FAT TALKS TO BONE

摘要 肥胖和骨质疏松症在我们的社会中很普遍，但它们之间的关系却令人困惑。而肥胖症 长期以来，人们一直认为对骨骼健康有益，最近的研究表明， 肥胖个体的相当大的子集。因此，尽管脂肪在人口统计学上具有重要意义，但它对骨骼的影响 仍然是个谜。尽管有争议，但对脂肪产生的分子的影响的研究，如瘦素和 脂联素，表明这些选定的脂肪因子影响骨骼。然而，脂肪组织是一个复杂的器官， 关于脂肪本身是如何调节骨骼的，以及哪种脂肪种类，几乎没有机械性的见解。是这样的 信息在临床上是相关的，因为内脏脂肪占优势的个体是骨量减少的，而 皮下脂肪和棕色脂肪可能会对骨量产生积极影响。 确定各种形式的脂肪如何作用于骨细胞，为 改善肥胖引起的骨骼并发症。然而，在患者中，这个问题的解决受到以下因素的限制 缺乏一种动物模型，在这种动物模型中，脂肪丰富的操纵最终会导致健壮的骨骼 表型。为此，我们培育了完全缺乏内脏脂肪、皮下脂肪和棕色脂肪的小鼠。尽管 在这些“无脂肪”(FF)小鼠的性腺功能低下状态下，骨小梁体积显著增加(400-500%)。 由于成骨细胞活性增强。出乎意料的是，面对它的骨量显著增加， FF小鼠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，内脏 脂肪通过阻止破骨细胞诱导的重塑来减少骨量。 我们的观察证实，通过有待确定的机制，脂肪向骨骼发出信号并减少 肥胖可能会极大地增加骨量，挑战肥胖通常会改善骨骼的概念 健康。最重要的是，脂肪细胞前体完全挽救了FF小鼠的骨骼表型 移植。这种移植介导的FF骨正常化提供了直接 探讨删除各种脂肪细胞产品对骨积累的影响以及内脏、皮下 和/或棕色脂肪组织以骨骼为靶标。因此，我们假设脂肪减少了骨骼的积累 成骨细胞和破骨细胞依赖的方式。

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.