Altered Glucose and Lipid Metabolism in Obesity and CVD

描述(由申请人提供)： 肥胖与代谢异常有关，代谢异常会增加患2型糖尿病和心血管疾病(CVD)的风险。与正常体重或低水平内脏脂肪肥胖者相比，内脏脂肪组织大量堆积的肥胖者在口服葡萄糖挑战期间的胰岛素和血糖反应更高，血浆脂蛋白-脂谱恶化。我们将使用胰岛素介导的葡萄糖流入脂肪细胞的原发性损害的小鼠模型来确定肥胖相关心血管疾病发病的分子机制。只携带一个胰岛素刺激GLUT4转运体(GLUT4)功能拷贝的雄性小鼠首先表现出GLUT4表达减少，尤其是在白色脂肪组织(Wat)。WAT中GLUT4的降低会导致内脏肥胖、胰岛素敏感性进行性损害、脂代谢改变，最终导致2型糖尿病并相关的心血管疾病。因此，雄性GLUT4小鼠是研究与人类内脏肥胖相关的病理生理变化的极佳模型。有趣的是，脂肪细胞分泌蛋白的变化，如脂肪细胞特有的Acrp30，先于GLUT4小鼠其他代谢参数的可测量变化。我们和其他人已经证明了Acrp30通过对碳水化合物和脂肪代谢的特定影响，对肝脏和肌肉中的胰岛素抵抗产生了深远的影响。该建议的目的是i)了解特定影响男性(而不是女性)GLUT4小鼠或肌肉中过表达GLUT4的GLUT4小鼠的代谢变化潜在的分子机制；i)从遗传学角度测试纠正男性GLUT4中Acrp30下调是否会预防或延缓胰岛素抵抗、内脏肥胖和/或心血管疾病的发生。此外，我们将测试Acrp30-/-小鼠中循环Acrp30的完全缺乏是否会引起雌性GLUT4小鼠的代谢紊乱，从而加剧雄性GLUT4小鼠的疾病进展；iii)与C57BL/6J小鼠相比，评估高脂饮食诱导的GLUT4小鼠疾病进展的变化；以及iv)确定WAT基因的转录和翻译变化是否与内脏肥胖以及噻唑烷二酮类胰岛素敏感剂治疗后的改变有关，以期发现新的治疗靶点。结合这一方法，该方法将提供肥胖相关心血管疾病小鼠模型的全面系统特征，该模型源于早期胰岛素介导的葡萄糖流向WAT的损害，并首次直接解决Acrp30的变化是否影响疾病进展。

DESCRIPTION (provided by applicant): Obesity is associated with metabolic abnormalities that increase the risk of type 2 diabetes and cardiovascular disease (CVD). Obese patients with a substantial accumulation of visceral adipose tissue are characterized by higher insulinemic and glycemic responses during an oral glucose challenge and a deteriorated plasma lipoprotein-lipid profile compared to normal body weight or obese individuals with low level visceral adiposity. We will use a mouse model with a primary impairment in insulin-mediated glucose flux into adipocytes to define the molecular mechanisms underlying the pathogenesis of obesity associated CVD. Male mice carrying only one functional copy of the insulin-stimulatable GLUT4 transporter (GLUT4) first display reduced GLUT4 expression specifically in white adipose tissue (WAT). Reduced GLUT4 in WAT leads to visceral obesity, progressive impairment in insulin sensitivity, altered lipid metabolism, and eventually to type 2 diabetes with associated CVD. As such, male GLUT4 mice represent an excellent model to study pathophysiological changes associated with visceral obesity in humans. Interestingly, changes in adipose cell secretory proteins, such as the adipocyte-specific Acrp30, precede the onset of measurable changes in other metabolic parameters in GLUT4 mice. We and others have demonstrated profound effects of Acrp30 on insulin resistance in liver and muscle through specific effects on carbohydrate and lipid metabolism. The objectives of this proposal are I) to understand the molecular mechanisms underlying the metabolic changes that specifically affect male, but not female GLUT4 mice or GLUT4 mice that overexpress GLUT4 in muscle; lI) to test genetically whether correction of Acrp30 downregulation in male GLUT4 will prevent or delay the onset of insulin resistance, visceral obesity and/or CVD. Additionally, we will test whether complete lack of circulating Acrp30 in Acrp30-/-mice will provoke metabolic disturbance in female GLUT4 and exacerbate disease in male GLUT4 mice; III) to assess the effects of high fat diet-induced changes in disease progression in GLUT4 compared to C57BL/6J mice; and IV) to determine transcripitional and translational changes in WAT associated with visceral obesity and alterations following treatment with thiazolidinedione insulin sensitizers in hope of identifying novel therapeutic targets. Combined, this approach will provide a comprehensive systematic characterization of a mouse model of obesity associated CVD derived from early impairment of insulin-mediated glucose flux into WAT, and directly address for the first time whether alterations in Acrp30 influence disease progression.