Interleukin-10 and Regulation of Skeletal Muscle Insulin Action

IL-10 和骨骼肌胰岛素作用的调节

• 批准号: 8325167
• 负责人: JASON K KIM
• 金额: $ 32.25万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325167
• 关键词: 1,2-diacylglycerol; 1-Phosphatidylinositol 3-Kinase; 3-Phosphoinositide Dependent Protein Kinase-1; Acute; Adipose tissue; Affect; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Architecture; Attenuated; Breeding; C57BL/6 Mouse; CCL2 gene; CCR; Chronic; Cytokine Inducible SH2-Containing Protein; Data; Defect; Development; Dichloromethylene Diphosphonate; Diet; Diglycerides; Down-Regulation; Energy Metabolism; Euglycemic Clamping; Fatty Acids; Fatty acid glycerol esters; Genes; Genetic; Glucose Clamp; Goals; Health; Human; Infiltration; Inflammation; Inflammatory; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Interleukin-10; Interleukin-6; Intracellular Accumulation of Lipids; Intramuscular; JUN gene; Label; Leptin; Lipids; Liposomes; MAPK8 gene; Macrophage Inflammatory Protein-1; Measures; Mediating; Metabolic; Metabolic syndrome; Methods; Modeling; Molecular Profiling; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Pathway interactions; Phenotype; Phosphorylation; Phosphotransferases; Plasma; Play; Protein Kinase C; Protein-Serine-Threonine Kinases; Proteins; Regulation; Reporting; Research; Role; STAT3 gene; Serine; Signal Transduction; Signaling Protein; Skeletal Muscle; TNF gene; Testing; Transgenic Mice; Triglycerides; Tumor Necrosis Factor-alpha; Wild Type Mouse; adenylate kinase; attenuation; base; cytokine; diabetic; feeding; glucose metabolism; in vivo; insight; insulin sensitivity; insulin signaling; lipid metabolism; macrophage; migration; monocyte; mouse model; new therapeutic target; novel; overexpression; prevent; protective effect; resistance mechanism; therapeutic target; transgene expression

DESCRIPTION (provided by applicant): Skeletal muscle insulin resistance plays a primary role in the development of type 2 diabetes and may be causally associated with inflammation and altered lipid metabolism. Circulating levels of fatty acids and pro-inflammatory cytokines are elevated in obese, diabetic subjects and shown to cause insulin resistance in skeletal muscle. In contrast, plasma levels of IL-10, an anti-inflammatory cytokine, are positively related to insulin sensitivity and reduced in subjects with metabolic syndrome. We have recently shown that acute treatment with IL-10 prevents lipid-mediated insulin resistance in muscle that is associated with increased insulin signaling in mice. To further examine the role of IL-10 in skeletal muscle insulin action, we have recently generated transgenic mice with muscle-specific overexpression of IL-10 (MCK-IL10 mice). Our preliminary data indicate that MCK-IL10 mice are protected from lipid- mediated defects in insulin signaling and glucose metabolism in muscle. We also find that diet-induced insulin resistance is associated with increased macrophage infiltration in skeletal muscle, and these effects are attenuated in MCK-IL10 mice. We hypothesize that IL-10 prevents muscle insulin resistance by 1) blocking lipid-mediated activation of PKC-8/JNK/IKK and down regulation of insulin signaling, and/or 2) suppressing obesity-associated macrophage infiltration and inhibiting the deleterious effects of macrophage-derived cytokines on glucose metabolism. Based on our preliminary data showing altered intramuscular lipid levels in IL-10 treated mice, the Aim 1 will examine the effects of muscle IL-10 overexpression on glucose and lipid metabolism. In Aim 2, we will identify the mechanism by which MCK-IL10 mice are protected from lipid-mediated insulin resistance using chronic high-fat feeding, acute lipid infusion, and genetically obese mouse models. The Aim 3 will determine the role of macrophage infiltration in muscle insulin resistance in diet-induced obesity and acute lipid infusion models. We will also observe macrophage migration using monocyte labeling and examine the effects of macrophage depletion using clodronate on lipid-mediated insulin resistance. Lastly, we will investigate the role of alternatively-activated macrophages in MCK-IL10 phenotypes. Overall, our proposed studies will identify a novel role of IL-10 in the regulation of skeletal muscle insulin action and discover new therapeutic targets in the treatment of insulin resistance and type 2 diabetes. PUBLIC HEALTH RELEVANCE. Skeletal muscle insulin resistance plays a major role in the development of type 2 diabetes, which impacts more than 170 million people worldwide and may be causally associated with inflammation and altered lipid metabolism. The proposed studies will examine the mechanisms by which interleukin-10 regulates skeletal muscle insulin action and prevents lipid-mediated insulin resistance in skeletal muscle. Our findings will provide important insights into the role of obesity and inflammation in insulin resistance and further identify novel therapeutic targets in the treatment of type 2 diabetes.

描述（由申请人提供）：骨骼肌胰岛素抵抗在2型糖尿病的发展中起主要作用，可能与炎症和脂质代谢改变有因果关系。脂肪酸和促炎细胞因子的循环水平在肥胖和糖尿病患者中升高，并导致骨骼肌中的胰岛素抵抗。相反，血浆IL-10（一种抗炎细胞因子）水平与胰岛素敏感性呈正相关，代谢综合征患者的IL-10水平降低。我们最近的研究表明，用IL-10进行急性治疗可以防止小鼠肌肉中脂质介导的胰岛素抵抗，这与胰岛素信号的增加有关。为了进一步研究IL-10在骨骼肌胰岛素作用中的作用，我们最近培育了肌肉特异性过表达IL-10的转基因小鼠（MCK-IL10小鼠）。我们的初步数据表明MCK-IL10小鼠免受脂质介导的胰岛素信号和肌肉葡萄糖代谢缺陷的影响。我们还发现饮食诱导的胰岛素抵抗与骨骼肌中巨噬细胞浸润增加有关，而这些影响在MCK-IL10小鼠中减弱。我们假设IL-10通过1)阻断脂质介导的PKC-8/JNK/IKK的激活和胰岛素信号的下调，和/或2)抑制肥胖相关的巨噬细胞浸润和抑制巨噬细胞来源的细胞因子对葡萄糖代谢的有害作用来预防肌肉胰岛素抵抗。基于我们的初步数据显示IL-10处理小鼠肌内脂质水平发生改变，Aim 1将研究肌肉IL-10过表达对葡萄糖和脂质代谢的影响。在Aim 2中，我们将通过使用慢性高脂喂养、急性脂质输注和遗传性肥胖小鼠模型来确定MCK-IL10小鼠免受脂质介导的胰岛素抵抗的机制。Aim 3将确定巨噬细胞浸润在饮食性肥胖和急性脂质输注模型中肌肉胰岛素抵抗中的作用。我们还将使用单核细胞标记观察巨噬细胞迁移，并研究氯膦酸钠对脂质介导的胰岛素抵抗的巨噬细胞消耗的影响。最后，我们将研究选择性活化巨噬细胞在MCK-IL10表型中的作用。总之，我们提出的研究将确定IL-10在骨骼肌胰岛素作用调节中的新作用，并发现治疗胰岛素抵抗和2型糖尿病的新靶点。公共卫生相关性。骨骼肌胰岛素抵抗在2型糖尿病的发展中起着重要作用，全球有超过1.7亿人患有2型糖尿病，并可能与炎症和脂质代谢改变有因果关系。拟议的研究将探讨白介素-10调节骨骼肌胰岛素作用和预防骨骼肌脂质介导的胰岛素抵抗的机制。我们的发现将为肥胖和炎症在胰岛素抵抗中的作用提供重要的见解，并进一步确定治疗2型糖尿病的新治疗靶点。

项目成果

Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle.

• DOI: 10.2337/db08-1261
• 发表时间: 2009-11
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Hong EG;Ko HJ;Cho YR;Kim HJ;Ma Z;Yu TY;Friedline RH;Kurt-Jones E;Finberg R;Fischer MA;Granger EL;Norbury CC;Hauschka SD;Philbrick WM;Lee CG;Elias JA;Kim JK
• 通讯作者: Kim JK

Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice.

• DOI: 10.1038/nm.4031
• 发表时间: 2016-03
• 期刊: Nature medicine
• 影响因子: 82.9
• 作者: Min SY;Kady J;Nam M;Rojas-Rodriguez R;Berkenwald A;Kim JH;Noh HL;Kim JK;Cooper MP;Fitzgibbons T;Brehm MA;Corvera S
• 通讯作者: Corvera S

Defective daily temperature regulation in a mouse model of amyotrophic lateral sclerosis.

肌萎缩侧索硬化症小鼠模型的日常温度调节缺陷。

• DOI: 10.1016/j.expneurol.2018.07.008
• 发表时间: 2019
• 期刊: Experimental neurology
• 影响因子: 5.3
• 作者: Braun,MaurineC;Castillo-Ruiz,Alexandra;Indic,Premananda;Jung,DaeYoung;Kim,JasonK;BrownJr,RobertH;Swoap,StevenJ;Schwartz,WilliamJ
• 通讯作者: Schwartz,WilliamJ

Maternal exposure to high-fat diet during pregnancy and lactation predisposes normal weight offspring mice to develop hepatic inflammation and insulin resistance.

• DOI: 10.14814/phy2.14811
• 发表时间: 2021-03
• 期刊: Physiological reports
• 影响因子: 2.5
• 作者: Saengnipanthkul S;Noh HL;Friedline RH;Suk S;Choi S;Acosta NK;Tran DA;Hu X;Inashima K;Kim AM;Lee KW;Kim JK
• 通讯作者: Kim JK

The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity.

• DOI: 10.1083/jcb.200809113
• 发表时间: 2008-12-29
• 期刊: JOURNAL OF CELL BIOLOGY
• 影响因子: 7.8
• 作者: Hinoi, Eiichi;Gao, Nan;Jung, Dae Young;Yadav, Vijay;Yoshizawa, Tatsuya;Myers, Martin G., Jr.;Chua, Streamson C., Jr.;Kim, Jason K.;Kaestner, Klaus H.;Karsenty, Gerard
• 通讯作者: Karsenty, Gerard