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: 10057224
• 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/10057224
• 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; 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.

肌肉减少症是一种与衰老有关的肌肉质量和力量的进行性损失，在25%的老年人中存在