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

小鼠和人类核纤层病诱导的脂肪营养不良中脂肪细胞损失的机制

基本信息

批准号：
10029064
负责人：
Ormond A MacDougald
金额：
$ 31.2万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10029064
关键词：
3T3-L1 Cells Address Adipocytes Adipose tissue Adolescence Adult Affect Age Alleles Animal Model Animals Appearance Area Autophagocytosis Biology Blood Glucose Brown Fat Cell Death Cells Cellularity Characteristics Chromosome Structures Cultured Cells Data Defect Deposition Development Diabetes Mellitus Disease Exhibits Familial partial lipodystrophy Fasting Fatty Liver Fatty acid glycerol esters Gene Expression Genes Glucose Intolerance Human Immune Targeting Impairment In Vitro Insulin Insulin Resistance Knowledge Lamin Type A Leptin Leptin deficiency Life Link Lipodystrophy Literature Liver LoxP-flanked allele Maintenance Mesenchymal Metabolic Metabolic dysfunction Morphology Mus Muscular Dystrophies Musculoskeletal Mutation Nuclear Lamin Nuclear Structure Pathway interactions Patients Phenotype Premature aging syndrome Puberty Signal Pathway Testing Time Tissues Transgenic Mice Work adipocyte differentiation adiponectin autosomal dominant mutation experimental study glucose metabolism human disease in vivo lamin C lipid biosynthesis lipid metabolism loss of function loss of function mutation mouse model mutant new therapeutic target novel overexpression patient population postnatal premature prevent transcription factor

项目摘要

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.

抽象的脂肪营养不良是一种以脂肪组织丧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），是由突变引起的 LMNA基因，编码核层粘连蛋白A和C。在正常通过青春期发展之后，丢失是未知的。为了解决这个短缺，我们在小鼠的脂肪细胞（LMNAADKO）中有选择地删除了LMNA。我们观察到了惊人的损失成年lmnaadko小鼠中的白脂肪组织，以及肝脏中脂肪沉积的增加，禁食状态和联邦状态下的血糖水平升高，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展 lmnaadko小鼠中的脂肪组织，与青春期逐渐失去了一致。这些表型紧密反映了在人FPLD2患者中观察到的表型。重要的是，我们也有尚未表现出迹象的高度动机LMNA R482Q患者人群脂肪营养不良。对其WAT的分析将为前进提供前所未有的机会我们对这种疾病及其进展的理解。我们提出了来自组织中的实验这些患者以查明WAT细胞性最早的缺陷，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的： SA1）确定在Lmnaadko小鼠中由于脂肪生成受损或是脂肪细胞更新增加的结果，SA2）确定 lmnaadko小鼠是否通过固有或外在细胞发生脂肪细胞的丧失机制和SA3）评估年轻的FPLD2患者，他们尚未显示明显的迹象脂肪营养不良，LMNA突变对形态学，基因表达，信号的影响脂肪组织库的途径和细胞组成。