The Role of Ghrelin and the GHSR-1a receptor in Sarcopenic Obesity

Ghrelin 和 GHSR-1a 受体在少肌性肥胖中的作用

• 批准号: 10515637
• 负责人: Jose M. Garcia
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10515637
• 关键词: Adipocytes; Adipose tissue; Adult; Age; Aging; Agonist; Appetite Stimulants; Area; Attenuated; Biogenesis; Body Composition; Brown Fat; C57BL/6 Mouse; Cardiovascular Diseases; Chronic; Clinical; Data; Deposition; Development; Diabetes Mellitus; Eating; Elderly; Energy Metabolism; Epidemic; Fatigue; Fatty acid glycerol esters; Fiber; Functional disorder; GHS-R1a; General Population; Goals; Hand Strength; Health Care Costs; High Prevalence; Home; Hormones; Hospitalization; Individual; Injury; Kinetics; Knockout Mice; Knowledge; Lead; Length of Stay; Ligands; Lipids; Lipolysis; Mediating; Mediator; Mitochondria; Molecular; Morbidity - disease rate; Motor Activity; Mus; Muscle; Muscle Fibers; Muscle function; Muscular Atrophy; Obesity; Outcome; Pathway interactions; Performance; Physical Performance; Population; Quality of life; Reactive Oxygen Species; Relaxation; Resistance; Rodent Model; Role; Skeletal Muscle; Stains; Testing; Therapeutic; Thermogenesis; Transgenic Mice; Triglycerides; Veterans; Weight; Work; age group; age related; antagonist; clinical development; disability; disability risk; effective therapy; fall risk; fatty acid metabolism; fatty acid oxidation; feeding; frailty; ghrelin; high risk; human old age (65+); improved; in vivo; lipid biosynthesis; lipid metabolism; middle age; military veteran; mimetics; mitochondrial dysfunction; molecular marker; mortality; muscle form; muscle strength; novel; novel therapeutics; obesity prevention; pharmacologic; prevent; receptor; sarcopenia; sarcopenic obesity; targeted treatment; therapy development

Sarcopenia, a progressive loss of muscle mass and strength associated with aging, is present in 25% of older individuals. Obesity is also very common in this age group and both conditions lead to increased disability, morbidity and mortality. Their combination is termed sarcopenic obesity and is associated with the highest risks of disability, mortality and increased healthcare costs. Despite its relevance, treatments for sarcopenic obesity are not available and the molecular mechanisms leading to this condition are incompletely understood. Ghrelin, the endogenous ligand for the GHSR-1a receptor, is an orexigenic hormone that regulates muscle and fat mass. We recently showed that ghrelin deletion is sufficient to prevent sarcopenic obesity in older mice. It attenuates the decrease in pAMPK and increases the number of type IIa (oxidative) muscle fibers, while also preventing obesity. Also, we have recently shown that ghrelin exerts its effects in muscle and in adipose tissue, at least in part, independently of the GHSR-1a. However, the mechanisms mediating these effects are incompletely understood. The overall goals of this proposal are to characterize the mechanisms mediating the role of ghrelin and its receptor (GHSR-1a) in sarcopenic obesity, and to evaluate the potential for GHSR-1a antagonism as a therapeutic approach in this setting. We hypothesize that in a rodent model of age- related sarcopenic obesity: 1) Ghrelin induces skeletal muscle dysfunction by: a) Causing mitochondrial dysfunction and fiber type distribution changes, and b) Modulating fatty acid metabolism and ectopic lipid deposition; 2) Ghrelin induces fat accumulation by modulating food intake, thermogenesis, and fatty acid metabolism in adipose tissue, and 3) GHSR-1a antagonism/deletion will partially prevent sarcopenic obesity by upregulating AMPK-dependent pathways that regulate fiber type distribution in muscle and mitochondrial function and lipid metabolism in skeletal muscle and adipose tissue. The specific aims are: 1) Characterize the mechanisms mediating the effects of ghrelin in muscle in sarcopenic obesity. Young (8-month old), middle age (18-month old) and old (28-month old) adult ghrelin WT&KO mice will be evaluated for body composition, food intake, locomotor activity and muscle performance. Muscle mass, fiber type and markers of AMPK activation, mitochondrial function, fatty acid metabolism, and lipid storage will be evaluated in muscles. The effect of chronic ghrelin administration, and pair-feeding will also be tested. 2) Determine the mechanisms mediating the effects of ghrelin on adiposity and adipocyte function in sarcopenic obesity. Young, middle age and old adult ghrelin WT and KO mice will be evaluated for energy expenditure, body composition, food intake and locomotor activity. Molecular mediators of thermogenesis, mitochondrial function, AMPK activation and lipid metabolism will be probed in white and brown fat pads. The effect of chronic ghrelin administration, and pair-feeding will also be tested. 3) Establish the extent to which GHSR-1a mediate the effects of ghrelin. Young, middle age and old adult GHSR-1a WT and KO mice will be evaluated for body composition, food intake, locomotor activity, muscle performance and energy expenditure. Fiber typing and molecular markers in muscle and fat will be studied as indicated in aims 1 and 2 above. The effect of chronic ghrelin administration in GHSR-1a WT and KO, and pharmacological inhibition of GHSR-1a (using the GHSR-1a antagonist HM04) in ghrelin WT and KO also will be tested. To determine the role of AMPK in this setting, the effects of HM04 will also be tested in WT and AMPKα2i transgenic mice that express the inactive form AMPKα in skeletal muscle. Characterizing the mechanisms mediating the effects of ghrelin and GHSR-1a is novel and relevant because ghrelin, GHSR-1a agonists and antagonists are in clinical development. A better understanding of their mechanisms of action will allow us to develop novel therapies for sarcopenic obesity.

肌肉减少症是一种与衰老相关的肌肉质量和力量逐渐丧失的现象，25% 的老年人存在这种情况 个人。肥胖在这个年龄段也很常见，这两种情况都会导致残疾增加， 发病率和死亡率。它们的组合被称为肌肉减少性肥胖，与最高的 残疾、死亡和医疗费用增加的风险。尽管具有相关性，但治疗方法 肌肉减少性肥胖以及导致这种情况的分子机制尚不明确 都没有完全理解。 Ghrelin 是 GHSR-1a 受体的内源性配体，是一种 调节肌肉和脂肪量的促食欲激素。我们最近表明，ghrelin 缺失是 足以预防老年小鼠的肌肉减少性肥胖。它可以减弱 pAMPK 的下降， 增加 IIa 型（氧化）肌纤维的数量，同时还可以预防肥胖。另外，我们最近还 表明生长素释放肽在肌肉和脂肪组织中发挥其作用，至少部分地独立于 GHSR-1a。然而，介导这些效应的机制尚不完全清楚。 该提案的总体目标是描述调节 ghrelin 作用的机制 及其受体 (GHSR-1a) 在肌肉减少性肥胖中的作用，并评估 GHSR-1a 的潜力 在这种情况下，拮抗作为一种治疗方法。我们假设在年龄的啮齿动物模型中 相关的肌肉减少性肥胖： 1) Ghrelin 通过以下方式诱导骨骼肌功能障碍： a) 引起线粒体 功能障碍和纤维类型分布变化，b) 调节脂肪酸代谢和异位脂质 沉积； 2) 胃饥饿素通过调节食物摄入、产热和脂肪酸来诱导脂肪积累 脂肪组织中的代谢，3) GHSR-1a 拮抗/缺失将部分预防肌肉减少性肥胖 通过上调 AMPK 依赖性途径来调节肌肉和线粒体中的纤维类型分布 骨骼肌和脂肪组织的功能和脂质代谢。具体目标是： 1) 表征肌肉减少症患者肌肉中生长素释放肽作用的机制 肥胖。幼年（8月龄）、中年（18月龄）和老年（28月龄）成年ghrelin WT&KO小鼠 将评估身体成分、食物摄入量、运动活动和肌肉性能。肌肉质量， 纤维类型和 AMPK 激活、线粒体功能、脂肪酸代谢和脂质储存的标记 将在肌肉中进行评估。长期施用生长素释放肽和配对喂养的效果也将得到测试。 2) 确定ghrelin对肥胖和脂肪细胞影响的机制 在少肌性肥胖中发挥作用。将评估年轻、中年和老年成年生长素释放肽WT和KO小鼠 用于能量消耗、身体成分、食物摄入和运动活动。分子介质 生热作用、线粒体功能、AMPK 激活和脂质代谢将在白色和 棕色脂肪垫。长期施用生长素释放肽和配对喂养的效果也将得到测试。 3) 确定 GHSR-1a 介导 ghrelin 作用的程度。青年、中年、老年 将评估成年 GHSR-1a WT 和 KO 小鼠的身体成分、食物摄入量、运动活动、 肌肉性能和能量消耗。肌肉和脂肪中的纤维分型和分子标记将 按照上述目标 1 和 2 进行研究。长期给予 ghrelin 对 GHSR-1a WT 和 GHSR-1a WT 的影响 KO，以及 ghrelin WT 和 KO 中 GHSR-1a 的药理学抑制（使用 GHSR-1a 拮抗剂 HM04） 也将受到考验。为了确定 AMPK 在此设置中的作用，HM04 的效果也将在 WT 中进行测试 AMPKα2i 转基因小鼠在骨骼肌中表达非活性形式的 AMPKα。 表征介导 ghrelin 和 GHSR-1a 作用的机制是新颖且相关的，因为 ghrelin、GHSR-1a 激动剂和拮抗剂正处于临床开发阶段。更好地了解他们 作用机制将使我们能够开发出针对肌肉减少性肥胖的新疗法。