Effects of semaglutide on bone and muscle endpoints in adults with obesity: a pilot study.

索马鲁肽对肥胖成人骨骼和肌肉终点的影响：一项试点研究。

• 批准号: 10350212
• 负责人: Melanie Schorr Haines
• 金额: $ 11.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10350212
• 关键词: 18 year old; Acute; Adipose tissue; Adult; Affect; Agonist; Area; Body Composition; Body Weight decreased; Bone Density; Bone Resorption; Bone structure; C-terminal type I collagen telopeptide; Cardiometabolic Disease; Clinical Data; Control Groups; Cyclophosphamide; Data; Diet; Endocrine; Enrollment; Epidemic; Exercise; Extensor; FDA approved; Fracture; GDF8 gene; GLP-I receptor; Glucocorticoids; Habits; Hip Fractures; Human; Impairment; In Vitro; Individual; Knee; Knock-out; Life; Ligands; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Marrow; Measures; Meta-Analysis; Muscle; Muscular Atrophy; Obesity; Osteoblasts; Osteocalcin; Osteogenesis; Osteoporosis; Overweight; Pharmacology; Pilot Projects; Placebos; Prevalence; Prospective Studies; Protocols documentation; Protons; Public Health; Publishing; Randomized Controlled Trials; Research; Rodent; Rodent Model; Serum; Thigh structure; United States; Weight; adipocyte differentiation; adult obesity; bone; bone loss; bone marrow mesenchymal stem cell; bone mass; bone metabolism; bone preservation; bone strength; dietary; exercise program; fall risk; fracture risk; glucagon-like peptide 1; high risk; knock-down; lifestyle intervention; lipid biosynthesis; liraglutide; middle age; mortality; mouse model; muscle form; muscle strength; obesity treatment; osteoblast differentiation; pre-clinical; prevent; primary endpoint; prospective; recruit; reduced muscle mass; sarcopenia; skeletal; subcutaneous; treatment effect; weight loss intervention

PROJECT SUMMARY/ABSTRACT Obesity is a growing epidemic, with more than two-thirds of adults in the United States overweight or obese. Although diet-induced weight loss reduces obesity-related complications, it is increasingly recognized that serious complications of weight loss occur, including fractures and sarcopenia. This is an important public health issue given the large number of adults seeking weight loss, and the increasing prevalence rates of osteoporosis and sarcopenia. However, little is known about the effects of different pharmacologic therapies for weight loss on bone and muscle. The proposed research will investigate whether the glucagon-like peptide 1 receptor agonist (GLP-1 RA), liraglutide, which is FDA-approved for the treatment of obesity, mitigates bone resorption and muscle mass loss associated with weight loss. If this is true, then liraglutide may be a preferred pharmacologic therapy for weight loss, especially in adults with obesity and osteoporosis or sarcopenia. Preclinical data suggest that GLP-1 RAs may be anabolic to bone and muscle. GLP-1 promotes bone formation while suppressing bone resorption in vitro. In rodent models, GLP-1 RAs increase bone density and strength and increase muscle mass. However, clinical data regarding the effects of GLP-1 RAs, as prescribed for weight loss, on bone metabolism markers, as well as muscle mass and strength, are lacking. Osteoblasts and adipocytes are differentiated from common mesenchymal bone marrow stem cells. Weight loss increases marrow adipose tissue (MAT), which can be measured by MR spectroscopy in humans, and is associated with decreased bone mineral density. In vitro data suggest that GLP-1 RAs inhibit marrow adipogenesis while promoting osteoblast differentiation, but whether decreasing MAT is a mechanism by which GLP-1 RAs affect bone mass in humans is not known. Our hypothesis is that 3 months of daily subcutaneous liraglutide will result in lower bone resorption markers, higher bone formation markers, less muscle mass loss, and a reduction in MAT compared to a lifestyle intervention resulting in a comparable amount of weight loss, Healthy Habits for Life (HHL), in 40 otherwise healthy adults with obesity. The current proposal is a pilot study with two aims: Aim 1 investigates the effects of liraglutide on bone metabolism markers and MAT compared to an intensive lifestyle intervention for weight loss, while Aim 2 investigates the effects of liraglutide on muscle mass and strength compared to an intensive lifestyle intervention for weight loss. The proposed protocol builds on Dr. Melanie Schorr Haines’s K23 project and growing area of expertise in the endocrine determinants of body composition, with a focus on muscle, and their contribution to cardiometabolic disease and skeletal integrity. This pilot study will provide critical preliminary data for an R01 proposal to conduct a prospective, randomized, controlled trial to determine whether GLP-1 RAs result in preservation of bone density and muscle mass despite weight loss in individuals with obesity.

项目摘要/摘要 肥胖是一种日益流行的疾病，超过三分之二的美国成年人超重或超重 太胖了。虽然饮食诱导的减肥可以减少肥胖相关的并发症，但人们越来越认识到这一点 会出现严重的减肥并发症，包括骨折和骨质疏松症。这是一个重要的公众 健康问题，因为寻求减肥的成年人数量众多，而且 骨质疏松和骨质疏松症。然而，人们对不同药物治疗的效果知之甚少。 减轻骨骼和肌肉的重量。这项拟议的研究将调查胰升糖素样肽1是否 受体激动剂(GLP-1RA)，利拉鲁肽，FDA批准用于治疗肥胖，缓解骨骼 与体重减轻相关的吸收和肌肉质量下降。如果这是真的，那么利拉鲁肽可能是首选 减肥的药物疗法，特别是肥胖和骨质疏松症或骨质疏松症的成年人。 临床前研究表明，GLP-1RAS可能对骨骼和肌肉具有合成代谢作用。GLP-1促进骨骼 在体外抑制骨吸收的同时形成。在啮齿动物模型中，GLP-1 RAS增加骨密度和 增强力量，增加肌肉质量。然而，按照处方，有关GLP-1 RAS疗效的临床数据 在减肥方面，骨代谢指标以及肌肉质量和力量都缺乏。 成骨细胞和脂肪细胞是从普通骨髓间充质干细胞分化而来的。 体重减轻会增加骨髓脂肪组织(MAT)，这可以通过人类的磁共振波谱来测量， 并与骨密度下降有关。体外数据显示GLP-1RAS抑制骨髓 促进成骨细胞分化的同时促进脂肪生成，但减少MAT是否是一种机制 GLP-1RAS对人体骨量的影响尚不清楚。 我们的假设是，每天皮下注射3个月的利拉鲁肽将导致下部骨骼。 吸收标志物，更高的骨形成标志物，更少的肌肉质量损失，以及垫子的减少 与生活方式干预相比，健康的习惯可以减少同等数量的体重 生活(HHL)，在其他方面健康的肥胖者40例。目前的建议是一项试验性研究，目的有两个： 目的1观察利拉鲁肽对骨代谢指标和MAT的影响，并与强化治疗进行比较。 生活方式干预减肥，而目标2调查利拉鲁肽对肌肉质量和 与密集的生活方式干预相比，强度更大，可以减肥。 拟议的方案建立在Melanie Schorr Haines博士的K23项目和不断增长的专业领域的基础上 在身体成分的内分泌决定因素中，重点是肌肉，以及它们对 心脏新陈代谢疾病和骨骼完整性。这项初步研究将为R01提供关键的初步数据 建议进行一项前瞻性、随机、对照试验，以确定GLP-1 RAS是否导致 尽管肥胖患者体重减轻，但仍能保持骨密度和肌肉质量。