Dysregulated Muscle Lipid Metabolism in African-Americans

描述（由申请人提供）：在美国，非裔美国女性（AAW）的肥胖和糖尿病患病率高于白人女性（CW）。虽然环境因素可能有影响，但肥胖的AAW已被证明具有内在的代谢缺陷，可以抑制骨骼肌的脂质氧化。然而，更令人吃惊的是，新出现的证据表明，这些缺陷可能在非肥胖的AAW中预先存在，使该种族比CW更容易出现脂肪增加。这一点非常重要，因为由此导致的肌内脂质含量增加与胰岛素抵抗和糖尿病密切相关。尽管这些发现具有重要意义，但解释这种种族/民族特异性代谢功能障碍的细胞机制仍未明确。我们的主要假设是，肥胖/糖尿病前AAW的骨骼肌氧化长链脂肪酸（LCFA）的能力固有受损，导致生物活性脂质的细胞毒性积累，并导致胰岛素抵抗和糖尿病的沉淀。然而，在瘦型连续肌中，耐力运动训练（EET）刺激线粒体生物发生，提高肌肉氧化LCFA的能力。我们的第二个假设是AAW会通过增加骨骼肌氧化脂质的能力来响应EET，从而降低患肥胖和糖尿病的倾向。本研究的目的是1)确定瘦骨病AAW中骨骼肌LCFA氧化功能障碍的预先存在的细胞位点，2)确定AAW是否对EET有反应。为了实现我们的目标，我们将调查12名久坐、瘦弱的AAW和CW，他们的年龄、BMI （< 25 kg/m2）和月经状况相匹配。来自两个种族的肥胖受试者将被评估以进行比较。骨骼肌LCFA氧化能力将通过捕获由完整肌条和匀浆（腹直肌）氧化产生的标记14CO2来测量，以确定脂质代谢中的特定细胞缺陷是由于1)线粒体前事件2)LCFA对酰基辅酶a的线粒体激活3)LCFA在线粒体膜上的运输和/或4)运输后线粒体氧化系统。全身胰岛素敏感性测量将用于确定骨骼肌脂质代谢状态与胰岛素作用之间的关联强度。aim 1和新招募的一部分受试者将进行7天和8周的EET（循环），以确定慢性肌肉活动（股外侧肌）对AAW中线粒体生物发生、LCFA氧化和胰岛素作用的影响。我们的研究结果将用于后续的RO1应用，以实现我们的长期目标，即了解AAW中与肥胖和糖尿病相关的更高发病率和死亡率的机制。

DESCRIPTION (provided by applicant): The prevalence of obesity and diabetes is greater among African-American (AAW) than Caucasian women (CW) in the United States. Although environmental factors may be influential, obese AAW have been shown to possess inherent metabolic defects that suppress lipid oxidation by skeletal muscle. More startling however, is the emerging evidence that these defects may pre-exist in non-obese AAW, predisposing this racial group toward a more rapid onset of fat gain vs. CW. This is fundamentally important because the resultant increase in intramuscular lipid content is strongly linked with insulin resistance and diabetes. Despite the significance of these findings, the cellular mechanisms to explain this racial/ethnic specific metabolic dysfunction remain undefined. Our primary hypothesis is that pre-obese/diabetic AAW possess skeletal muscle with an inherent impairment in the capacity to oxidize long-chain fatty acids (LCFA), leading to a cytotoxic accumulation of bioactive lipids, and precipitation of insulin resistance and diabetes. However, in lean CW, endurance exercise training (EET) stimulates mitochondrial biogenesis, elevating the muscles capacity to oxidize LCFA. Our secondary hypothesis is that AAW will respond to EET by increasing the capacity of skeletal muscle to oxidize lipids, thus reducing the propensity toward developing obesity and diabetes. The aims of the present investigation are 1) to identify the pre-existing cellular site(s) of dysfunction in skeletal muscle LCFA oxidation in lean AAW and 2) to determine whether AAW are responsive to EET. To accomplish our aims, we will investigate 12 sedentary, lean AAW and CW matched for age, BMI (< 25 kg/m2), and menstrual status. Obese subjects from both races will be assessed for comparisons. Skeletal muscle LCFA oxidative capacity will be measured by trapping labeled 14CO2 derived from oxidation by intact muscle strips and homogenates (rectus abdominus) in order to identify the specific cellular defects in lipid metabolism as being due to 1) pre-mitochondrial events 2) mitochondrial activation of LCFA to acyl-CoA 3) the transport of LCFA across the mitochondrial membrane and/or 4) the post-transport mitochondrial oxidative system. Measures of whole body insulin sensitivity will be made to determine the strength of association between the status of skeletal muscle lipid metabolism and insulin action. A subset of subjects from aim 1 and new recruits will undergo 7 days and 8 weeks of EET (cycling) to determine the impact of chronic muscle activity (vastus lateralis) on mitochondrial biogenesis, oxidation of LCFA, and insulin action in AAW. Our findings will be used for subsequent RO1 applications to achieve our Iong-term objective of understanding the mechanism(s) that underlie the greater morbidity and mortality associated with obesity and diabetes in AAW.