Adipose FHL1 in energy homeostasis

脂肪 FHL1 在能量稳态中的作用

基本信息

批准号：
10717734
负责人：
Frederick Anokye-Danso
金额：
$ 47.32万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-06 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10717734
关键词：
15 year old Adipocytes Adipose tissue Agreement Amino Acid Substitution Animal Model Applications Grants Attention Attenuated Biochemistry Biological Process Biology Bypass Cardiomyopathies Case Study Cell Differentiation process Cell model Cells Cellular biology Compensation Data Development Elements Energy Metabolism Enzymes Exhibits FHL1 gene FHL2 gene Fibroblasts Functional disorder Gene Expression Genes Goals High Fat Diet Homeostasis Human Hypertrophy Impairment In Vitro Incidence Investigation Knock-out Knockout Mice LIM Domain Link Luciferases Mediating Mediator Metabolic Metabolic Diseases Metabolism Mitotic Cell Cycle Molecular Molecular Biology Mus Muscle Muscular Dystrophies Myocardium N-terminal Obesity Pathogenesis Pathway interactions Patients Phenotype Physiological Positioning Attribute Principal Investigator Protein Family Protein Isoforms Proteins Regulation Reporting Research Research Personnel Resistance Role Serine Signal Transduction Skeletal Muscle Transcriptional Regulation Tryptophan Vertebral column adipocyte differentiation adipokines blood glucose regulation boys diet-induced obesity energy balance experimental study glucose metabolism in vivo in vivo evaluation insight insulin sensitivity knock-down lipid biosynthesis lipid metabolism loss of function member metabolic phenotype mouse model novel novel therapeutic intervention novel therapeutics older patient overexpression paralogous gene postnatal protein protein interaction subcutaneous transcription factor transplant model

项目摘要

SUMMARY Tremendous advances have been made in the study of adipose biology but there are gaps in our understanding of adipose development and functions. The long-term goal of our research is to understand how adipose tissues regulate whole-body energy metabolism, insulin sensitivity and glucose homeostasis. To achieve these goals, we have developed cellular and animal models to study the effects of gene perturbations in relation to adipose tissues development. One such gene is Four-and-half-LIM domain 1 (FHL1), a protein highly expressed in skeletal and cardiac muscles, and has recently been implicated in human adipose tissue development. A case report on a 15-year old patient with a complete deletion of FHL1 with adjacent MAP7D3 gene exhibited a near total loss of adipose tissues accompanied by muscular hypertrophy, rigid spine and short stature. The specific role of FHL1 in adipose development and function is unknown. In preliminary experiments, we identified FHL1 as a major co-transcription factor of PPARg, suggesting a role in transcriptional regulation of adipose tissues. To mimic the loss of adipose tissues in the human patient, we created a mouse model where FHL1 is globally deficient. Whole body Fhl1 knockout mice were resistant to diet-induced obesity (DIO). Interestingly, a previous study has shown that mice lacking a related paralog, FHL2, are also resistant to DIO. We found that FHL1 deficiency in murine preadipocytes partially attenuated differentiation into adipocytes, and a single amino acid substitution from tryptophan to serine at position 122 within FHL1 specifically abrogated PPARg isoform 2 (PPARg2) expression, but not isoform 1 (PPARg1). In agreement, knockdown of FHL1 in human adipocytes preferentially reduced PPARg2 expression, but not PPARg1. It has been reported that PPARg2 is adipose- specific, necessary and sufficient in activation of adipogenesis in fibroblast. In addition to activation of PPARg, FHL1 cooperates with PPARg in activation of PPARg-dependent gene expression. Based on our preliminary data, we hypothesized that FHL1 regulates adipocyte differentiation, at least in part, through transcriptional regulation of PPARg. This proposal seeks to investigate the cellular, molecular and physiological mechanisms by which FHL1 regulates adipose tissue development and energy homeostasis. Specific Aim 1 will examine the roles of FHL1 and FHL2 in murine adipocyte differentiation. Specific Aim 2 will address the underlying molecular mechanisms linking FHL1 and transcriptional regulation of adipocyte differentiation. Specific Aim 3 will investigate the in vivo functions of FHL1 in adipose-specific knockout mice and in human transplant models. Together, the proposed experiments will provide mechanistic insights into adipose biology, pathophysiology of obesity, potentially lead to novel therapeutic strategies for obesity and related metabolic diseases.

概括在脂肪生物学的研究中已经取得了巨大进步，但我们的理解存在差距脂肪的发展和功能。我们研究的长期目标是了解脂肪组织如何调节全身能量代谢，胰岛素敏感性和葡萄糖稳态。为了实现这些目标，我们已经开发了细胞和动物模型来研究基因扰动与脂肪有关的影响组织发育。一个这样的基因是四半结构域1（FHL1），一种高度表达的蛋白骨骼和心脏肌肉，最近与人脂肪组织的发育有关。案件关于一名15岁患者的报告，该患者完全删除了FHL1具有相邻MAP7D3基因的报告脂肪组织的总损失，伴有肌肉肥大，僵硬的脊柱和矮小的身材。具体 FHL1在脂肪发育和功能中的作用尚不清楚。在初步实验中，我们确定了FHL1 作为PPARG的主要共转录因子，表明在脂肪组织的转录调节中起作用。到模仿人类患者中脂肪组织的损失，我们创建了一个小鼠模型，其中FHL1在全球范围内不足。全身FHL1敲除小鼠对饮食诱导的肥胖症（DIO）具有抗性。有趣的是，以前研究表明，缺乏相关旁系同源物FHL2的小鼠对DIO也有抵抗力。我们发现FHL1 鼠前膜细胞缺乏部分减弱为脂肪细胞的分化，单个氨基酸从色氨酸替换为在FHL1中的位置122的丝氨酸特异性废除PPARG同工型2 （PPARG2）表达，但不是同工型1（PPARG1）。一致，人类脂肪细胞中FHL1的敲低优先降低PPARG2表达，而不是PPARG1。据报道，PPARG2是脂肪具体，必要的，足以激活成纤维细胞中的成生成。除了激活PPARG， FHL1与PPARG合作，在PPARG依赖性基因表达的激活中。根据我们的初步数据我们假设FHL1至少部分通过转录调节调节脂肪细胞分化 PPARG。该建议旨在研究细胞，分子和生理机制 FHL1调节脂肪组织的发育和能量稳态。具体目标1将检查鼠脂肪细胞分化中的FHL1和FHL2。特定的目标2将解决潜在的分子连接FHL1和脂肪细胞分化的转录调节的机制。具体的目标3将研究FHL1在脂肪特异性敲除小鼠和人移植模型中的体内功能。共同提出的实验将提供有关脂肪生物学，病理生理学的机械见解肥胖，有可能导致肥胖和相关代谢疾病的新型治疗策略。