Decreased Fat Oxidation - Metabolic Inflexibility in African-American Women

脂肪氧化减少 - 非裔美国女性代谢不灵活

• 批准号: 8280424
• 负责人: James P DeLany
• 金额: $ 44.93万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280424
• 关键词: Acyl Coenzyme A; Address; Adipose tissue; African American; Biopsy; Blood capillaries; Cardiovascular Diseases; Caucasians; Caucasoid Race; Ceramides; Characteristics; Chronic Disease; Comparative Study; Data; Deposition; Development; Diabetes Mellitus; Diet Habits; Enzymes; Evaluation; Exercise; Exercise stress test; Fatty acid glycerol esters; Genetic; Hepatic; Hypertension; Individual; Insulin Resistance; Intramuscular; Lead; Link; Lipids; Liver; Mediator of activation protein; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Outcome; Peripheral; Phenotype; Physiology; Plasma; Play; Prevalence; Reporting; Risk; Risk Factors; Role; Skeletal Muscle; Slow-Twitch Muscle Fibers; Socioeconomic Status; Techniques; Triglycerides; Visceral; Woman; base; capillary; density; fatty acid oxidation; feeding; glucose production; health disparity; in vivo; insight; insulin sensitivity; oxidation; racial difference; vastus lateralis

DESCRIPTION (provided by applicant): Mechanisms responsible for the racial disparity in obesity and Type 2 diabetes (T2DM) that are particularly apparent in African-American (AA) women compared to Caucasian women are not understood. While factors such as socioeconomic status and dietary habits likely play a role, emerging data suggests that differences in substrate utilization may contribute to these disparities. Evidence suggests that AA women are metabolically inflexible after an overnight fast, during exercise, or during high fat feeding, and do not increase fat oxidation to levels observed in Caucasian women. Low fat oxidation could result in redirection of lipid into adipose tissue for storage, as well as increased storage of triglyceride and lipotoxic metabolites within skeletal muscle, leading to insulin resistance (IR) and increased risk for development of diabetes. Greater insulin resistance is observed in AA women. These observations in AA compared to Caucasian women are similar to the metabolic inflexibility observed in obese insulin resistant compared to lean individuals. While AA women demonstrate IR, they have lower levels of visceral and hepatic lipid accumulation. This is a paradoxical finding as visceral and hepatic lipid stores are strong risk factors for IR and metabolic diseases. Taken together, the data suggests that IR is phenotypically distinct in AA compared to Caucasian women, and that the lower insulin sensitivity may be due differences in skeletal muscle, leading to peripheral IR. However, we could find no reports comparing hepatic and peripheral insulin sensitivity, and very limited data in AA women for skeletal muscle characteristics that have been demonstrated to be related to insulin resistance in obese and T2DM subjects. Limited data supports a role for increased muscle lipid accumulation in skeletal muscle and insulin resistance in AA women, but we could find no data on lipotoxic lipid levels or mitochondrial content in AA women. Based on these observations, our hypothesis is that inherent differences in skeletal muscle in AA women results in impaired fat oxidation and accumulation of lipid and lipid metabolites within skeletal muscle, and is a link between the development of obesity, insulin resistance and Type 2 diabetes in AA women. To address this hypothesis we have developed 3 Aims: 1) Determine fat oxidation during sub-maximal exercise in AA and Caucasian women; 2) Determine lipid accumulation and skeletal muscle characteristics (e.g. muscle fiber type, capillary density, oxidative capacity, mitochondrial content) that have been shown to be related to insulin sensitivity; and 3) Assess insulin sensitivity (peripheral and hepatic), and examine the relationship between insulin sensitivity, fat oxidation and skeletal muscle characteristics. Before we can begin to tease apart environmental and genetic factors that play a role in racial differences in fat oxidation and insulin sensitivity, we need to gain a better understanding of the underlying physiology. The detailed in vivo and ex vivo evaluations we propose using state of the art techniques will provide detailed phenotype information that will provide valuable insight into the increased prevalence of Type II diabetes observed in AA women.

描述（由申请人提供）：与白人女性相比，肥胖和 2 型糖尿病 (T2DM) 方面的种族差异在非洲裔美国 (AA) 女性中尤为明显，其机制尚不清楚。虽然社会经济地位和饮食习惯等因素可能发挥作用，但新出现的数据表明，基质利用率的差异可能会导致这些差异。有证据表明，AA 女性在禁食过夜、运动期间或高脂肪喂养期间代谢不灵活，并且不会将脂肪氧化增加到白种人女性中观察到的水平。低脂肪氧化可能导致脂质重新定向到脂肪组织中进行储存，以及骨骼肌内甘油三酯和脂毒性代谢物的储存增加，从而导致胰岛素抵抗（IR）并增加患糖尿病的风险。 AA 女性的胰岛素抵抗程度更高。与白人女性相比，AA 中的这些观察结果与肥胖胰岛素抵抗者与瘦人相比观察到的代谢不灵活相似。虽然 AA 女性表现出 IR，但她们的内脏和肝脏脂质积累水平较低。这是一个矛盾的发现，因为内脏和肝脏的脂质储存是 IR 和代谢疾病的强烈危险因素。综上所述，数据表明，与白人女性相比，AA 中的 IR 在表型上有所不同，胰岛素敏感性较低可能是由于骨骼肌的差异，导致外周 IR。然而，我们没有找到比较肝脏和外周胰岛素敏感性的报告，并且 AA 女性骨骼肌特征的数据非常有限，这些特征已被证明与肥胖和 T2DM 受试者的胰岛素抵抗相关。有限的数据支持 AA 女性骨骼肌中肌肉脂质积累增加和胰岛素抵抗的作用，但我们找不到关于 AA 女性脂毒性脂质水平或线粒体含量的数据。基于这些观察，我们的假设是，AA 女性骨骼肌的固有差异导致脂肪氧化受损以及骨骼肌内脂质和脂质代谢物的积累，并且是 AA 女性发生肥胖、胰岛素抵抗和 2 型糖尿病之间的联系。 为了解决这一假设，我们制定了 3 个目标：1）确定 AA 和白人女性在次最大运动期间的脂肪氧化； 2) 确定已被证明与胰岛素敏感性相关的脂质积累和骨骼肌特征（例如肌纤维类型、毛细血管密度、氧化能力、线粒体含量）； 3) 评估胰岛素敏感性（外周和肝脏），并检查胰岛素敏感性、脂肪氧化和骨骼肌特征之间的关系。在我们开始梳理影响脂肪氧化和胰岛素敏感性种族差异的环境和遗传因素之前，我们需要更好地了解潜在的生理学。我们建议使用最先进的技术进行详细的体内和离体评估，将提供详细的表型信息，这将为了解 AA 女性中观察到的 II 型糖尿病患病率增加提供有价值的见解。