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

描述（由申请人提供）： 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是肥胖。肥胖是胰岛素抵抗、代谢综合征和心血管疾病的危险因素。尽管它的公共卫生的重要性，肥胖症的发病机制还没有得到很好的理解。已经有文献证明，肥胖的人和动物的脂肪组织中的氧化应激增加是对过量营养摄入的反应。然而，脂肪氧化应激在肥胖发病机制中的作用及其相关的代谢改变尚不清楚。为了解决这一问题，我们通过删除锰超氧化物歧化酶（MnSOD）产生了脂肪细胞中超氧化物产生增加的小鼠，锰超氧化物歧化酶是负责将线粒体基质中的超氧化物解毒为过氧化氢的唯一酶。脂肪细胞特异性MnSOD KO（AdSod 2KO）小鼠是瘦的，具有增加的全身脂肪氧化并且抵抗饮食诱导的葡萄糖耐受不良、胰岛素抗性和肝脂肪变性。该提案的总体目标是阐明AdSod 2KO小鼠中响应于HFD而增强脂肪氧化和改善代谢稳态的潜在机制。该提案有两个具体目标：具体目标1将确定脂肪细胞MnSOD缺失和/或氧化应激增强全身脂肪氧化的潜在机制。在此目标下，我们将首先确定白色和棕色脂肪组织、肝脏和骨骼肌在增强全身脂肪氧化中的作用，然后研究全身脂肪氧化的增加是否是由脂肪酸的偶联或非偶联线粒体氧化引起的，最后确定可以增加白色脂肪组织中脂肪酸氧化的氧化还原依赖性机制。具体目标2将确定成熟脂肪细胞中MnSOD缺失和/或增强的氧化应激保护小鼠免受HFD诱导的葡萄糖耐受不良、胰岛素抵抗和肝脂肪变性的组织特异性机制。在此目标下，我们将检查脂肪细胞MnSOD缺失是否影响脂解，确定脂肪细胞MnSOD缺失和/或氧化应激是否增强HFD和β细胞功能期间的全身胰岛素敏感性，并确定已知和未知的脂肪分泌因子，这些因子可以介导AdSod 2KO小鼠HF喂养期间对代谢的有益全身效应。这些研究对肥胖研究具有重要影响，因为它为脂肪组织氧化应激及其对全身能量代谢和胰岛素敏感性的影响提供了新的范式。我们相信，这项研究将为代谢的氧化还原调节提供新的见解，并可以确定新的靶点，这些靶点可以被调节以增强全身脂肪氧化，并防止肥胖期间胰岛素抵抗和糖尿病的发展。

DESCRIPTION (provided by applicant): 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.