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 肥胖是一种流行病，在美国超过三分之二的成年人超重或 肥胖。尽管饮食引起的体重减轻会减少与肥胖相关的并发症，但越来越多地认识到 体重减轻的严重并发症发生，包括骨折和肌肉减少症。这是一个重要的公众 鉴于大量寻求减肥的成年人的健康问题，并且患病率的增加 骨质疏松症和肌肉减少症。但是，关于不同药理疗法的影响知之甚少 骨骼和肌肉的体重减轻。拟议的研究将研究胰高血糖素样肽1是否 受体激动剂（GLP-1 RA），Liraglutide，fda批准用于治疗肥胖症，可减轻骨骼 分辨率和肌肉质量损失与体重减轻有关。如果这是真的，那么liraglutide可能是首选 体重减轻的药理治疗，尤其是肥胖和骨质疏松症或肌肉减少症的成年人。 临床前数据表明，GLP-1 RA可能是骨骼和肌肉的代谢。 GLP-1促进骨骼 在体外抑制骨骼分辨率的同时形成。在啮齿动物模型中，GLP-1 RAS会增加骨密度和 力量并增加肌肉质量。但是，有关GLP-1 RAS影响的临床数据，如规定 为了减肥，缺乏对骨代谢标记以及肌肉质量和力量的体重。 成骨细胞和脂肪细胞与常见的间充质骨髓干细胞区分开。 体重减轻增加骨髓脂肪组织（MAT），可以通过人类MR光谱法测量， 并与骨矿物质密度降低有关。体外数据表明GLP-1 RAS抑制骨髓 在促进成骨细胞分化的同时，脂肪生成，但是减少垫子是否是一种机制 GLP-1 RA会影响人类的骨骼质量。 我们的假设是，每天3个月的皮下Liraglutide将导致较低的骨骼 分辨率标记，较高的骨形成标记，较少的肌肉质量损失和垫子的减少 与生活方式干预相比，减轻了可比的体重，健康习惯 生命（HHL），有40名其他健康的成年人肥胖。当前的提案是一项试点研究，其目的是两个： AIM 1研究Liraglutide对骨代谢标记和MAT的影响与密集型 减轻体重的生活方式干预，而AIM 2研究Liraglutide对肌肉质量的影响 与体重减轻的强化生活方式干预相比，力量。 拟议的协议以Melanie Schorr Haines博士的K23项目和不断增长的专业知识为基础 在内分泌中，确定身体成分，重点是肌​​肉及其对 心脏代谢疾病和骨骼完整性。这项试点研究将为R01提供关键的初步数据 提议进行前瞻性，随机，对照试验，以确定GLP-1 RAS是否导致 保存肥胖个体的骨密度和肌肉质量目的地体重减轻。