Adipose FHL1 in energy homeostasis

脂肪 FHL1 在能量稳态中的作用

• 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
• 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

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.

总结 在脂肪生物学的研究中已经取得了巨大的进展，但我们的理解仍存在差距 脂肪的发育和功能。我们研究的长期目标是了解脂肪组织 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干扰对脂肪代谢的影响。 组织发育一个这样的基因是四个半LIM结构域1（FHL 1），一种在哺乳动物中高度表达的蛋白质。 骨骼肌和心肌，最近与人类脂肪组织发育有关。的情况 报告1例15岁FHL 1基因完全缺失伴邻近MAP 7 D3基因缺失的患者， 脂肪组织完全丧失，伴有肌肉肥大、脊柱僵硬和身材矮小。具体 FHL 1在脂肪发育和功能中的作用尚不清楚。在初步实验中，我们鉴定了FHL 1 作为PPARg的主要共转录因子，表明在脂肪组织的转录调节中发挥作用。到 为了模拟人类患者脂肪组织的损失，我们建立了一个小鼠模型，其中FHL 1是全球性的。 不足全身Fhl 1基因敲除小鼠对饮食诱导的肥胖症（DIO）有抵抗力。有趣的是，此前 研究表明，缺乏相关paraffin FHL 2的小鼠也对DIO具有抗性。我们发现FHL 1 缺乏小鼠前脂肪细胞部分减弱分化成脂肪细胞，和一个单一的氨基酸 FHL 1内122位色氨酸取代为丝氨酸特异性消除了PPARg同种型2 （PPARg 2）表达，但不表达同种型1（PPARg 1）。与此一致，在人脂肪细胞中FHL 1的敲低 优先降低PPARg 2表达，但不降低PPARg 1表达。据报道，PPARg 2是脂肪- 在成纤维细胞中脂肪形成激活中特异性、必要性和充分性。除了激活PPARg， FHL 1与PPARg协同激活PPARg依赖的基因表达。根据我们的初步数据， 我们假设FHL 1至少部分通过转录调节来调节脂肪细胞分化 的PPARg。这项建议旨在研究细胞，分子和生理机制， FHL 1调节脂肪组织发育和能量稳态。具体目标1将研究以下方面的作用： FHL 1和FHL 2在小鼠脂肪细胞分化中的作用具体目标2将解决潜在的分子 FHL 1与脂肪细胞分化的转录调控机制。第3章将 研究脂肪特异性敲除小鼠和人类移植模型中FHL 1的体内功能。 总之，所提出的实验将提供对脂肪生物学， 肥胖症，潜在地导致肥胖症和相关代谢疾病的新的治疗策略。