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: 8213559
• 负责人: MATTHEW W HULVER
• 金额: $ 32.47万
• 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/8213559
• 关键词: Animals; C3H/HeJ Mouse; Cell Culture Techniques; Development; Environment; Enzymes; Epidemic; Fatty Acids; Genes; Genetic Transcription; Heparin; Hormonal; Human; Human Cell Line; Hyperglycemia; Hyperinsulinism; Hyperlipidemia; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Infusion procedures; Insulin; Insulin Resistance; Invaded; Knock-out; Lead; Leptin resistance; Ligands; Link; Lipids; Liver; Measures; Mediating; Messenger RNA; Metabolic; Metabolic Diseases; Morbid Obesity; Mus; Muscle; Muscle Fibers; 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; insulin tolerance; 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）：肥胖和2型糖尿病是两种密切相关的代谢性疾病，其患病率以流行率增加。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有关，这是一种与受损的胰岛素信号转导相一致的现象。PI及其同事最近证明，骨骼肌中的SCD 1是导致脂肪酸（FA）氧化减少和肌内三酰甘油（IMTG）合成增加的核心机制。 迄今为止，尚未阐明肥胖人骨骼肌中介导升高的SCD 1活性的转录途径。 越来越多的证据表明，肥胖和代谢紊乱，包括胰岛素抵抗和T2 DM，与炎症密切相关。 Toll样受体（TLR）是跨膜受体，其在活化后通过转录活化核因子κ β（NF-κ B）（一种调节许多促炎基因表达的转录因子）在诱导炎症反应中起重要作用。 Toll样受体和NF-κ B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，通过NF-κ B的Toll样受体4（TLR 4）信号转导调节骨骼肌中的SCD 1转录和脂质蓄积。具体目标1：证明TLR 4信号通过NF-κ B调节小鼠和人类细胞系培养物中的SCD 1转录和脂质积累。具体目标2：证明TLR 4通过NF-kB信号传导有助于SCD 1的转录调节、脂质蓄积和高脂血症情况下小鼠骨骼肌中胰岛素抵抗的发展。具体目标3：证明TLR 4通过NF-κ B信号传导增加SCD 1活性，并有助于人体游离脂肪酸诱导的骨骼肌脂质蓄积和胰岛素抵抗。 Specific Aim 1提出在细胞培养中使用功能获得或丧失策略来证明TLR 4和NF-kB在转录上调节SCD 1。 具体目标2提出使用TLR 4突变体（C3 H/HeJ）和NF-kB敲除（nfkb 1- p105）动物来证明TLR 4和NF-kB两者对于SCD 1调节至关重要。 具体目标3提出研究TLR 4和NF-κ B在高血脂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识别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转录调节中的作用。 硬脂酰辅酶A去饱和酶-1是一种脂肪生成酶，已知其有助于肥胖人骨骼肌中的脂质积聚。 骨骼肌中的脂质积累有助于胰岛素抵抗的发展，胰岛素抵抗是2型糖尿病发展的危险因素。 重要的是，本申请中提出的实验可能导致用于治疗肥胖相关胰岛素抵抗的新的药理学靶点。

项目成果

Acute low-dose endotoxin treatment results in improved whole-body glucose homeostasis in mice.

• DOI: 10.1016/j.metabol.2016.12.008
• 发表时间: 2017-03
• 期刊: Metabolism: clinical and experimental
• 作者: Stevens JR;McMillan RP;Resendes JT;Lloyd SK;Ali MM;Frisard MI;Hargett S;Keller SR;Hulver MW
• 通讯作者: Hulver MW

Common gut microbial metabolites of dietary flavonoids exert potent protective activities in β-cells and skeletal muscle cells.

• DOI: 10.1016/j.jnutbio.2018.09.004
• 发表时间: 2018-12
• 期刊: The Journal of nutritional biochemistry
• 作者: Bitner BF;Ray JD;Kener KB;Herring JA;Tueller JA;Johnson DK;Tellez Freitas CM;Fausnacht DW;Allen ME;Thomson AH;Weber KS;McMillan RP;Hulver MW;Brown DA;Tessem JS;Neilson AP
• 通讯作者: Neilson AP

Low levels of lipopolysaccharide modulate mitochondrial oxygen consumption in skeletal muscle.

• DOI: 10.1016/j.metabol.2014.11.007
• 发表时间: 2015-03
• 期刊: Metabolism: clinical and experimental
• 作者: Frisard MI;Wu Y;McMillan RP;Voelker KA;Wahlberg KA;Anderson AS;Boutagy N;Resendes K;Ravussin E;Hulver MW
• 通讯作者: Hulver MW

Regulation of substrate oxidation preferences in muscle by the peptide hormone adropin.

• DOI: 10.2337/db14-0388
• 发表时间: 2014-10
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Gao S;McMillan RP;Jacas J;Zhu Q;Li X;Kumar GK;Casals N;Hegardt FG;Robbins PD;Lopaschuk GD;Hulver MW;Butler AA
• 通讯作者: Butler AA

Therapeutic effects of adropin on glucose tolerance and substrate utilization in diet-induced obese mice with insulin resistance.

脂肪素对具有胰岛素抵抗的饮食诱导的肥胖小鼠中葡萄糖耐受性和底物利用的治疗作用。

• DOI: 10.1016/j.molmet.2015.01.005
• 发表时间: 2015-04
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Gao S;McMillan RP;Zhu Q;Lopaschuk GD;Hulver MW;Butler AA
• 通讯作者: Butler AA