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的重点对性腺功能丧失的生物能和代谢后果的重点科罗拉多州评分（共同得分）中的女性是基于总体假设，即性腺丧失功能增加了慢性病的风险。最好的例子是骨骼的加速下降绝经的矿物质密度和骨质疏松症的风险。但是，性腺的程度衰老增加了骨质疏松症以外的慢性疾病的风险知之甚少。尤其是与妇女的健康有关，因为中期女性是不可避免的，但在男性中很少见在生活中很久。在当前的分数奖励期间，我们提出了临床翻译动物中明确的证据表明，雌二醇的丧失（E2）是过量腹部脂肪积累的触发因素和代谢功能障碍。我们证明了绝经前女性卵巢功能的抑制（促性腺激素释放恐怖激动剂;; gnrhag）破坏能量稳态，并导致明显的 E2补充阻止的腹部皮下和内脏脂肪增加。我们也生成了有趣的初步数据，以支持以下假设通过酶11β-羟基甾体脱氢酶1（HSD1）通过E2调节脂肪组织。临床前证据强烈支持糖皮质激素代谢作为腹部肥胖的调节剂。根据以下内容，目标 1在下一个奖项期间是确定脂肪组织和全身性糖皮质激素是否代谢受E2的调节。因为共同得分的目标是提高范式 - AIM 2对性别差异的挑战研究将研究刺激激素（FSH）作为一种能量稳态和心脏代谢功能的介体。 FSH最近被暗示为代谢作用的调解人传统上归因于E2的丧失。与对照相比，小鼠用FSH抗体处理的骨骼质量增加并提高肥胖，包括减少内脏和皮下脂肪。鉴于了解E2和FSH是否可能是重要的治疗靶标，而不仅仅是E2，我们将进行首次对概念证明研究 E2与FSH对抑制小鼠FSH的结果的影响。项目1、2 （临床前）和3（基本）都将解决有关E2缺乏效率是否对E2的影响的差距增加的腹部肥胖是通过改变的糖皮质激素代谢和/或FSH介导的。项目1中女性的脂肪组织样品和项目2和3中的动物的脂肪组织样本将受到审问使用类似的方法来加速这些研究领域的翻译相关性。最后，因为我们控制E2状态的实验中的血液和组织样本在许多方面具有很高的价值学科，我们将在项目1中的妇女银行标本，可用于支持外部与全国分数（和其他）调查员的合作。