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: 7571698
• 负责人: MATTHEW W HULVER
• 金额: $ 31.59万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571698
• 关键词: Animals; C3H/HeJ Mouse; Cell Culture Techniques; Development; Environment; Enzymes; Epidemic; Fatty Acids; Genes; Genetic Transcription; H-Cadherin; Heparin; Hormonal; Human; Human Cell Line; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Insulin; Insulin Resistance; Invaded; Knock-out; Knowledge; Lead; Leptin resistance; Ligands; Link; Lipids; Liver; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Morbid Obesity; Mus; Muscle; Muscle Fibers; Mutant Strains Mice; NF-kappa B; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Nutritional; Obesity; Organ; Palmitates; Pancreas; Pathogenesis; Pathway interactions; Play; Prevalence; Receptor Signaling; Regulation; Reporting; Resistance; Risk Factors; Role; Signal Pathway; Signal Transduction; Skeletal Muscle; 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; obesity treatment; public health relevance; receptor; research study; response; stearoyl-coenzyme A; toll-like receptor 4; transcription factor

DESCRIPTION (provided by applicant): 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 (NF-kB), 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 that TLR4 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 (nfkb1- 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. Project Narrative (Public Health Relevance): The primary objective of the current proposal is to discern the role of toll-like recpeptor-4 and nuclear factor kappa beta activation in the transcriptional regulation of stearoyl-CoA desaturase-1. Stearoyl-CoA deaturase-1 is a lipogenic enzyme that is known to contribute to lipid accumulation in skeletal muscle of obese humans. Lipid accumulation in skeletal muscle contributes to the development of insulin resistance, which is a risk factor for the development of type 2 diabetes. Importantly, the experiments proposed in the current application may lead to novel pharmacological targets for the treatment of obesity-associated insulin resistance.

描述（由申请人提供）：肥胖症和2型糖尿病是两种密切相关的代谢性疾病，发病率正以流行病的速度上升。PI和其他人已经表明，人类肥胖与骨骼肌细胞内脂质异常积累有关，这种现象与胰岛素信号转导受损同时发生。PI及其同事最近证明，骨骼肌中的SCD1是肥胖患者减少脂肪酸（FA）氧化和增加细胞内甘油三酯（IMTG）合成的核心机制。迄今为止，肥胖人群骨骼肌中介导SCD1活性升高的转录途径尚未被阐明。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，与炎症密切相关。toll样受体（TLR）是跨膜受体，在激活后，通过转录激活核因子κ β (NF-kB)在诱导炎症反应中发挥重要作用，NF-kB是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。PI提供的初步证据表明，toll样受体4 （TLR4）通过NF-kB信号传导调节骨骼肌SCD1转录和脂质积累。具体目的1：证明TLR4信号通过NF-kB调节SCD1转录和脂质积累在小鼠和人类细胞系培养。特异性目的2：证明TLR4信号通过NF-kB参与高脂血症小鼠骨骼肌SCD1、脂质积累和胰岛素抵抗的转录调节。特定目的3：证明TLR4信号通过NF-kB增加SCD1活性，并有助于人类游离脂肪酸诱导的骨骼肌脂质积累和胰岛素抵抗。Specific Aim1提出在细胞培养中使用功能增益或损失策略来证明TLR4和NF-kB在转录上调节SCD1。Specific Aim 2提出使用TLR4突变体（C3H/HeJ）和NF-kB敲除（nfkb1- p105）动物来证明TLR4和NF-kB对SCD1调控都至关重要。特异性目的3旨在研究TLR4和NF-kB在人类高脂血症诱导的骨骼肌脂质积累和胰岛素抵抗中的作用。项目叙述（公共卫生相关性）：当前提案的主要目的是辨别toll样受体-4和核因子κ β激活在硬脂酰辅酶a去饱和酶-1转录调控中的作用。硬脂酰辅酶a去饱和酶-1是一种脂肪生成酶，已知有助于肥胖人群骨骼肌中的脂质积累。骨骼肌中的脂质积累有助于胰岛素抵抗的发展，这是2型糖尿病发展的一个危险因素。重要的是，当前应用中提出的实验可能会导致治疗肥胖相关胰岛素抵抗的新药理学靶点。