Novel pathways for fat burning that protects from high fat diet-induced metabolic

项目总和 美国的肥胖率正在上升，最近的统计数据估计，超过35.7%的 成年人和16.9%的儿童和青少年被认为肥胖。肥胖是胰岛素的一个危险因素 抵抗力、代谢综合征和心血管疾病。尽管它对公共健康很重要， 肥胖的发病机制还不是很清楚。糖尿病大鼠脂肪组织氧化应激增加 肥胖的人类和动物对过量的营养摄入的反应已经被记录在案。然而， 脂肪氧化应激在肥胖发病机制及其相关代谢改变中的作用 在听不懂的时候。为了解决这个问题，我们培育了体内超氧化物生成增加的小鼠 唯一的酶--锰超氧化物歧化酶的缺失对脂肪细胞的影响 负责将超氧化物解毒为线粒体基质中的过氧化氢。脂肪细胞- 特异性MnSODKO(AdSod2KO)小鼠瘦，有增加全身脂肪氧化和抵抗 饮食导致的葡萄糖耐受、胰岛素抵抗和肝脏脂肪变性。这件事的首要目标是 建议阐明脂肪氧化增强和代谢改善的机制。 AdSod2KO小鼠对HFD反应的动态平衡。这项提议有两个具体目标：具体 目标1将确定脂肪细胞MnSOD缺失和/或氧化的潜在机制 应激促进了全身脂肪的氧化。在这个目标下，我们将首先确定 白色和棕色脂肪组织、肝脏和骨骼肌促进全身脂肪氧化，然后 研究全身脂肪氧化的增加是由偶联还是去偶联引起的 线粒体氧化脂肪酸，并最终确定氧化还原依赖的机制可以增加 白色脂肪组织中的脂肪酸氧化。特定目标2将确定组织特定的机制 成熟脂肪细胞中MnSOD缺失和/或增强的氧化应激保护作用 高脂饲料诱导的小鼠糖耐量异常、胰岛素抵抗和肝脏脂肪变性。在这一目标下，我们 将检查脂肪细胞MnSOD缺失是否影响脂肪分解，确定脂肪细胞MnSOD是否 缺失和/或氧化应激增强HFD期间全身胰岛素敏感性和细胞功能 并确定已知和未知的脂肪分泌因子，这些因子可以调节有益的全身 饲喂HF对AdSod2KO小鼠代谢的影响。这些研究对肥胖有很高的影响 研究为脂肪组织氧化应激及其对整体的影响提供了新的范式 身体能量代谢和胰岛素敏感性。我们相信，这项研究将提供新的见解 关于新陈代谢的氧化还原调节，并可以识别可以调节的新靶点 增强全身脂肪氧化，预防胰岛素抵抗和糖尿病的发生 在肥胖期间。

PROJECT SUMMURY Obesity rates are increasing in the United States, with recent statistics estimating more than 35.7% of adults and 16.9% of children and adolescents are considered obese. Obesity is a risk factor for insulin resistance, the metabolic syndrome and cardiovascular disease. Despite its public health importance, the pathogenesis of obesity is not well understood. Increased oxidative stress in adipose tissue of obese humans and animals in response to excess nutrient intake has been documented. However, the role of adipose oxidative stress in the pathogenesis of obesity and its associated metabolic alterations in not understood. To address this, we generated mice with increased superoxide production in adipocytes through deletion of manganese superoxide dismutase (MnSOD), the sole enzyme responsible for detoxifying superoxide to hydrogen peroxide in the mitochondrial matrix. The adipocyte- specific MnSOD KO (AdSod2KO) mice are lean, have increased whole body fat oxidation and resist diet-induced glucose intolerance, insulin resistance and hepatic steatosis. The overarching goal of this proposal is to elucidate the mechanisms underlying enhanced fat oxidation and improved metabolic homeostasis in response to HFD in AdSod2KO mice. This proposal has two specific aims: Specific Aim 1 will identify the underlying mechanisms by which adipocyte MnSOD deletion and/or oxidative stress enhanced whole body fat oxidation. Under this aim, we will first determine the contribution of white and brown adipose tissue, liver and skeletal muscle in enhancing whole body fat oxidation, then investigate whether the increase in whole body fat oxidation results from coupled or uncoupled mitochondrial oxidation of fatty acid and finally identify redox-dependent mechanisms that can increase fatty acid oxidation in white adipose tissue. Specific Aim 2 will determine tissue-specific mechanisms by which MnSOD deletion and/or enhanced oxidative stress in mature adipocytes protects against HFD-induced glucose intolerance, insulin resistance and hepatic steatosis in mice. Under this aim, we will examine whether adipocyte MnSOD deletion affects lipolysis, determine if adipocyte MnSOD deletion and/or oxidative stress enhance whole body insulin sensitivity during HFD and ¿-cell function and identify known and unknown adipose-secreted factors that could mediate the beneficial systemic effect on metabolism during HF feeding in AdSod2KO mice. These studies have high impact on obesity research as it provides a new paradigm for adipose tissue oxidative stress and its impact on whole body energy metabolism and insulin sensitivity. We believe that this research will provide new insights on the redox-regulation of metabolism and could identify new targets that could be modulated to enhance whole body fat oxidation and protects from the development of insulin resistance and diabetes during obesity.