UNCOUPLING PROTEIN 3 AND MUSCLE SUBSTRATE UTILIZATION

UCP3是一种新型解偶联蛋白，在骨骼肌中高表达，与人类脂肪酸氧化、肥胖和2型糖尿病有遗传联系。作为氧化磷酸化的解偶联剂，UCP3具有调节能量代谢的潜力。本研究的目的是确定UCP3在调节肌肉底物利用中的作用。最近的数据表明，肌肉UCP33 mRNA表达的变化与肌肉脂肪酸摄取和氧化的代谢变化呈正相关。脂肪酸及其衍生物调节各种细胞过程，因此必须严格调节以维持细胞的完整性和功能。包括肥胖和2型糖尿病在内的几种疾病状态与脂肪酸及其衍生物的细胞浓度升高有关，这表明不能充分调节细胞脂肪酸浓度可能会产生病理后果。我们假设，在脂肪酸和有毒中间体的状态下，通过刺激-氧化。由于肌肉脂质积累与胰岛素抵抗有关，我们也预测缺乏UCP3的肌肉可能具有胰岛素抵抗。本研究的具体目的是：1)确定肌肉UCP3是否特异性影响脂肪氧化而不是葡萄糖氧化，2)确定缺乏UCP3的病理生理意义（例如胰岛素抵抗），3)确定UCP3增加的保护作用。我们将通过检查UCP3敲除小鼠肌肉中缺乏UCP3的代谢影响，以及过度表达UCP3的肌细胞中UCP3增加的代谢影响来解决这些问题。

DESCRIPTION UCP3 is a novel uncoupling protein that is highly expressed in skeletal muscle and that has been genetically linked to fatty acid oxidation, obesity and type 2 diabetes in humans. As an uncoupler of oxidative phosphorylation, UCP3 has the potential to regulate energy metabolism. The purpose of this research is to determine the role of UCP3 in regulating muscle substrate utilization. Recent data indicate that changes in muscle UCP33 mRNA expression correlate positively with metabolic shifts in muscle fatty acid uptake and oxidation. Fatty acids and their derivatives modulate various cellular processes and must therefore by tightly regulated to maintain cell integrity and function. Several disease states, including obesity and type 2 diabetes, are associated with increased cell concentrations of fatty acids and their derivatives, suggesting that failure to adequately regulate cell fatty acid concentrations may have pathological consequences. We hypothesize that by stimulating beta-oxidation during states when fatty acids and toxic intermediates. Since muscle lipid accumulation has been linked to insulin-resistance, we also predict that muscles lacking UCP3 may be insulin resistant. The specific aims of this study are to: 1) determine whether muscle UCP3 specifically factors fat oxidation over that of glucose, 2) identify pathophysiological implications of absent UCP3 (e.g. insulin resistance) and 3) identify protective effects of increased UCP3. We will address these aims by examining the metabolic effects of absent UCP3 in muscles from UCP3 knock-out mice, and the metabolic effects of increased UCP3 in myocytes that over-express UCP3.