 60 days will result in a larger increase in small adipocytes (<40 5m) when compared with GnRHAG+E2. Because fat mass increases during GnRHAG+PL, an increase in the number of small adipocytes will be interpreted as an increase in adipogenesis and not as evidence of adipocyte atrophy; H1b) The incorporation of 2H in the non-stromal cell fraction DNA will be increased in response to GnRHAG+PL, as compared with GnRHAG+E2. Because the non-stromal fraction contains mature adipocytes, an increase in 2H- enriched DNA should reflect adipogenesis; H2) Ovarian hormone suppression will increase mRNA expression of factors associated with adipogenesis, macrophage infiltration, and inflammation (C/EBP1, PPAR3, CD68, Emr-1, IL-6, TNF-1) when compared with baseline (before vs after GnRHAG+PL) and when compared with E2 add-back (GnRHAG+PL vs GnRHAG+E2); and H3) Ovarian hormone suppression will increase BMP-derived adipocytes when compared with baseline (before vs after GnRHAG+PL) and when compared with E2 add-back (GnRHAG+PL vs GnRHAG+E2). To the best of our knowledge, this will be the first in vivo study of the role of E2 as a regulator of adipogenesis in humans. Because it is believed that adipocytes are programmed to achieve a certain volume of fat, an increase in adipocyte number would lead to a gain in fat mass that would be very difficult to reverse. Thus, identifying strategies that effectively prevent an increase in adipogenesis during ovarian hormone withdrawal would be of high clinical importance. PUBLIC HEALTH RELEVANCE: Women are largely protected against abdominal adiposity prior to the menopause. The loss of estrogen at the time of the menopause triggers an increase in abdominal fat accumulation, which likely contributes to increased risk for the metabolic syndrome, type 2 diabetes mellitus, coronary artery disease, and hypertension. The proposed studies will test the novel hypothesis that estrogen deficiency results in abdominal fat gain by triggering an increase in the number of fat cells.

描述（由申请人提供）：雌二醇 (E2) 缺乏会引发女性体重增加，特别是腹部脂肪增加。绝经后向中枢性肥胖的转变可能会增加代谢综合征和相关慢性疾病（即 2 型糖尿病、冠状动脉疾病、高血压）的风险。长期目标是了解 E2 缺乏介导腹部肥胖增加的机制。 R21 的主要目的 (PA1) 是确定绝经前女性的卵巢激素抑制（已知会导致脂肪增加）是否会引发腹部脂肪组织中脂肪生成的增加（即细胞数量的增加）。这将通过测量细胞大小分布的变化和非基质（即成熟脂肪细胞）部分细胞 DNA 中氘 (2H) 的掺入来评估。次要目标是确定： SA2) 卵巢激素抑制对脂肪生成相关因子（C/EBP1、PPAR3）以及巨噬细胞浸润标志物（CD68、Emr-1）和炎症（IL-6、TNF-1）的 mRNA 表达的影响；和 SA3) 使用细胞表面标记物（Notch 4、血小板源性生长因子受体 (PDGFR) 2、整合素 15、CD36）可通过流式细胞术检测新的脂肪细胞是否来自非驻留骨髓祖细胞 (BMP)。为了实现这些目标，我们将对 24 名绝经前女性进行研究，通过促性腺激素释放激素激动剂治疗联合安慰剂 (GnRHAG+PL) 或雌二醇 (GnRHAG+E2) 进行卵巢激素抑制 30 天和 60 天的前后。假设是： H1a) 与 GnRHAG+E2 相比，GnRHAG+PL 60 天将导致小脂肪细胞 (<40 × 5m) 的更大增加。由于 GnRHAG+PL 期间脂肪量增加，因此小脂肪细胞数量的增加将被解释为脂肪生成的增加，而不是脂肪细胞萎缩的证据； H1b)与GnRHAG+E2相比，响应GnRHAG+PL，非基质细胞部分DNA中2H的掺入将会增加。由于非基质部分含有成熟的脂肪细胞，因此 2H 富集 DNA 的增加应反映脂肪生成； H2) 与基线相比（GnRHAG+PL 之前与之后）以及与 E2 添加回相比（GnRHAG+PL 与 GnRHAG+E2）相比，卵巢激素抑制将增加与脂肪生成、巨噬细胞浸润和炎症相关的因子（C/EBP1、PPAR3、CD68、Emr-1、IL-6、TNF-1）的 mRNA 表达；和 H3) 与基线相比（GnRHAG+PL 之前与之后）以及与 E2 回加（GnRHAG+PL 与 GnRHAG+E2）相比，卵巢激素抑制将增加 BMP 衍生的脂肪细胞。据我们所知，这将是第一个关于 E2 作为人类脂肪生成调节剂作用的体内研究。因为人们相信脂肪细胞被编程为达到一定体积的脂肪，所以脂肪细胞数量的增加将导致脂肪量的增加，而这种增加很难逆转。因此，确定有效防止卵巢激素停药期间脂肪生成增加的策略具有很高的临床重要性。 公众健康相关性：女性在绝经前很大程度上可以预防腹部肥胖。更年期雌激素的流失会导致腹部脂肪堆积增加，这可能会增加患代谢综合征、2 型糖尿病、冠状动脉疾病和高血压的风险。拟议的研究将检验一个新假设，即雌激素缺乏会引发脂肪细胞数量增加，从而导致腹部脂肪增加。