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.

项目总结/摘要 肥胖是一种日益严重的流行病，在美国，超过三分之二的成年人超重或肥胖。 肥胖虽然饮食引起的体重减轻减少肥胖相关的并发症， 体重减轻会发生严重的并发症，包括骨折和肌肉减少症。这是一个重要的公众 健康问题，因为大量的成年人寻求减肥，以及越来越多的流行率， 骨质疏松症和肌肉减少症。然而，关于不同药物治疗对 骨骼和肌肉的重量减轻。这项拟议中的研究将调查胰高血糖素样肽1 受体激动剂（GLP-1 RA）利拉鲁肽，FDA批准用于治疗肥胖， 与体重减轻相关的吸收和肌肉质量损失。如果这是真的，那么利拉鲁肽可能是首选 用于减肥的药物治疗，特别是在患有肥胖症和骨质疏松症或肌肉减少症的成年人中。 临床前数据表明，GLP-1 RA可能对骨骼和肌肉具有合成代谢作用。GLP-1促进骨 形成，同时抑制体外骨吸收。在啮齿动物模型中，GLP-1 RA增加骨密度， 力量和增加肌肉质量。然而，关于GLP-1 RA作用的临床数据， 对于减肥，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由普通的骨髓间充质干细胞分化而来。 体重减轻会增加骨髓脂肪组织（MAT），这可以通过人类的MR光谱测量， 并与骨矿物质密度降低有关。体外数据表明GLP-1 RA抑制骨髓 脂肪形成，同时促进成骨细胞分化，但是否减少MAT是一种机制， 尚不清楚GLP-1 RA对人体骨量的影响。 我们的假设是，每日皮下注射利拉鲁肽3个月将导致骨密度降低 骨吸收标志物、更高的骨形成标志物、更少的肌肉质量损失和MAT减少 与生活方式干预相比，生活方式干预导致了相当数量的体重减轻， 生活（HHL），在40个其他健康的成年人肥胖。目前的建议是一项试点研究，有两个目标： 目的1研究利拉鲁肽与强化治疗相比对骨代谢标志物和MAT的影响。 目的2研究利拉鲁肽对肌肉质量的影响， 强度相比，密集的生活方式干预减肥。 拟议的协议建立在Melanie Schorr Haines博士的K23项目和不断增长的专业领域的基础上 身体组成的内分泌决定因素，重点是肌肉，以及它们对 心脏代谢疾病和骨骼完整性。该试点研究将为R 01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 RA是否导致 保持骨密度和肌肉质量，尽管肥胖个体体重减轻。