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Pref-1 receptor: Identification and characterization in inhibiting adipogenesis

Pref-1 受体：抑制脂肪生成的鉴定和表征

基本信息

批准号：
10689082
负责人：
Hei Sook Sul
金额：
$ 37.84万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-13 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10689082
关键词：
Ablation Adipocytes Adipose tissue Affinity Binding Biochemical Biological Assay CCAAT-enhancer-binding protein-delta Cell membrane Cells Chemicals Chemistry Cultured Cells Development Diabetes Mellitus Diazomethane Disease Management EGF gene Esters Extracellular Domain Fatty acid glycerol esters Future Gene Expression Glucose Goals Health Heterodimerization Homeostasis IRAK1 gene In Situ In Vitro Insulin Knockout Mice Ligands Lipodystrophy MEKs Maintenance Membrane Glycoproteins Membrane Proteins Metabolic syndrome Methods Molecular Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Nude Mice Obesity Peptides Population Recombinants Research Signal Pathway Signal Transduction Site Sorting Testing Weight adipocyte differentiation autocrine constitutive expression experimental study gain of function improved in vivo inhibitor lipid biosynthesis loss of function mouse model neutralizing antibody overexpression paracrine preadipocyte factor 1 prevent progenitor receptor receptor binding therapeutic target

项目摘要

Pref-1 (Preadipocyte factor-1) is a widely used preadipocyte marker that we originally cloned and identified. Pref-1 is expressed in preadipocytes, downregulated during adipocyte differentiation, and is absent in adipocytes. Pref-1 is synthesized as a plasma membrane protein with 6 EGF-repeats in the extracellular domain. Pref-1 ectodomain is cleaved by TACE to generate the biologically active soluble Pref-1. Gain- and loss-of function studies in cultured cells, as well as in mice in vivo showed Inhibition of adipogenesis by Pref-1 in autocrine/paracrine manner. Thus, whereas Pref-1ablated mice have higher adipose tissue mass, Pref-1 overexpression in adipose tissue causes partial lipodystrophy with ectopic fat storage. Pref-1 activates MEK/ERK to induce Sox9, which in turn suppresses C/EBPb and C/EBPd, to inhibit adipocyte differentiation. However, the Pref-1 receptor at the plasma membrane that initiates Pref-1 signaling is yet to be identified. By using recently developed diazirine photo-reactive linker combined with robust NHS-ester chemistry in situ, the putative plasma membrane receptor for Pref-1 has recently been identified. The goal of this research is to firmly establish and characterize the Pref-1 receptor which is the most proximal and critical component of Pref-1 signaling and to study the downstream components to inhibit adipocyte differentiation. To accomplish this goal, biochemical, cellular and molecular approaches as well as gain- and loss-of function studies in vitro and in vivo will be taken. In the long run, elucidating mechanisms underlying Pref-1 binding to the Pref-1 receptor and its downstream signaling pathway will help to develop strategies to control adipogenesis.

Pref-1（Preadipocyte factor-1）是我们最初克隆和鉴定的广泛使用的前脂肪细胞标志物。Pref-1在前脂肪细胞中表达，在脂肪细胞分化过程中下调，并且在脂肪细胞中不存在。Pref-1是一种在细胞外结构域中具有6个EGF重复序列的质膜蛋白。Pref-1胞外域被TACE切割以产生具有生物活性的可溶性Pref-1。在培养的细胞中以及在小鼠体内进行的功能获得和丧失研究显示Pref-1以自分泌/旁分泌方式抑制脂肪形成。因此，尽管Pref-1消融的小鼠具有更高的脂肪组织质量，但脂肪组织中的Pref-1过表达导致部分脂肪营养不良伴异位脂肪储存。Pref-1激活MEK/ERK以诱导Sox 9，Sox 9反过来抑制C/EBPb和C/EBPd，从而抑制脂肪细胞分化。然而，启动Pref-1信号传导的质膜上的Pref-1受体尚未被鉴定。通过使用最近开发的二氮丙啶光反应性连接体结合稳健的NHS-酯化学原位，最近已经鉴定了Pref-1的推定质膜受体。本研究的目的是确定和表征Pref-1受体，这是Pref-1信号传导的最接近和关键的组分，并研究抑制脂肪细胞分化的下游组分。为了实现这一目标，将采取生物化学、细胞和分子方法以及体外和体内功能获得和丧失研究。从长远来看，阐明Pref-1结合Pref-1受体及其下游信号通路的机制将有助于开发控制脂肪生成的策略。