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

基本信息

批准号：
8923259
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-16 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8923259
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 Health 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 response sedentary statistics

项目摘要

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.

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肥胖，尽管它影响公共健康，但它仍然是胰岛素抵抗、代谢综合征和心血管疾病的危险因素。重要性，肥胖的发病机制尚不清楚。肥胖人类和动物的脂肪组织中的氧化应激因过量营养摄入而增加，但脂肪的作用已被证实。肥胖发病机制中的氧化应激及其相关的代谢改变尚不清楚。为了解决这个问题，我们通过删除锰超氧化物歧化酶（MnSOD）（负责将超氧化物解毒为过氧化氢的唯一酶）来培养脂肪细胞中超氧化物产量增加的小鼠。脂肪细胞特异性 MnSOD KO (AdSod2KO) 小鼠身材瘦削，全身脂肪氧化增加，并能抵抗饮食引起的葡萄糖不耐受，该提案的首要目标是阐明 AdSod2KO 小鼠中脂肪氧化增强和代谢稳态改善的机制。该提案有两个具体目标：具体目标 1 将确定其潜在机制。脂肪细胞 MnSOD 缺失和/或氧化应激增强了全身脂肪氧化。在此目标下，我们将首先确定白色和棕色脂肪组织、肝脏和脂肪细胞的贡献。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。将确定成熟脂肪细胞中 MnSOD 缺失和/或氧化应激增强可防止 HFD 诱导的葡萄糖不耐受、胰岛素抵抗和在此目标下，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 缺失和/或氧化应激是否会增强 HFD 期间的全身胰岛素敏感性和细胞功能，并识别已知和未知的脂肪分泌因子。这些研究对肥胖研究具有重大影响，因为它为脂肪组织提供了新的范例。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，并可以确定可调节的新靶标，以增强全身脂肪氧化并防止其发展。肥胖期间的胰岛素抵抗和糖尿病。