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: 10292456
• 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 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10292456
• 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; General Population; Goals; Hand Strength; Health Care Costs; High Prevalence; Home; Hormones; Hospitalization; Individual; Kinetics; Knockout Mice; Knowledge; Lead; Length of Stay; Ligands; Lipids; Lipolysis; Mediating; Mediator of activation protein; Mitochondria; Molecular; Morbidity - disease rate; Motor Activity; Mus; Muscle; Muscle Fibers; Muscle Mitochondria; Muscle function; Muscular Atrophy; Obesity; Outcome; Pathway interactions; Performance; Pharmacology; Physical Performance; Play; 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 injury; fall risk; fatty acid metabolism; fatty acid oxidation; feeding; frailty; ghrelin; ghrelin receptor; 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; 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.

肌肉减少症是肌肉质量的逐渐丧失和与agging相关的力量，有25％的老年人 个人也是这个时代组的版本 发病率和死亡率。 尽管有相关性，但拒绝，死亡率和增加 肌肉减少性肥胖不可用，分子机制导致了这种情况 不完全理解。 定期肌肉和脂肪质量的甲状根激素。 足以防止老鼠的肌肉减少肥胖。 增加了IIA型（氧化）肌肉纤维的数量，同时也增加了Ofession公主。 表明，生长素素的施加是肌肉和脂肪组织中的ETS，至少部分独立于 但是，GHSR-1A。 该提案的总体目标是表征介导生长素作用的机制 及其受体（GHSR-1A）在肌肉减少性肥胖症中，并评估GHSR-1A的潜力 在这种情况下，拮抗作用是在这种情况下。 相关的肌肉减少肥胖：1）生长素释放骨骼肌肉功能障碍：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）生长素蛋白通过调节食物摄入和脂肪酸诱导脂肪积累 脂肪组织中的代谢和3）GHSR-1A拮抗/划分将部分预防肌肉减少症 通过上调依赖AMPK的途径，该途径调节肌肉和mitchondrial中的纤维类型分布 骨骼肌和脂肪组织中的功能和脂质代谢。 1）表征介导生长素蛋白在肌肉中的作用的机制 肥胖症。 将评估身体成分，食物摄入量，运动活性和肌肉表现。 AMPK激活，mitchondrial功能，脂肪酸代谢和脂质储存的纤维类型和标记 将在肌肉中进行评估。 2）确定介导生长素蛋白对肥胖和脂肪细胞影响的机制 肌肉减少肥胖症的功能。 用于能量消耗，身体成分，食物摄入和运动活动。 热生成，mitchondrial功能，AMPK激活和脂质代谢将以白色和白色探测 棕色的脂肪垫也将测试慢性发酵液和配对的效果。 3）确定GHSR-1A在多大程度上介导生长素蛋白的作用。 成人GHSR-1A WT和KO小鼠将评估身体成分，食物摄入量，运动活动， 肌肉性能和能量消耗。 在上面的目标1和2中所示。 HSR-1A中的KO和药理学（使用THSR-1A拮抗剂HM04）在Ghrelin WT和KO中 还将进行测试。 和AMPKα2i转基因小鼠在骨骼肌中表达不活跃的AMPKα。 表征介导GHSR-1A效应的机制是新颖的，并且相关效应 Ghrelin，GHSR-1A激动剂和拮抗剂正在临床发育中。 作用机理柳树开发新的肌肉减少肥胖疗法。