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。脂肪组织的机制 在青春期正常发育后丢失的情况是未知的。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。我们观察到显着的损失 成年 LMNAADKO 小鼠的白色脂肪组织，以及肝脏中脂肪沉积的增加， 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 对照相比。对年轻小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 患者中观察到的表型非常相似。重要的是，我们还有 接触尚未表现出症状的高度积极的 LMNA R482Q 患者群体 脂肪营养不良。对他们的 WAT 的分析将提供前所未有的进步机会 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 这些患者能够查明 WAT 细胞结构的最早缺陷，包括 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： SA1) 确定 LMNAADKO 小鼠是否因核纤层蛋白 A/C 缺乏而导致脂肪组织损失 由于脂肪生成受损或脂肪细胞更新增加的结果，SA2）确定 LMNAADKO 小鼠脂肪细胞的损失是通过内在还是外在细胞发生的 机制和 SA3）在尚未表现出明显体征的年轻 FPLD2 患者中进行评估 脂肪营养不良，LMNA 突变对形态、基因表达、信号传导的影响 脂肪组织库的途径和细胞组成。

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.