Interdisciplinary Study of Marrow Adiposity, Mineral Metabolism, and Energy Balance

 描述（由申请人提供）：我们的长期目标是确定骨髓脂肪组织（MAT）的起源和功能，其与营养状况的关系及其对骨骼重塑的影响。R24合作实验室开发了一种“团队科学”方法，通过让每个调查团队（MacDougald [密歇根]、Horowitz [耶鲁]、Klibanski [哈佛]和罗森[MMCRI]）的资源和人才协同工作来实现这一目标。关于骨髓脂肪功能的最初探究源于以下观察， 在神经性厌食症和肥胖症的相反临床综合征中，报道了显著的MAT。随后，我们使用来自R24合作实验室的资源来确定MAT是一种独特的、具有生物活性的脂肪储存库，其反映了代谢状态并影响骨骼 重塑我们开发了小鼠模型，谱系追踪方法，新的成像技术和代谢组学，以更好地了解MAT。作为这个转化平台的一部分，我们还结合了平行的人类和动物模型来实现我们的总体目标。我们证明，在人类和小鼠中，高脂饮食（HFD）或慢性热量限制诱导的骨髓肥胖状态与低BMD相关（2-6）。我们还首次注意到，MAT的增加是由于诱导了一种独特类型的脂肪细胞，对环境或营养应激有反应，具有内分泌和旁分泌特性（7）。我们对这种更新的总体假设是，MAT通过发育上不同的骨髓脂肪细胞祖细胞（MAP）的分化而扩增，导致动态分泌库具有独特的调节急性和慢性过程中循环脂肪酸和脂质通量的能力。 营养压力我们还推测，这种储存有助于通过旁分泌和内分泌手段调节全身代谢和骨重建。为了验证这些假设，我们提出了两个目标：1.确定营养变化如何影响啮齿动物和人类的骨骼重塑和MAT。这将通过3个子目标来实现：第一，我们将研究HFD在四种具有不同骨髓脂联素水平的小鼠模型中的骨骼效应;第二，我们将研究高脂喂养和禁食如何影响人类的骨骼重塑和MAT;第三，我们将研究MAT库中调节脂质饱和度的机制，以及从调节MAT中分泌棕榈酸和其他饱和脂质是否对骨骼有害;此外，我们将开发动物模型来特异性地和诱导性地调节MAT中的基因。2.确定小鼠和人MAT中的脂肪细胞祖细胞。这将通过在小鼠和人中使用双报告基因模型删除骨髓内的特定基因和人骨髓抽吸物明确鉴定骨髓脂肪细胞祖细胞（MAP）的研究来实现。综上所述，在本提案中，我们将使用综合方法和团队科学来定义MAT的功能意义和起源。

 DESCRIPTION (provided by applicant): Our long-term goal is to determine the origin and function of marrow adipose tissue (MAT), its relationship to nutrient status and its effects on skeletal remodeling. The R24 Collaboratory has developed a `team science' approach to address this goal by having the resources and talents of each investigative team (MacDougald [Michigan], Horowitz [Yale], Klibanski [Harvard], and Rosen [MMCRI]) working synergistically on each aim. The initial inquiry about the function of marrow fat originated from the observation that in the opposing clinical syndromes of anorexia nervosa and obesity, significant MAT was reported. Subsequently, we used resources from the R24 Collaboratory to establish that MAT is a unique, biologically active, adipose depot that reflects metabolic status and influences skeletal remodeling. We developed mouse models, lineage-tracing methodology, novel imaging technology and metabolomics to better understand MAT. As part of this translational platform, we also incorporated parallel human and animal models to address our overall goals. We demonstrated that in humans and mice, states of induced marrow adiposity by a high fat diet (HFD) or chronic caloric restriction, are associated with low BMD (2-6). We also noted for the first time that increases in MAT are due to induction of a unique type of adipocyte, responsive to environmental or nutrient stress, with endocrine and paracrine properties (7). Our overarching hypothesis for this renewal is that MAT expands through differentiation of a developmentally distinct marrow adipocyte progenitor (MAP), resulting in a dynamic secretory depot with a unique capacity to regulate the flux of circulating fatty acids and lipids during acute and chronic nutritional stresses. We also hypothesize that this depot contributes to the regulation of whole body metabolism and bone remodeling through paracrine and endocrine means. To test those hypotheses, we propose 2 aims: 1.To determine how nutrient changes affect skeletal remodeling and MAT in rodents and humans. This will be accomplished through 3 subaims: 1st, we will study the skeletal effects of a HFD in four mouse models with different marrow adiponectin levels; 2nd, we will examine how high fat feeding and fasting affects skeletal remodeling and MAT in humans; 3rd, we will investigate mechanisms for regulating lipid saturation within MAT depots, and whether secretion of palmitate and other saturated lipids from regulated MAT is detrimental to bone; in addition, we will develop animal models to specifically and inducibly modulate genes within MAT. 2. To define the adipocyte progenitor in mouse and human MAT. This will be achieved by studies in mice and man using double reporter models to delete specific genes within the marrow, and human bone marrow aspirates to definitively identify the marrow adipocyte progenitor (MAP). In summary, in this proposal we will use an integrated approach and team science for these two aims to define the functional significance and origin of MAT.