Hepatic Estrogen Signaling and Protection Against Insulin Resistance

肝脏雌激素信号传导和胰岛素抵抗保护

• 批准号: 8389808
• 负责人: Melissa Nicole Martinez
• 金额: $ 2.66万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8389808
• 关键词: Adenoviruses; Affect; African American; Award; Boxing; Bypass; Cardiovascular Diseases; Cardiovascular system; Communities; Defect; Diabetes Mellitus; Diet; Dominant-Negative Mutation; Dyslipidemias; Estrogen Receptor alpha; Estrogens; Euglycemic Clamping; Failure; Fatty Acids; Fatty acid glycerol esters; Female; Figs - dietary; Gene Expression; Genes; Genetic; Gluconeogenesis; Glucose; Glucose Clamp; Glucose Intolerance; Glucose tolerance test; Health; Hepatic; High Density Lipoproteins; Hispanic Americans; Hour; Hyperglycemia; Insulin; Insulin Resistance; Knock-out; Lead; Lipids; Liver; Mediating; Menopause; Metabolic; Minority; Molecular; Molecular Target; Morbidity - disease rate; Mus; National Research Service Awards; Nuclear; Obesity; Operative Surgical Procedures; Ovariectomy; Pathway interactions; Population; Postmenopause; Predisposition; Production; Proto-Oncogene Proteins c-akt; Research; Resistance; Signal Transduction; Techniques; Testing; Time; Triglycerides; Underrepresented Minority; Very low density lipoprotein; Virus; Woman; cardiovascular disorder risk; cardiovascular risk factor; career; feeding; forkhead protein; glucose disposal; glucose metabolism; glucose production; glucose tolerance; improved; in vivo; innovation; insulin sensitivity; insulin signaling; intraperitoneal; lipid metabolism; men; mortality; mouse model; novel; prevent; research study; sensor

DESCRIPTION (provided by applicant): Menopause represents a shift from a period of cardiovascular protection to cardiovascular risk, and thus provides an opportunity to define mechanisms that confer cardiovascular protection. Increased cardiovascular risk after menopause is associated with the metabolic complications of obesity arising from hepatic insulin resistance. Hepatic insulin resistance contributes to hyperglycemia and dyslipidemia characterized by increased very low density lipoprotein (VLDL) and low levels of high density lipoprotein (HDL). The transcription factor forkhead box O1 (FoxO1) acts as an energy sensor in the liver to help coordinate glucose and lipid metabolism. Insulin signaling inactivates FoxO1, which decreases hepatic glucose production and VLDL secretion. With high-fat feeding, insulin resistance arises in the liver, and insulin fails to inactivate FoxO1, resulting in increased glucose production, and secretion of VLDL. We have found that female mice with intact estrogen signaling are able to inactive FoxO1 in the liver despite high-fat feeding and decreased insulin action to AKT, but that after surgical menopause by ovariectomy this protection from insulin resistance is lost. Additionally, inactivation of FoxO1 in the liver prevents triglyceride elevations after ovariectomy. Our overarching hypothesis is that hepatic estrogen signaling mediated by estrogen receptor alpha (ER1) promotes insulin sensitivity by bypassing the signaling defect to FoxO1 created by high-fat feeding. In our first AIM, we use metabolic clamp techniques in mice with a liver-specific deletion of the ER1 gene to assess if hepatic estrogen signaling can promote insulin sensitivity. In our second AIM, we determine if hepatic estrogen signaling is sufficient to prevent, ameliorate, or delay high fat diet-induced insulin resistance. In our third AIM, we determine if genetic inactivation of FoxO1 can prevent glucose intolerance caused by high-fat feeding after surgical menopause by ovariectomy. These experiments apply an innovative approach to simultaneously quantify whole-body and liver insulin sensitivity, trace hepatic handling of glucose, and define molecular targets which may augment glucose metabolism after menopause. Obesity and insulin resistance affect the Hispanic and African American community in a disproportionate manner. This award will not only make it possible for me as an under- represented minority to pursue a research career but may also impact the disparities in cardiovascular disease for minority populations. The support of the Ruth L. Kirchstein National Research Service Award to promote diversity in health related research will make it possible to understand the mechanisms of cardiovascular disease associated with diabetes and obesity.

描述（由申请人提供）：更年期代表从心血管保护的时期转变为心血管风险，因此提供了定义提供心血管保护的机制的机会。更年期后的心血管风险增加与肝胰岛素抵抗引起的肥胖症的代谢并发症有关。肝胰岛素抵抗有助于高血糖和血脂异常，其特征在于非常低密度脂蛋白（VLDL）和低密度脂蛋白（HDL）的水平升高。转录因子叉子盒O1（FOXO1）在肝脏中充当能量传感器，以帮助协调葡萄糖和脂质代谢。胰岛素信号传导使FOXO1失活，后者降低了肝葡萄糖的产生和VLDL分泌。随着高脂肪喂养，肝脏中会产生胰岛素耐药性，胰岛素未能使FOXO1失活，从而导致葡萄糖产生增加和VLDL的分泌。我们发现，具有完整的雌激素信号传导的雌性小鼠能够在肝脏中不活跃的FOXO1，尽管摄入高脂并减少了对AKT的胰岛素作用，但是在卵巢上的超级外科手术后，这种保护损失了这种免受胰岛素抵抗的保护。另外，肝脏中FOXO1的失活可防止卵巢切除术后甘油三酸酯的升高。我们的总体假设是，雌激素受体α（ER1）介导的肝脏雌激素信号传导通过绕过由高脂喂养产生的FOXO1信号缺陷来促进胰岛素敏感性。在我们的第一个目标中，我们在具有ER1基因的肝脏特异性缺失的小鼠中使用代谢夹具技术来评估肝脏雌激素信号是否可以促进胰岛素敏感性。在我们的第二个目标中，我们确定肝脏雌激素信号是否足以预防，改善或延迟高脂肪饮食诱导的胰岛素抵抗。在我们的第三个目标中，我们确定FOXO1的遗传失活是否可以防止卵巢切除术后手术更年期后高脂喂养引起的葡萄糖不耐症。这些实验采用创新方法来同时量化葡萄糖的全身和肝胰岛素敏感性，跟踪肝脏处理，并定义分子靶标，这可能会增强更年期后的葡萄糖代谢。肥胖和胰岛素抵抗以不成比例的方式影响西班牙裔和非裔美国人社区。该奖项不仅可以使我成为少数群体从事研究职业的不足，而且可能会影响少数民族人口的心血管疾病差异。露丝·基尔奇斯坦国家研究服务奖（Ruth L. Kirchstein National Research Service）的支持，以促进与卫生相关研究的多样性，将使您了解与糖尿病和肥胖有关的心血管疾病的机制。