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

• 批准号: 10215493
• 负责人: BRYAN C BERGMAN
• 金额: $ 57.88万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10215493
• 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; 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

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）存在于肌肉纤维之间和肌肉筋膜下，IS 与胰岛素抵抗和肌肉减少症正相关。尚不清楚的是IMAT晋升的减少方式 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的差距 因为，在满足需求之前，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分泌组引起炎症和收缩蛋白表达降低的相对效力 体外胰岛素敏感性。我们的中心假设是IMAT分泌组促进肌肉 炎症并降低肌肉质量，强度和胰岛素敏感性。这是基础的理由 提案是阐明IMAT如何促进肌肉大小，力量和胰岛素敏感性的减小 能够开发新的治疗干预措施，以预防或治疗肌肉减少症和2型糖尿病。到 实现我们的目标，我们提出了两个具体目标：特定目标1。确定IMAT和内脏脂肪 与皮下脂肪组织相比，组织具有代谢不良的分泌组 人类。我们的初步数据表明，IMAT分泌炎症性细胞因子和类类类药物类似 增值税。我们的工作假设是，IMAT和增值税分泌炎症细胞因子，脂肪因子，类花生酸， 与SAT相比，促进代谢功能障碍的细胞外基质蛋白。我们建议 测量IMAT，增值税和坐在精益，肥胖和肥胖的个人中的分泌组 2个糖尿病。肌肉质量，强度和胰岛素敏感性将使用MRI，等速动力学测量 和高胰岛素/毛血糖夹。将比较IMAT分泌组件的组件 SAT和增值税，与供体胰岛素灵敏度，强度和肌肉质量相关，以揭示潜力 IMAT改变肌肉功能的机甲。特定目标2。建立IMAT的效力 分泌炎症反应并降低胰岛素敏感性和收缩蛋白 体外表达。基于强大的初步数据，我们的工作假设是IMAT和增值税 分泌组将增加炎症反应，并降低胰岛素敏感性和收缩蛋白 相对于SAT的表达。体外反应将通过组比较 IMAT分泌组将与细胞培养结果的变化相关，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不同 通过直接在人类中采样imat。这项贡献将是重要的，因为Imat从未有过 从人类中收集以进行详细研究，并将揭示肌间脂肪组织作为一种新的治疗性 靶向对抗肌肉减少症和2型糖尿病的目标。