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

新型脂肪燃烧途径可防止高脂肪饮食引起的代谢

• 批准号: 8632675
• 负责人: Sihem Boudina
• 金额: $ 32.41万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632675
• 关键词: Address; Adipocytes; Adipose tissue; Adolescent; Adoption; Adult; Affect; Animals; Body fat; Brown Fat; Burn injury; Cardiovascular Diseases; Cell physiology; Child; Communication; Country; Coupled; Development; Diabetes Mellitus; Diet; Disease; Energy Metabolism; Enzymes; Epidemic; Exhibits; Fatty Liver; Fatty acid glycerol esters; Food; Glucose Intolerance; Goals; Homeostasis; Human; Hydrogen Peroxide; Insulin Resistance; Intake; Ions; Leptin; Life Style; Lipolysis; Liver; Manganese Superoxide Dismutase; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Mitochondrial Matrix; Mus; Nonesterified Fatty Acids; Nutrient; Obesity; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pathogenesis; Pathway interactions; Production; Proteins; Public Health; Regulation; Research; Risk Factors; Role; Skeletal Muscle; Superoxides; Testing; Tissues; United States; blood glucose regulation; cost; fatty acid oxidation; feeding; improved; in vivo; insight; insulin secretion; insulin sensitivity; lipid biosynthesis; mouse model; novel; oxidation; public health relevance; response; sedentary; statistics

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.

项目总结 美国的肥胖率正在上升，最近的统计数据估计超过35.7% 成人和16.9%的儿童和青少年被认为是肥胖。肥胖是胰岛素的危险因素 抵抗力、代谢综合征和心血管疾病。尽管它对公众健康很重要， 肥胖症的发病机理还不清楚。脂肪组织氧化应激增加 肥胖的人类和动物响应于过量的营养摄入已经被记录。但 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 不被理解。为了解决这一问题，我们产生了超氧化物产生增加的小鼠， 通过缺失锰超氧化物歧化酶（MnSOD）， 负责在线粒体基质中将超氧化物解毒为过氧化氢。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和抵抗 饮食诱导的葡萄糖耐受不良、胰岛素抵抗和肝脂肪变性。这个项目的首要目标是 建议是阐明增强脂肪氧化和改善代谢的机制， 在AdSod 2KO小鼠中响应于HFD的稳态。该提案有两个具体目标： 目的1将确定脂肪细胞MnSOD缺失和/或氧化损伤的潜在机制。 应激增强全身脂肪氧化。在这个目标下，我们将首先确定 白色和棕色脂肪组织、肝脏和骨骼肌在增强全身脂肪氧化方面， 研究全身脂肪氧化的增加是否是由偶联或非偶联引起的 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。具体目标2将确定组织特异性机制 通过MnSOD缺失和/或成熟脂肪细胞中增强的氧化应激来防止 HFD诱导的小鼠葡萄糖耐受不良、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缺失是否影响脂解，确定脂肪细胞MnSOD 缺失和/或氧化应激增强HFD期间的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，可以介导有益的系统性 对AdSod 2KO小鼠HF喂养期间代谢的影响。这些研究对肥胖有很大的影响 研究，因为它提供了一个新的范例，脂肪组织氧化应激及其对整体的影响 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 代谢的氧化还原调节，并可以确定新的目标，可以调制， 增强全身脂肪氧化，防止胰岛素抵抗和糖尿病的发展 在肥胖期间。