FAT TALKS TO BONE

脂肪与骨骼对话

• 批准号: 9978044
• 负责人: Steven L Teitelbaum
• 金额: $ 38.13万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-11 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978044
• 关键词: Adipocytes; Adipose tissue; Age; Animal Model; Biomechanics; Brown Fat; Complex; Event; Face; Fatty acid glycerol esters; Fracture; Health; Individual; Leptin; Mediating; Mus; Obesity; Organ; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Patients; Phenotype; Property; Resolution; Role; Signal Transduction; Skeleton; Societies; Therapeutic; Transplantation; Visceral; Visceral fat; adipokines; adiponectin; bone; bone cell; bone mass; clinically relevant; improved; insight; osteoclastogenesis; osteogenic; progenitor; skeletal; subcutaneous; substantia spongiosa

Abstract Obesity and osteoporosis are endemic in our society yet their relationship is perplexing. While obesity has long been considered beneficial for skeletal health, recent studies suggest bone mass is diminished in a substantial subset of obese individuals. Thus, despite its demographic importance, the influence of fat on bone remains enigmatic. Although controversial, studies of the effect of fat-produced molecules, such as leptin and adiponectin, indicate these selected adipokines impact bone. Adipose tissue is, however, a complex organ and there is little mechanistic insight as to how fat, per se, and which variety of fat, regulates the skeleton. Such information is clinically relevant as individuals with a predominance of visceral fat are osteopenic whereas subcutaneous and brown fat may positively influence bone mass. Determination of how fat, in its various forms, targets bone cells will provide the framework for ameliorating the skeletal complications of obesity. Resolution of this issue, in patients, is limited, however, by the absence of an animal model in which manipulation of fat abundance eventuates in a robust skeletal phenotype. To this end, we generated mice completely lacking visceral, subcutaneous and brown fat. Despite the hypogonadal state of these "fat free" (FF) mice, trabecular bone volume is strikingly increased (400-500%) due to enhanced osteoblast activity. Unexpectedly in face of its marked increase in bone mass, osteoclastogenesis in FF mice is also markedly enhanced. This observation raises the possibility that visceral fat diminishes bone mass by arresting osteoclast-induced remodeling. Our observations establish that, by mechanisms to be determined, fat signals to bone and decreased adiposity may greatly increase bone mass, challenging the concept that obesity generally improves skeletal health. Most importantly, the skeletal phenotype of FF mice is completely rescued by adipocyte precursor transplantation. This transplantation-mediated normalization of FF bone provides the opportunity to directly explore the impact of deleting various adipocyte products on bone accrual and how visceral, subcutaneous and/or brown adipose tissue targets the skeleton. Hence, we hypothesize that fat diminishes bone accrual in an osteoblast- and osteoclast-dependent manner.

抽象的 肥胖和骨质疏松症在我们的社会中是流行的，但它们的关系令人困惑。肥胖有 长期以来被认为对骨骼健康有益，最近的研究表明，骨骼质量在A中减少 肥胖个体的大量子集。因此，尽管人口的重要性，但脂肪对骨骼的影响 保持神秘。尽管引起了争议，但研究脂肪产生的分子的作用，例如瘦素和 脂联素，表明这些选定的脂肪因子会影响骨骼。但是，脂肪组织是一个复杂的器官， 关于脂肪，本质上以及哪种脂肪如何调节骨骼的机械洞察力几乎没有。这样的 信息在临床上具有相关性，因为具有内脏脂肪的个体是骨质减少的 皮下和棕色脂肪可能会积极影响骨骼质量。 确定脂肪以各种形式的靶向骨细胞将为骨细胞提供的框架 改善肥胖的骨骼并发症。但是，在患者中解决此问题的解决， 缺乏动物模型，其中在稳健的骨骼中操纵脂肪丰度的操纵 表型。为此，我们产生了完全缺乏内脏，皮下和棕色脂肪的小鼠。尽管 这些“无脂肪”（FF）小鼠的性态态，小梁骨体积显着增加（400-500％） 由于成骨细胞活性增强。面对骨骼质量显着增加的意外， FF小鼠中的破骨细胞生成也显着增强。这种观察增加了内脏的可能性 脂肪通过阻止破骨细胞诱导的重塑来减少骨骼。 我们的观察结果表明，通过确定的机制，脂肪信号向骨头和减少 肥胖可能会大大增加骨骼质量，挑战肥胖通常改善骨骼的概念 健康。最重要的是，FF小鼠的骨骼表型完全被脂肪细胞前体挽救 移植。这种移植介导的FF骨归一化为直接提供了机会 探索删除各种脂肪细胞产品对骨骼应计的影响以及内脏地下的影响 和/或棕色脂肪组织靶向骨骼。因此，我们假设脂肪减少了骨骼 成骨细胞和破骨细胞依赖性方式。