O-GlcNAc modification in metabolic homeostasis

O-GlcNAc 修饰对代谢稳态的影响

基本信息

批准号：
10227068
负责人：
Xiaoyong Yang
金额：
$ 40.41万
依托单位：
YALE UNIVERSITY
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：
2019-09-12 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227068
关键词：
Adipocytes Adipose tissue Adolescent Adult Affect Blood Vessels Body fat Caloric Restriction Cardiovascular Diseases Cell Fraction Cell Proliferation Conditioned Culture Media Consumption Cues Cytoplasmic Protein Data Diabetes Mellitus Diet Economics Enterobacteria phage P1 Cre recombinase Fatty acid glycerol esters Generations Goals Health Hexosamines High Fat Diet Homeostasis In Vitro Knock-in Knock-in Mouse Knock-out Knockout Mice Lead Link Lipids Lipodystrophy Mass Spectrum Analysis Mediating Membrane Metabolic Metabolism Mitochondrial Proteins Modification Molecular Mus Nuclear Proteins Nutrient Nutritional Nutritional status O-GlcNAc transferase Obesity Obesity associated disease Organ Pathway interactions Phenotype Post-Translational Protein Processing Proteins Public Health Regulation Reporter Role Signal Transduction Transgenic Organisms United States Work adiponectin adult obesity base comorbidity detection of nutrient diet-induced obesity dietary gain of function in vitro testing in vivo insight lipid biosynthesis novel novel strategies obesity development overexpression pandemic disease paracrine promoter response sensor stem cells transcriptome sequencing

项目摘要

Obesity has become a global pandemic that poses massive economic and public health burdens worldwide. Adipose tissue has an enormous plasticity in response to nutrient availability. Nutrient flux into the hexosamine biosynthetic pathway leads to the posttranslational modification of nuclear, cytoplasmic, and mitochondrial proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) moieties. O-GlcNAc transferase (OGT) is responsible for the addition of GlcNAc moieties to target proteins. Our preliminary results show that deletion of OGT in mature adipocytes results in lipodystrophy and transgenic overexpression of OGT promotes diet-induced obesity. Additionally, conditioned medium from OGT-deficient adipocytes modulates preadipocyte proliferation and differentiation in vitro. To illustrate how nutrient-sensing OGT impacts adipose tissue homeostasis, we hypothesize that OGT in mature adipocytes controls adipogenesis through paracrine regulation of preadipocyte proliferation and differentiation. Aim 1 will assess in vivo adipogenesis in adipose-specific OGT knockout and knockin mice. Aim 2 will determine the effects of adipose OGT on dietary regulation of adipogenesis and whole-body metabolism. Aim 3 will identify how OGT in mature adipocytes regulates preadipocyte proliferation and differentiation in a paracrine manner. Completion of the proposed studies will define adipocyte OGT as a nutrient sensor that mediates the paracrine regulation of adipogenesis and controls the development of obesity and co-morbidities.

肥胖已成为全球大流行，在全球范围内构成了巨大的经济和公共卫生。脂肪组织对养分的可用性具有巨大的可塑性。六胺生物合成途径的营养通量导致通过O链式的β-N-乙酰葡萄糖胺（O-GLCNAC）部分的核，细胞质和线粒体蛋白的翻译后修饰。 O-GLCNAC转移酶（OGT）负责将GlcNAC部分添加到靶蛋白中。我们的初步结果表明，成熟脂肪细胞中OGT的缺失导致脂肪营养不良和 OGT的转基因过表达促进了饮食诱导的肥胖症。另外，来自OGT缺陷脂肪细胞的条件培养基调节体外脂肪细胞增殖和分化。为了说明营养感应的OGT如何影响脂肪组织稳态，我们假设成熟脂肪细胞中的OGT通过对脂肪细胞前增殖和分化的旁分泌调节来控制脂肪形成。 AIM 1将评估脂肪特异性OGT敲除和敲除小鼠中的体内脂肪形成。 AIM 2将确定脂肪OGT对脂肪生成和全身代谢的饮食调节的影响。 AIM 3将确定成熟脂肪细胞中的OGT如何以旁分泌方式调节前脂肪细胞增殖和分化。拟议研究的完成将把脂肪细胞OGT定义为一种营养传感器，介导脂肪生成的旁分泌调节并控制肥胖和合并症的发展。