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：
10837652
负责人：
Ormond A MacDougald
金额：
$ 23.4万
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 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10837652
关键词：
3T3-L1 Cells Address Adipocytes Adipose tissue Adolescence Adult Affect Animal Model Architecture Biology Blood Glucose Brown Fat Cell Culture Techniques Cell Nucleus Cells Cellularity Cessation of life Characteristics Chromatin Chromosome Structures Clinical Cultured Cells Data Defect Deposition Development Diabetes Mellitus Disease Environmental Risk Factor Exhibits Familial partial lipodystrophy Fasting Fatty Liver Fatty acid glycerol esters Gene Expression Genes High Fat Diet Hormones Human Human Characteristics Hyperglycemia Hyperinsulinism Impairment In Vitro Inflammation Inflammatory Insulin Insulin Resistance Knock-in Knock-in Mouse Knowledge Lamin Type A Leptin Life Lipids Lipodystrophy Lipolysis Liver Maintenance Mesenchymal Metabolic Metabolic dysfunction Modeling Molecular Morphology Mus Musculoskeletal Mutation Nuclear Nuclear Lamin Nuclear Structure Parents Pathogenicity Patients Phenotype Proteomics Puberty Testing Time Tissues Transgenic Mice Variant adipocyte differentiation adiponectin autosome gain of function glucose metabolism human disease in vivo lamin C lipid biosynthesis lipid metabolism loss of function mouse model mutant new therapeutic target novel overexpression patient population postnatal premature prevent recruit transcription factor transcriptome sequencing

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 patients with FPLD2. To further investigate the function of lamin A/C in adipose tissue and mechanisms by which adipocytes are lost, we have now developed inducible LmnaiADKO mice as well as seven knock-in mouse lines, each containing a mutation that causes lipodystrophy. We hypothesize that lamin A/C is required to maintain mature adipocyte characteristics, and we will ascertain molecular and cellular mechanisms that underly loss of mature adipocytes in mouse models and human patients. To test our hypotheses, we propose 1) to determine in inducible LmnaiADKO mice whether loss of adipose tissues with lamin A/C deficiency is due to dysregulation of genes associated with lipogenesis, lipolysis, or inflammation. 2) to characterize seven lines of mice that contain lipodystrophic variants across Lmna, and test whether mechanisms of adipocyte loss in these mice reflect those found in inducible LmnaADKO mice, as well as in human patients with FPLD2. 3) to study effects of LMNA variant on adipocyte and nuclear morphology, gene expression, cellular composition of adipose tissue depots, and chromatin architecture longitudinally in young patients who do not have all signs of disease, and in healthy controls and parents with FPLD2.

抽象的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 FPLD2 人类患者中观察到的表型非常相似。进一步调查核纤层蛋白 A/C 在脂肪组织中的功能以及脂肪细胞丢失的机制，我们现在已经开发出可诱导的 LmnaiADKO 小鼠以及七个敲入小鼠品系，每个品系含有导致脂肪营养不良的突变。我们假设核纤层蛋白 A/C 需要保持成熟的脂肪细胞特征，我们将确定分子和细胞小鼠模型和人类患者成熟脂肪细胞损失的机制。到为了检验我们的假设，我们建议 1) 确定诱导型 LmnaiADKO 小鼠是否丧失脂肪组织存在核纤层蛋白 A/C 缺陷是由于相关基因失调所致脂肪生成、脂肪分解或炎症。 2) 表征七个品系的小鼠，其中包含 Lmna 中的脂肪营养不良变异，并测试这些中脂肪细胞损失的机制是否小鼠反映了在诱导型 LmnaADKO 小鼠以及 FPLD2 人类患者中发现的结果。 3) 研究LMNA变异对脂肪细胞和核形态、基因表达的影响，脂肪组织库的细胞组成和年轻人的纵向染色质结构没有所有疾病体征的患者以及患有 FPLD2 的健康对照和父母。