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: 7768417
• 负责人: MATTHEW W HULVER
• 金额: $ 36.58万
• 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/7768417
• 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(申请人提供)：肥胖和2型糖尿病是两种密切相关的代谢性疾病，其患病率正在以流行病的速度增加。PI和其他研究人员已经表明，人类肥胖与骨骼肌细胞内脂质的异常积累有关，这种现象与胰岛素信号转导受损同时发生。PI和他的同事们最近证明，骨骼肌中的SCD1是肥胖导致脂肪酸(FA)氧化减少和肌内三酰甘油(IMTG)合成增加的核心机制。到目前为止，肥胖者骨骼肌中SCD1活性升高的转录途径(S)还没有被阐明。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(Toll-like Receptor，TLR)是一种跨膜受体，激活后通过转录激活核因子-kB(NF-kB)在诱导炎症反应中发挥重要作用。核因子-kB是一种转录因子，调节许多促炎基因的表达。Toll样受体和核因子-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)通过核因子-kB信号调节SCD1转录和骨骼肌中脂质的积累。特异性目的1：证实TLR4信号通过核因子-kB调节人和鼠细胞系培养物中SCD1的转录和脂质的积累。特异性目的2：证实TLR4信号通过核因子-kB参与高脂血症小鼠骨骼肌中SCD1的转录调控、脂肪堆积和胰岛素抵抗的发生。具体目的3：证明TLR4信号通过核因子-kB增加SCD1活性，并促进游离脂肪酸诱导的骨骼肌脂沉积和胰岛素抵抗。特异性Aim1提出在细胞培养中使用获得或失去功能的策略来证明TLR4和NF-kB在转录上调节SCD1。特定目的2建议使用TLR4突变(C3H/HeJ)和NF-kB基因敲除(nfkb1-p105)动物来证明TLR4和NF-kB对SCD1的调控都是至关重要的。具体目标3建议研究TLR4和核因子-kB在高脂诱导的人类骨骼肌脂类堆积和胰岛素抵抗中的作用。项目叙述(与公共卫生相关)：当前提案的主要目标是辨别Toll样受体-4和核因子kappaβ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脱氢酶-1是一种脂肪生成酶，可促进肥胖人群骨骼肌中的脂肪堆积。骨骼肌中的脂肪堆积有助于胰岛素抵抗的发展，而胰岛素抵抗是2型糖尿病发生的危险因素。重要的是，目前申请中提出的实验可能会为肥胖相关的胰岛素抵抗的治疗带来新的药理靶点。