Regulation of brown and beige adipocyte development through Ebf2

通过 Ebf2 调节棕色和米色脂肪细胞的发育

• 批准号: 8868110
• 负责人: Patrick Seale
• 金额: $ 34.8万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868110
• 关键词: Acute; Adipocytes; Adipose tissue; Adult; Animals; B-Lymphocytes; Binding; Body Weight; Brown Fat; Cells; Cessation of life; Chromatin; Chronic Disease; Dermis; Dermomyotome; Development; Diabetes Mellitus; Embryo; Embryonic Development; Enhancers; Fatty acid glycerol esters; Gene Targeting; Genes; Goals; Health; Heart Diseases; Insulin Resistance; Link; Malignant Neoplasms; Mediating; Metabolic Diseases; Metabolism; Methods; Methylation; Molecular; Multipotent Stem Cells; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nucleosomes; Obesity; Pathway interactions; Pattern; Phenotype; Physiological; Population; Positioning Attribute; Process; Public Health; Regulation; Role; Site; Skeletal Muscle; Somites; Specific qualifier value; Stem cells; Structure; Testing; Therapeutic; Therapeutic Effect; Tissues; Transcription Coactivator; Transgenic Mice; Work; adipocyte differentiation; cell type; design; histone modification; in vivo; insight; mouse model; novel; precursor cell; premature; programs; spatiotemporal; transcription factor

DESCRIPTION (provided by applicant): Obesity is a leading cause of chronic illness and premature death in the U.S. A promising avenue to reduce obesity and diabetes is through increasing the amount and/or function of energy-dissipating fat cells, called brown and beige adipocytes. Conversely, reduced brown/beige fat activity may predispose some people to type 2 diabetes and obesity. It is thus critical to study how these cell types develop and function. Brown and beige fat cells in adult tissues arise from committed precursor cells called preadipocytes. However, the molecular pathways that regulate preadipocyte commitment or identity are unknown. In this project, we will determine the function of Early B Cell Factor-2 (Ebf2), a transcription factor, in brown fat-lineage commitment and evaluate whether activation of Ebf2 in fat tissue protects animals against obesity and metabolic disease. Brown fat, skeletal muscle, dermis and some white fat cells originate from multipotent mesodermal structures in the embryo called somites. Ebf2 is required for brown and beige fat development and its expression identifies committed brown fat preadipocytes in somites, days before any sign of brown fat differentiation. We hypothesize that Ebf2 expression commits multipotent stem cells to a brown fat-specific fate in somites. To investigate this, we will determine if expression of Ebf2 in somit- derived stem cells converts them into brown preadipocytes and assess whether loss of Ebf2 or certain of its downstream target genes in preadipocytes activates alternative cell fates. Lineage tracing will be used to assess the fate of Ebf2-expressing cells in vivo. Ebf2 turns on a complete brown fat-specific program in adipocytes, but its mechanism of action or physiological effects have not been clarified. We hypothesize that Ebf2 binds to brown fat-specific genes in preadipocytes and makes the chromatin at these sites competent for the binding of other transcriptional activators in adipocytes. To test this, we will analyze the binding of Ebf2 and other key factors, Ppar? and c/EBP�, during the differentiation of wildtype and Ebf2-deficient preadipocytes. Given that Ebf2 expression strongly promotes brown and beige fat differentiation, we hypothesize that activation of Ebf2 in adipose tissue suppresses metabolic disease. To test this, we will analyze the systemic metabolism of mice that ectopically express Ebf2 in adipose tissue and develop a mouse model to investigate whether Ebf2 can acutely induce WAT browning in adults. Taken together, these studies will provide critical insights into how stem cells undergo brown fat lineage commitment. Understanding how Ebf2 functions in brown/beige fat commitment will be crucial for designing approaches to increase brown/beige fat mass for therapeutic effect.

描述（由适用提供）：肥胖是美国慢性疾病和过早死亡的主要原因，这是减少肥胖和糖尿病的有前途的途径，是通过增加能量消除能量降低脂肪细胞的数量和/或功能，称为棕色和米色脂肪细胞。相反，减少的棕色/米色脂肪活性可能使某些人易于使用2型糖尿病和肥胖症。因此，研究这些细胞类型的发展和功能至关重要。成人组织中的棕色和米色脂肪细胞来自称为前体细胞的坚定前体细胞。但是，调节沉淀物承诺或身份的分子途径尚不清楚。在该项目中，我们将确定早期B细胞因子2（EBF2）（转录因子）在棕色脂肪限制承诺中的功能，并评估EBF2在脂肪组织中的激活是否可以保护动物免受肥胖和代谢疾病的影响。棕色脂肪，骨骼肌，真皮和一些白色脂肪细胞起源于胚胎中的多能中胚层结构，称为Commons。 EBF2是棕色和米色脂肪发育所必需的，其表达鉴定出在公共中的棕色脂肪前脂肪细胞，几天前，棕色脂肪分化的任何迹象。我们假设EBF2表达将多能干细胞归于公地中的棕色脂肪特异性脂肪。为了研究这一点，我们将确定在衍生的干细胞中EBF2的表达是否会将其转化为棕色的前脂肪细胞，并评估EBF2的丧失还是其前脂肪细胞中其某些下游靶基因是否会激活替代细胞命运。谱系跟踪将用于评估体内表达EBF2的细胞的命运。 EBF2在脂肪细胞中打开了一个完整的棕色脂肪特异性程序，但尚未阐明其作用或物理作用的机理。我们假设EBF2与前脂肪细胞中的棕色脂肪特异性基因结合，并使这些位点的染色质在脂肪细胞中有能力结合其他转录激活剂的结合。为了测试这一点，我们将分析EBF2和其他关键因素PPAR的结合？和C/EBP。鉴于EBF2表达强烈促进棕色和米色脂肪分化，我们假设脂肪组织中EBF2的激活抑制了代谢疾病。为了测试这一点，我们将分析在经济表达脂肪组织中经济表达EBF2的小鼠的全身代谢，并开发小鼠模型，以研究EBF2是否可以急性诱导成人的水褐变。综上所述，这些研究将提供有关干细胞如何承担棕色脂肪谱系承诺的关键见解。了解EBF2在棕色/米色脂肪承诺中的功能如何对于设计增加棕色/米色脂肪质量的方法至关重要。