Bioenergetic and metabolic consequences of the loss of ovarian function in women

女性卵巢功能丧失的生物能和代谢后果

基本信息

批准号：
10225533
负责人：
Wendy M Kohrt
金额：
$ 44.7万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-20 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10225533
关键词：
Abdomen Address Adipocytes Adipose tissue Aging Agonist Animals Antibodies Area Area Under Curve Award Back Bioenergetics Biological Biological Specimen Banks Blood Blood specimen Bone Density Bone Marrow Chronic Disease Chronology Clinical Research Collaborations Colorado Cortisone Country Data Discipline Energy Metabolism Enzymes Estradiol Estrogen Receptors Estrogens Failure Fatty acid glycerol esters Follicle Stimulating Hormone Future Glucocorticoids Goals Gonadotropin Hormone Releasing Hormone Health Homeostasis Hour Human Hydrocortisone Hydroxysteroid Dehydrogenases Impairment Insulin Resistance Intervention Knock-out Knowledge Lead Life Light Mediating Mediator of activation protein Menopause Metabolic Metabolic dysfunction Metabolism Microdialysis Mitochondria Mus Obesity Oral Osteoporosis Outcome Ovarian Ovarian Ablation Ovariectomy Physical activity Placebos Postmenopause Premenopause Process Randomized Regulation Research Research Personnel Rest Risk Rodent Serum Sex Differences Tissue Sample Urine Vascular Endothelium Visceral Visceral fat Woman Women&apos s Health abdominal fat age effect base bone loss bone mass cardiometabolism clinical translation density experimental study gonad function indexing men middle age ovarian failure pre-clinical prevent primary outcome response secondary outcome skeletal subcutaneous therapeutic target

项目摘要

The focus of Project 1 on Bioenergetic and Metabolic Consequences of the Loss of Gonadal Function in Women in the Colorado SCORE (CO-SCORE) is based on the overarching hypothesis that the loss of gonadal function increases risk for chronic disease. The best-studied example of this is the accelerated decline in bone mineral density at menopause and the resulting risk for osteoporosis. However, the extent to which gonadal aging increases risk for chronic diseases other than osteoporosis is poorly understood. This is particularly relevant to women’s health, because gonadal failure is inevitable in women in mid-life but rare in men until much later in life. During the current SCORE award period, we advanced the clinical translation of the unequivocal evidence in animals that loss of estradiol (E2) is a trigger for excess abdominal fat accumulation and metabolic dysfunction. We demonstrated that suppression of ovarian function in premenopausal women (gonadotropin releasing hormone agonist;; GnRHAG) disrupts energy homeostasis, and results in a marked increase in abdominal subcutaneous and visceral fat that is prevented by E2 add-back. We also generated intriguing preliminary data to support the hypothesis that the conversion of cortisone to cortisol in abdominal adipose tissue by the enzyme 11β-hydroxysteroid dehydrogenase 1 (HSD1) is regulated by E2. Preclinical evidence strongly supports glucocorticoid metabolism as a regulator of abdominal adiposity. Accordingly, Aim 1 in the next award period is to determine whether adipose tissue and systemic glucocorticoid metabolism are regulated by E2 in women. Because a goal of the CO-SCORE is to advance paradigm- challenging research on sex differences, Aim 2 will investigate follicle stimulating hormone (FSH) as a mediator of energy homeostasis and cardiometabolic function. FSH was implicated recently as a mediator of metabolic actions traditionally attributed to the loss of E2. When compared with controls, mice treated with an FSH antibody had increased bone mass and decreased adiposity, including reductions in visceral and subcutaneous fat. Given the importance of understanding whether both E2 and FSH may be important therapeutic targets, rather than just E2, we will conduct the first proof-of-concept study of the effects of E2 vs FSH on outcomes that are responsive to the inhibition of FSH in mice. Projects 1, 2 (preclinical), and 3 (basic) will all address gaps in knowledge on whether the effects of E2-deficiency to increase abdominal adiposity are mediated by altered glucocorticoid metabolism and/or increased FSH. Adipose tissue samples from women in Project 1 and from animals in Projects 2 and 3 will be interrogated using similar approaches to accelerate the translational relevance of these areas of research. Finally, because blood and tissue samples from experiments in which we control E2 status are of great value across many disciplines, we will bank specimens from women in Project 1 that can be used to support external collaborations with SCORE (and other) investigators across the country.

项目 1 的重点是性腺功能丧失的生物能和代谢后果科罗拉多州女性 SCORE (CO-SCORE) 基于这样一个总体假设：性腺丧失功能失调会增加罹患慢性疾病的风险，研究最充分的例子是骨骼加速衰退。然而，绝经期的矿物质密度和由此产生的骨质疏松症的风险程度。人们对衰老会增加骨质疏松症以外的慢性疾病的风险知之甚少。与女性健康相关，因为女性在中年时目标失败是不可避免的，但男性在中年之前很少见在当前的 SCORE 颁奖期间，我们推进了该技术的临床转化。动物身上明确的证据表明，雌二醇 (E2) 的损失会引发腹部脂肪过度堆积和代谢功能障碍。我们证明了绝经前女性的卵巢功能受到抑制。（促性腺激素释放激素激动剂；；GnRHAG）会破坏能量稳态，并导致显着的结果。我们还产生了 E2 回加来防止腹部皮下和内脏脂肪的增加。有趣的初步数据支持这样的假设：可的松在腹部转化为皮质醇 11β-羟基类固醇脱氢酶 1 (HSD1) 的脂肪组织受 E2 调节。证据强烈支持糖皮质激素代谢作为腹部肥胖的调节剂。 1.在下一个奖励期是确定脂肪组织和全身糖皮质激素是否女性的新陈代谢受 E2 调节，因为 CO-SCORE 的目标是推进范式- 目标 2 将研究卵泡刺激素 (FSH) 作为性别差异的挑战性研究 FSH 最近被认为是能量稳态和心脏代谢功能的调节剂。传统上归因于 E2 损失的代谢作用介质。与对照组相比，小鼠使用 FSH 抗体可增加骨量并减少脂肪含量，包括治疗后的骨量减少鉴于了解 E2 和 FSH 是否都可能是内脏和皮下脂肪的重要性。重要的治疗靶点，而不仅仅是 E2，我们将对其进行首次概念验证研究 E2 与 FSH 对小鼠中 FSH 抑制反应的影响。（临床前）和 3（基础）都将解决关于 E2 缺乏是否会影响 E2 的知识空白。腹部肥胖的增加是由糖皮质激素代谢改变和/或 FSH 增加介导的。将对项目 1 中的女性以及项目 2 和 3 中的动物的脂肪组织样本进行检查最后，因为使用类似的方法来加速这些研究领域的转化相关性。我们控制 E2 状态的实验中的血液和组织样本在许多方面具有重要价值学科，我们将储存项目 1 中女性的样本，这些样本可用于支持外部。与全国 SCORE（和其他）调查人员合作。