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

 描述(申请人提供)：我们的长期目标是确定骨髓脂肪组织(MAT)的来源和功能，它与营养状态的关系，以及它对骨骼重塑的影响。R24合作实验室开发了一种“团队科学”方法来解决这一目标，方法是让每个调查小组(MacDougald[密歇根]、Horowitz[耶鲁]、Klibanski[哈佛]和Rosen[MMCRI])的资源和人才协同工作，实现每个目标。对骨髓脂肪功能的初步探讨源于对 在神经性厌食症和肥胖症的对立临床症状中，有显著的MAT报道。随后，我们使用R24合作实验室的资源来确定MAT是一个独特的、具有生物活性的脂肪储存库，它反映了代谢状态并影响骨骼 改建。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。作为这个翻译平台的一部分，我们还合并了平行的人类和动物模型，以满足我们的总体目标。我们证明，在人类和小鼠中，通过高脂肪饮食(HFD)或慢性热量限制诱导的骨髓肥胖症状态与低BMD(2-6)相关。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，该细胞对环境或营养压力做出反应，具有内分泌和旁分泌特性(7)。我们对这种更新的主要假设是，MAT通过分化发育不同的骨髓脂肪细胞前体(MAP)而扩大，导致一个动态的分泌库，具有独特的能力在急性和慢性期间调节循环中的脂肪酸和脂类的流动。 营养压力。我们还假设这个储存库通过旁分泌和内分泌手段对全身新陈代谢和骨重建的调节做出贡献。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个子目标完成：第一，我们将研究一种高脂饮食对四种不同骨髓脂联素水平的小鼠模型的骨骼影响；第二，我们将检查高脂喂养和禁食如何影响人类的骨骼重塑和MAT；第三，我们将研究调节垫内脂肪饱和的机制，以及从受调节的垫内分泌棕榈酸酯和其他饱和脂肪是否对骨骼有害；此外，我们还将建立动物模型，以特异性和诱导性地调节MAT内的基因。2.确定小鼠和人脂肪细胞的祖细胞。这将通过在小鼠和人类身上进行的研究来实现，该研究使用双报告模型来删除骨髓中的特定基因，并通过人类骨髓抽吸物来确定骨髓脂肪细胞前体(MAP)。总之，在本提案中，我们将使用综合方法和团队科学来实现这两个目标，以确定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.