Decreased Fat Oxidation - Metabolic Inflexibility in African-American Women

描述（由申请人提供）：与白人女性相比，非洲裔美国女性（AA）中肥胖和2型糖尿病（T2DM）的种族差异机制尚不清楚。虽然社会经济地位和饮食习惯等因素可能起作用，但新出现的数据表明，底物利用的差异可能导致这些差异。有证据表明，AA女性在一夜禁食、运动或高脂肪喂养后代谢不灵活，并且不会将脂肪氧化增加到高加索女性所观察到的水平。低脂肪氧化可能导致脂质重定向到脂肪组织储存，以及骨骼肌中甘油三酯和脂毒性代谢物的储存增加，导致胰岛素抵抗（IR）和糖尿病发展的风险增加。在AA女性中观察到更大的胰岛素抵抗。与白人女性相比，AA女性的这些观察结果与肥胖胰岛素抵抗个体相比的代谢不灵活性相似。虽然AA女性表现为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，因为内脏和肝脏脂质储存是IR和代谢性疾病的强烈危险因素。综上所述，这些数据表明，与高加索女性相比，AA女性的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，我们没有发现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，这些数据已被证明与肥胖和T2DM受试者的胰岛素抵抗有关。有限的数据支持AA女性骨骼肌中肌脂积累增加和胰岛素抵抗的作用，但我们没有发现关于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女性骨骼肌的内在差异导致骨骼肌中脂肪氧化和脂质及脂质代谢物的积累受损，并且是AA女性肥胖、胰岛素抵抗和2型糖尿病发展之间的联系。为了解决这一假设，我们制定了3个目标：1)确定AA和高加索女性在亚极限运动期间的脂肪氧化；2)确定与胰岛素敏感性相关的脂质积累和骨骼肌特征（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。在我们开始梳理在脂肪氧化和胰岛素敏感性的种族差异中起作用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体外评估，将提供详细的表型信息，这将为观察到AA女性中II型糖尿病患病率增加提供有价值的见解。

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. PUBLIC HEALTH RELEVANCE: The likelihood of being obese or having diabetes is twice as high in African-American women compared to Caucasian women. Reasons for these health disparities are not understood, but growing evidence suggests that lower fat oxidation in AA women leads to accumulation of fat within skeletal muscle which can lead to the development of insulin resistance and diabetes. Before we can begin to understand the environmental and genetic factors that play a role in racial differences in obesity and diabetes, we need to gain a better understanding of the metabolism and skeletal muscle characteristics related to fat oxidation which may lead to the increased risk of development of metabolic diseases in AA women.