Inflammatory regulation of lipid accumulation in skeletal muscle with obesity

肥胖和2型糖尿病是两种密切相关的代谢性疾病，在 按流行率计算的流行率。PI和其他人已经表明，人类肥胖与 骨骼肌细胞内脂质的异常堆积，这一现象与 胰岛素信号转导受损。PI和他的同事们最近证明了SCD1在骨骼中 肌肉是减少脂肪酸(FA)氧化和增加细胞内脂肪含量的核心机制 肥胖与三酰甘油(IMTG)合成。到目前为止，转录途径(S)介导的升高 肥胖者骨骼肌中的SCD1活性尚未阐明。越来越多的证据表明 肥胖和代谢紊乱，包括胰岛素抵抗和2型糖尿病，与 发炎。Toll样受体(TLR)是一种跨膜受体，在激活后发挥重要的作用。 在转录激活核因子-kappaB(NFkB)诱导炎症反应中的作用 一种转录因子，调节许多促炎基因的表达。Toll样受体 而核因子-kB与脂质诱导的骨骼肌胰岛素抵抗有关。初步证据 由PI提供的信息表明，Toll样受体4(TLR4)通过核因子-kB信号调节SCD1 骨骼肌中的转录和脂肪积累。具体目标1：证明TLR4信号 核因子-kB调控人和鼠细胞SCD1转录和脂质堆积 台词。特定目的2：证明TLR4信号通过核因子-kB参与转录 小鼠骨骼肌中SCD1、脂质蓄积与胰岛素抵抗的发生发展 在高脂血症的情况下。具体目标3：证明TLR4信号通过核因子-kB增加 SCD1活性与游离脂肪酸诱导的骨骼肌脂蓄积和胰岛素有关 人类的抵抗力。特殊的Aim1建议在细胞培养中使用“获得或失去功能”的策略 为了证明TLR4和NF-kB在转录水平上调节SCD1。具体目标2建议使用 TLR4突变体(C3H/HeJ)和核因子-kB基因敲除(nfkb1-p105)动物的实验证明TLR4和 核因子-kB对SCD1的调控起着至关重要的作用。具体目标3建议审查TLR4和TLR4的作用 核因子-kB在高脂诱导的人类骨骼肌脂积聚和胰岛素抵抗中的作用。

Obesity and type 2 diabetes mellitus are two closely connected metabolic diseases that are increasing in prevalence at epidemic rates. The PI and others have shown that human obesity is associated with abnormal accumulation of lipids within the skeletal muscle cell, a phenomenon that occurs in-concert with impaired insulin signal transduction. The PI and colleagues recently demonstrated that SCD1 in skeletal muscle is a core mechanism contributing to reduced fatty acid (FA) oxidation and increased intramyocellular triacylglycerol (IMTG) synthesis with obesity. To date, the transcriptional pathway(s) mediating elevated SCD1 activity in skeletal muscle of obese humans have not been elucidated. Growing evidence suggests that obesity and metabolic disorders, including insulin resistance and T2DM, are tightly associated with inflammation. Toll-like receptors (TLR) are transmembrane receptors that, upon activation, play an important role in the induction of inflammatory responses by transcriptionally activating nuclear factor kappa beta (NFkB), a transcription factor that regulates the expression of many pro-inflammatory genes. Toll-like receptors and NF-kB have been linked to lipid-induced skeletal muscle insulin resistance. Preliminary evidence provided by the PI suggests that toll-like receptor 4 (TLR4) signaling through NF-kB modulates SCD1 transcription and lipid accumulation in skeletal muscle. SPECIFIC AIM 1: Demonstrate thatTLR4 signaling through NF-kB modulates SCD1 transcription and lipid accumulation in cultures of mouse and human cell lines. SPECIFIC AIM 2: Demonstrate that TLR4 signaling through NF-kB contributes to transcriptional regulation of SCD1, lipid accumulation, and the development of insulin resistance in skeletal muscle of mice in situations of hyperlidemia. SPECIFIC AIM 3: Demonstrate that TLR4 signaling through NF-kB increases SCD1 activity and contributes to free fatty acid-induced skeletal muscle lipid accumulation and insulin resistance in humans. Specific Aim1 proposes the use of "gain or loss of function" strategies in cell culture to demonstrate that TLR4 and NF-kB are transcriptionally regulating SCD1. Specific Aim 2 proposes the use of TLR4 mutant (C3H/HeJ) and NF-kB knockout (nfkbl -p105) animals to demonstrate that both TLR4 and NF-kB are critically important for SCD1 regulation. Specific Aim 3 proposes to examine the role of TLR4 and NF-kB in hyperlidemic-induced skeletal muscle lipid accumulation and insulin resistance in humans.