Mechanisms of adipocyte loss in laminopathy-induced lipodystrophy in mice and humans

摘要 脂肪营养不良是一种以脂肪组织损失和再分布为特征的疾病， 相关的代谢并发症，包括糖尿病。最常见的单基因 脂肪营养不良是家族性部分脂肪营养不良2型（FPLD 2），其由以下突变引起： LMNA基因，编码核纤层蛋白A和C。脂肪组织 在青春期正常发育后丢失，是未知的。为了弥补这一不足， 我们选择性地删除小鼠脂肪细胞中的LMNA（LMNAADKO）。我们观察到一个惊人的损失， 成年LMNAADKO小鼠中的白色脂肪组织，沿着肝脏中脂肪沉积增加， 空腹和进食状态下血糖水平升高，循环胰岛素水平升高 与LMNAf 1/fl对照相比。对年轻小鼠的分析显示， LMNAADKO小鼠中的脂肪组织，其与青春期一致地逐渐丧失。这些 表型与在人FPLD 2患者中观察到的表型密切对应。重要的是，我们还有 获得高度积极的LMNA R482Q患者人群，他们尚未表现出症状 脂肪代谢障碍分析他们的WAT将提供一个前所未有的机会， 我们对这种疾病及其进展的了解。我们建议在组织中进行实验， 这些患者可以确定WAT细胞结构的最早缺陷，包括WAT细胞的特定改变。 脂肪细胞基因表达为了检验我们的假设，我们提出以下具体目标： SA 1）在LMNAADKO小鼠中确定核纤层蛋白A/C缺乏引起的脂肪组织损失是否是 由于脂肪生成受损或脂肪细胞周转增加的结果，SA 2）确定 LMNAADKO小鼠脂肪细胞损失是否通过内在或外在细胞发生 机制和SA 3）在尚未显示明显体征的年轻FPLD 2患者中进行评估 LMNA突变对形态学、基因表达、信号传导的影响 途径和脂肪组织库的细胞组成。

Abstract Lipodystrophy is a disorder characterized by adipose tissue loss and redistribution, with associated metabolic complications including diabetes. The most common form of monogenic lipodystrophy is familial partial lipodystrophy type 2 (FPLD2), which is caused by a mutation in the LMNA gene, encoding nuclear lamins A and C. The mechanisms for how adipose tissues are lost, after developing normally through adolescence are unknown. To address this shortfall, we selectively deleted LMNA in adipocytes (LMNAADKO) of mice. We observed a striking loss of white adipose tissue in adult LMNAADKO mice, along with increased fat deposition in the liver, elevated blood glucose levels in both fasting and fed states, increased circulating insulin levels compared to the LMNAfl/fl controls. Analyses of young mice revealed development of white adipose tissue in LMNAADKO mice, which is progressively lost coincident with puberty. These phenotypes closely mirror those observed in human FPLD2 patients. Importantly, we also have access to a highly motivated LMNA R482Q patient population, who are not yet exhibiting signs of lipodystrophy. Analyses of their WAT will provide an unprecedented opportunity to advance our understanding of this disease and its progression. We propose experiments in tissue from these patients to pinpoint the earliest defects in WAT cellularity, including specific alterations in adipocyte gene expression. To test our hypotheses, we propose the following specific aims: SA1) determine in LMNAADKO mice whether loss of adipose tissues with lamin A/C deficiency is due to impaired adipogenesis or is the result of increased adipocyte turnover, SA2) ascertain in LMNAADKO mice whether loss of adipocytes occurs through intrinsic or extrinsic cellular mechanisms, and SA3) evaluate in young FPLD2 patients, who are not yet showing overt signs of lipodystrophy, the effects of LMNA mutation on morphology, gene expression, signaling pathways and cellular composition of adipose tissue depots.