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.

摘要 肥胖症和骨质疏松症在我们的社会中是地方病，但它们之间的关系是令人困惑的。虽然肥胖症 长期以来被认为有益于骨骼健康，最近的研究表明，骨量减少， 肥胖个体的重要子集。因此，尽管它在人口统计学上的重要性， 仍然是个谜尽管存在争议，但对脂肪产生的分子，如瘦素和 脂联素，表明这些选择的脂肪因子影响骨。然而，脂肪组织是一个复杂的器官， 对于脂肪本身如何以及哪种脂肪调节骨骼，几乎没有机械的见解。等 信息是临床相关的，因为内脏脂肪占优势的个体是骨质减少的，而 皮下脂肪和棕色脂肪可能对骨量有积极影响。 确定各种形式的脂肪是如何靶向骨细胞的， 改善肥胖症的骨骼并发症。然而，在患者中解决该问题受到以下限制： 缺乏一种动物模型，在这种模型中，脂肪丰度的操纵最终导致了强健的骨骼， 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）小鼠的性腺功能减退状态，骨小梁体积显著增加（400-500%） 因为成骨细胞活性增强出乎意料的是，面对其骨量的显著增加， FF小鼠中的破骨细胞生成也显著增强。这一观察结果提出了一种可能性， 脂肪通过阻止破骨细胞诱导的重塑而减少骨量。 我们的观察表明，通过尚待确定的机制，脂肪向骨骼发出信号并减少 肥胖可能会大大增加骨量，挑战肥胖通常会改善骨骼的概念。 健康最重要的是，FF小鼠的骨骼表型完全被脂肪细胞前体拯救 移植这种移植介导的FF骨正常化提供了直接 探索去除各种脂肪细胞产物对骨生成的影响，以及内脏、皮下 和/或棕色脂肪组织攻击骨骼因此，我们假设，脂肪减少骨的积累， 成骨细胞和破骨细胞依赖的方式。