Inflammatory regulation of lipid accumulation in skeletal muscle with obesity

肥胖骨骼肌脂质积累的炎症调节

• 批准号: 7433660
• 负责人: MATTHEW W HULVER
• 金额: $ 15.67万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-04 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7433660
• 关键词: Animals; C3H/HeJ Mouse; Cultured Cells; Development; Disruption; Environment; Epidemic; Fatty Acids; Genes; Genetic Transcription; H-Cadherin; Heparin; Hormonal; Human; Human Cell Line; Hyperglycemia; Hyperinsulinism; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Invaded; Knock-out; Knowledge; Leptin resistance; Ligands; Link; Lipids; Liver; Measurement; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Morbid Obesity; Mus; Muscle; Muscle Cells; Muscle Fibers; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; Obesity; Organ; Palmitates; Pancreas; Pathogenesis; Pathway interactions; Play; Prevalence; Rate; Receptor Signaling; Regulation; Reporting; Resistance; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; Skeletal system; Societies; Stearoyl-CoA Desaturase; TNFRSF5 gene; Tissues; Toll-like receptors; Transcriptional Regulation; Triglycerides; base; blood glucose regulation; fatty acid oxidation; glucose tolerance; glucose transport; insulin sensitivity; insulin signaling; loss of function; mutant; novel; receptor; response; toll-like receptor 4; transcription factor

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.

肥胖和2型糖尿病是两种密切相关的代谢疾病， 以流行病的速度流行。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积累，这种现象与 胰岛素信号转导受损。PI及其同事最近证明，骨骼肌中的SCD 1 肌肉是一个核心机制，有助于减少脂肪酸（FA）氧化和增加肌细胞内 三酰甘油（IMTG）合成与肥胖。到目前为止，转录途径介导的升高 尚未阐明肥胖人骨骼肌中的SCD 1活性。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， 炎症Toll样受体（TLR）是跨膜受体，其在活化后，在细胞内起重要的调节作用。 在通过转录激活核因子κ β（NF κ B）诱导炎症反应中的作用， 一种调节许多促炎基因表达的转录因子。toll样受体 和NF-kB与脂质诱导的骨骼肌胰岛素抵抗有关。初步证据 PI提供的结果表明，Toll样受体4（TLR 4）信号通过NF-κ B调节SCD 1 在骨骼肌中的转录和脂质积累。具体目标1：证明TLR 4信号传导 通过NF-kB调节小鼠和人类细胞培养物中的SCD 1转录和脂质积累 线特异性目的2：证明TLR 4通过NF-κ B信号转导有助于转录 小鼠骨骼肌中SCD 1的调节、脂质积累和胰岛素抵抗的发展 在高血脂症的情况下。具体目标3：证明通过NF-κ B的TLR 4信号传导增加 SCD 1活性，并有助于游离脂肪酸诱导的骨骼肌脂质蓄积和胰岛素 人类的抵抗力具体目标1建议在细胞培养中使用“功能获得或丧失”策略 以证明TLR 4和NF-kB在转录上调节SCD 1。具体目标2建议使用 TLR 4突变体（C3 H/HeJ）和NF-kB敲除（nfkbl-p105）动物，以证明TLR 4和NF-kB基因敲除（nfkbl-p105）动物的免疫应答。 NF-kB对SCD 1调节至关重要。具体目标3建议检查TLR 4的作用， NF-kB在高血脂诱导的骨骼肌脂质蓄积和胰岛素抵抗中的作用