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：
10447012
负责人：
Ormond A MacDougald
金额：
$ 35.1万
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/10447012
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。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Deciphering the Clinical Presentations in LMNA-related Lipodystrophy: Report of 115 Cases and a Systematic Review.

解读 LMNA 相关脂肪营养不良的临床表现：115 例报告和系统评价。

DOI：
发表时间：
2024-02-20
期刊：
影响因子：
0
作者：
Besci, Ozge;Foss de Freitas, Maria Christina;Guidorizzi, Natália Rossin;Guler, Merve Celik;Gilio, Donatella;Maung, Jessica N;Schill, Rebecca L;Hoose, Keegan S;Obua, Bonje N;Gomes, Anabela D;Yıldırım Şimşir, Ilgın;Demir, Korcan;Akinci, Baris;M
通讯作者：
M

Homozygous LMNA p.R582H pathogenic variant reveals increasing effect on the severity of fat loss in lipodystrophy.

纯合 LMNA p.R582H 致病性变异揭示了对脂肪营养不良中脂肪减少严重程度的影响越来越大。

DOI：
发表时间：
2020
期刊：
影响因子：
0
作者：
Soyaltin, Utku Erdem;Simsir, Ilgin Yildirim;Akinci, Baris;Altay, Canan;Adiyaman, Suleyman Cem;Lee, Kristen;Onay, Huseyin;Oral, Elif Arioglu
通讯作者：
Oral, Elif Arioglu

Preclinical models for investigating how bone marrow adipocytes influence bone and hematopoietic cellularity.

用于研究骨髓脂肪细胞如何影响骨和造血细胞构成的临床前模型。