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丢失和重新分布为特征的疾病， 相关的代谢并发症，包括糖尿病。最常见的单基因形式 脂肪营养不良是家族性部分性脂肪营养不良2型(FPLD2)，是由基因突变引起的 LMNA基因，编码核纤层蛋白A和C。脂肪组织 都是迷失的，经过青春期后正常发育都是未知的。为了解决这一不足， 我们选择性地删除了小鼠脂肪细胞(LMNAADKO)中的LMNA。我们观察到一个惊人的损失 成年LMNAADKO小鼠的白色脂肪组织，随着肝脏脂肪沉积的增加， 空腹和进食状态下血糖水平升高，循环胰岛素水平升高 与LMNAfl/fl控件相比。对幼鼠的分析揭示了白色的发育 LMNAADKO小鼠的脂肪组织，随着青春期逐渐消失。这些 表型与人类FPLD2患者的表型密切相关。重要的是，我们还有 接触热情高涨的LMNA R482Q患者群体，这些患者尚未表现出体征 脂肪营养不良的症状。分析他们的WAT将提供一个前所未有的机会来推进 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 这些患者能够准确定位Wat细胞的最早缺陷，包括 脂肪细胞基因表达。为了验证我们的假设，我们提出了以下具体目标： SA1)在LMNAADKO小鼠中确定层蛋白A/C缺陷的脂肪组织丢失是否 由于脂肪生成受损或脂肪细胞周转率增加，SA2)确定 LMNAADKO小鼠脂肪细胞的丢失是通过内源性还是外源性细胞发生的 机制和SA3)在年轻的FPLD2患者中进行评估，这些患者尚未显示出明显的体征 脂营养不良的LMNA突变对形态、基因表达、信号转导的影响 脂肪组织储藏的途径和细胞组成。

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.