Intermuscular adipose tissue (IMAT): protagonist in sarcopenia and insulin resistance in humans

肌间脂肪组织（IMAT）：人类肌肉减少症和胰岛素抵抗的主角

基本信息

批准号：
10448489
负责人：
BRYAN C BERGMAN
金额：
$ 57.43万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448489
关键词：
Achievement Address Adipose tissue Age Attention Bathing Biopsy Body fat Body mass index Cell Culture Techniques Closure by clamp Contractile Proteins Data Development Eicosanoids Ethnic Origin Extracellular Matrix Proteins Fascia Functional disorder Future Glucose Clamp Goals Health Human In Vitro Inflammation Inflammatory Inflammatory Response Insulin Insulin Resistance Intervention Intramuscular Isotonic Exercise Knowledge Laparoscopic Surgical Procedures Life Lipids Magnetic Resonance Imaging Measures Metabolic Metabolic dysfunction Mission Molecular Muscle Muscle Cells Muscle Fibers Muscle Weakness Muscle function Muscular Atrophy Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Operative Surgical Procedures Outcome Paracrine Communication Pathogenesis Play Positioning Attribute Prediabetes syndrome Production Proteins Public Health Research Sampling Sampling Studies Shapes Signal Transduction Signaling Molecule Skeletal Muscle Source Testing Thinness Tissues Triglycerides United States National Institutes of Health Visceral adipokines base combat cytokine disability glucose tolerance innovation insulin sensitivity muscle form muscle strength new therapeutic target novel novel therapeutic intervention obese person prevent protein expression receptor sensitivity recruit reduced muscle mass response sarcopenia sex subcutaneous

项目摘要

Abstract Intermuscular adipose tissue (IMAT) exists between muscle fibers and under the muscle fascia, and is positively related to insulin resistance and sarcopenia. What is not known is how IMAT promotes decreased muscle size, strength, and insulin sensitivity. Thus, there is a critical need to address these gaps in knowledge because, until that need is met, the potential for IMAT as a target for interventions that prevent/treat type 2 diabetes and sarcopenia is unlikely to be realized. The overall objective for this project is to quantify the secretome of IMAT relative to visceral (VAT) and subcutaneous adipose tissue (SAT), and determine the relative potency of the IMAT secretome to cause inflammation, and decreased contractile protein expression and insulin sensitivity in vitro. Our central hypothesis is that the IMAT secretome promotes muscle inflammation, and decreases muscle mass, strength, and insulin sensitivity. The rationale that underlies this proposal is that clarifying how IMAT promotes decreased muscle size, strength, and insulin sensitivity will enable development of novel therapeutic interventions to prevent or treat sarcopenia and type 2 diabetes. To achieve our objective, we propose two specific aims: Specific Aim 1. Determine that IMAT and visceral adipose tissue have a secretome that is metabolically adverse when compared to subcutaneous adipose tissue in humans. Our preliminary data show that IMAT secretes inflammatory cytokines and eicosanoids similar to VAT. Our working hypothesis is that IMAT and VAT secrete inflammatory cytokines, adipokines, eicosanoids, and extracellular matrix proteins that promote metabolic dysfunction when compared to SAT. We propose to measure the secretome of IMAT, VAT and SAT in lean, obese, and obese individuals with pre-diabetes and type 2 diabetes. Muscle mass, strength, and insulin sensitivity will be measured using MRI, isokinetic dynamometry and hyperinsulinemic/ euglycemic clamps, respectively. Components of the IMAT secretome will be compared to SAT and VAT, and correlated to donor insulin sensitivity, strength, and muscle mass to reveal potential mechansims by which IMAT alters muscle function. Specific Aim 2. Establish the potency of the IMAT secretome to cause an inflammatory response, and decrease insulin sensitivity and contractile protein expression in vitro. Based on strong preliminary data, our working hypothesis is that IMAT and VAT secretome will increase the inflammatory response, and decrease insulin sensitivity and contractile protein expression relative to that from SAT. In vitro responses will be compared by group, and constituents of the IMAT secretome will be correlated to the change in cell culture outcomes to reveal potential mechanisms of action. The proposed research is innovative because it represents a substantive departure from the status quo by directly sampling IMAT in humans. This contribution will be significant because IMAT has never been collected from humans for detailed studies, and will reveal intermuscular adipose tissue as a new therapeutic target to combat sarcopenia and type 2 diabetes.

抽象的肌间脂肪组织（IMAT）存在于肌纤维之间和肌筋膜下方，是与胰岛素抵抗和肌肉减少症呈正相关。尚不清楚的是 IMAT 如何促进减少肌肉大小、力量和胰岛素敏感性。因此，迫切需要解决这些知识差距因为，在满足这一需求之前，IMAT 作为预防/治疗 2 型干预措施的目标的潜力糖尿病和肌肉减少症不太可能实现。该项目的总体目标是量化 IMAT 相对于内脏 (VAT) 和皮下脂肪组织 (SAT) 的分泌组，并确定 IMAT 分泌组引起炎症的相对效力和收缩蛋白表达减少和体外胰岛素敏感性。我们的中心假设是 IMAT 分泌蛋白组促进肌肉炎症，并降低肌肉质量、力量和胰岛素敏感性。这背后的基本原理建议澄清 IMAT 如何促进肌肉尺寸、力量和胰岛素敏感性下降能够开发新的治疗干预措施来预防或治疗肌肉减少症和 2 型糖尿病。到为了实现我们的目标，我们提出两个具体目标：具体目标 1. 确定 IMAT 和内脏脂肪与皮下脂肪组织相比，组织具有代谢不利的分泌组人类。我们的初步数据表明，IMAT 分泌的炎症细胞因子和类二十烷酸与增值税。我们的工作假设是 IMAT 和 VAT 分泌炎症细胞因子、脂肪因子、类二十烷酸、与 SAT 相比，细胞外基质蛋白会促进代谢功能障碍。我们建议测量瘦、肥胖和患有糖尿病前期和糖尿病类型的肥胖个体的 IMAT、VAT 和 SAT 分泌组 2 糖尿病。将使用 MRI、等速测力法测量肌肉质量、力量和胰岛素敏感性和高胰岛素/正常血糖钳，分别。将比较 IMAT 分泌组的组成部分与 SAT 和 VAT 相关，并与供体胰岛素敏感性、力量和肌肉质量相关，以揭示潜力 IMAT 改变肌肉功能的机制。具体目标 2. 确立 IMAT 的效力分泌蛋白组引起炎症反应，并降低胰岛素敏感性和收缩蛋白体外表达。基于强有力的初步数据，我们的工作假设是 IMAT 和 VAT 分泌蛋白组会增加炎症反应，并降低胰岛素敏感性和收缩蛋白相对于 SAT 的表达。体外反应将按组和成分进行比较 IMAT 分泌蛋白组将与细胞培养结果的变化相关联，以揭示潜在的机制行动。拟议的研究具有创新性，因为它代表了与现状的实质性背离通过直接对人体 IMAT 进行采样。这一贡献将意义重大，因为 IMAT 从未从人类身上收集进行详细研究，并将揭示肌间脂肪组织作为一种新的治疗方法目标是对抗肌肉减少症和 2 型糖尿病。