Effects of Pre-existing Obesity on Consequences of the Loss of Ovarian Function

既往肥胖对卵巢功能丧失后果的影响

基本信息

批准号：
9127000
负责人：
Wendy M Kohrt
金额：
$ 26.27万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9127000
关键词：
Adipocytes Adipose tissue Affect Aromatase Aromatase Inhibition Aromatase Inhibitors Attenuated Bioenergetics Body Composition Body Weight decreased Cardiovascular Diseases Cellularity Deposition Desire for food Development Diabetes Mellitus Diet Dietary Fats Disease Dyslipidemias Energy Metabolism Energy Therapy Estradiol Estrogens Exercise Expenditure Fatty acid glycerol esters Functional disorder Goals Health Homeostasis Impairment Insulin Resistance Knowledge Lead Lipids Menopause Metabolic Metabolic Diseases Mitochondria Muscle Muscle Mitochondria Obesity Observational Study Operative Surgical Procedures Osteoporosis Ovarian Ovariectomy Overweight Peripheral Physical activity Population Postmenopause Pre-Clinical Model Premenopause Production Rattus Resistance Risk Rodent Model Role Skeletal Muscle Source Testing Tissues Visceral Weight Weight Gain Weight maintenance regimen Woman Women&apos s Health adverse outcome attenuation bone bone loss common treatment cost disorder risk energy balance experience feeding functional decline gonad function improved increased appetite inflammatory marker insight insulin sensitivity lipid biosynthesis malignant breast neoplasm mimetics oxidation preconditioning programs protective effect response skeletal muscle metabolism trafficking

项目摘要

While most women are overweight or obese when they reach menopause, we know little about how obesity affects this transition and its impact on metabolic health. We have hypothesized that the enhanced production of estrogens in peripheral tissues of obese women protects adipose tissue, skeletal muscle, and bone from the menopause-related decline in function. We have merged well-characterized preclinical models of obesity (obesity-resistant/prone rats) and menopause surgical ovariectomy (OVX) to study how pre-existing obesity affects this transition. In the first aim, we examine obesity's effects on the loss of ovarian estrogen production and its impact on energy balance, fuel utilization, and metabolic health. The role of extragonadal estrogen production in obesity's effects will be dissected with the use of aromatase inhibitors. Diet-induced weight loss is common in women with weight control problems, but the body compensates with homeostatic adaptations that drive weight regain. The loss of ovarian function in weight reduced women may exacerbate this metabolic drive to gain weight and create a potentiated vulnerability to metabolic disease. Regular exercise and estrogen have many overlapping effects on energy balance and fuel utilization that may counter these consequences to energy homeostasis and disease. In the second aim, we examine how energy restricted weight loss from obesity affects the drive to gain weight and the decline in metabolic health after the loss of ovarian function. The impact of regular exercise, with actions that reflect an estrogen mimetic, will be examined in weight reduced subjects. These studies will provide insight into how one of the most common preconditions of menopause, obesity, affects the loss of ovarian function and its consequences to energy homeostasis and metabolic disease. Observations from these studies may provide evidence that certain populations of obese woman (treated with aromatase therapy, energy restricted) who may be particularly vulnerable to menopausal weight gain and metabolic disease unless they maintain a program of regular physical activity.

虽然大多数女性到更年期时都超重或肥胖，但我们对肥胖的了解一无所知影响这种过渡及其对代谢健康的影响。我们假设增强肥胖女性外周组织中雌激素的产生可保护脂肪组织，骨骼肌和与更年期相关的功能下降的骨骼。我们合并了良好的临床前肥胖模型（抗肥胖症/易于大鼠）和更年期手术卵巢切除术（OVX）预先存在的肥胖会影响这种过渡。在第一个目标中，我们研究了肥胖对损失的影响卵巢雌激素的产生及其对能量平衡，燃料利用率和代谢健康的影响。这使用芳香酶，将解剖肥胖作用中雌激素后产生雌激素的作用抑制剂。饮食引起的体重减轻在体重控制问题的女性中很常见，但身体补偿促进体重的体内稳态适应。体重减轻女性的卵巢功能的丧失可能会加剧这种代谢驱动力，以增加体重并产生增强的代谢脆弱性疾病。定期运动和雌激素对能量平衡和燃料有许多重叠的影响利用可能应对能量稳态和疾病的后果。在第二个目标中我们研究了肥胖中限制能源减肥如何影响体重的动力和下降卵巢功能丧失后代谢健康。定期锻炼的影响，反映了雌激素模拟物将在体重减少的受试者中检查。这些研究将提供有关更年期，肥胖，肥胖，肥胖的最常见前提之一的见解影响卵巢功能的丧失及其对能量稳态和代谢疾病的后果。这些研究的观察结果可能提供证据表明某些肥胖妇女种群（治疗通过芳香化酶治疗，限制能量），他们可能特别容易受到更年期的体重增加和代谢疾病，除非它们保持常规体育锻炼计划。