O-GlcNAc modification in metabolic homeostasis

肥胖症已成为一种全球流行病，在全世界造成巨大的经济和公共卫生负担。脂肪组织具有巨大的可塑性，以响应营养供应。营养物质流入己糖胺生物合成途径导致O-连接的β-N-乙酰葡糖胺（O-GlcNAc）部分对细胞核、细胞质和线粒体蛋白进行翻译后修饰。O-GlcNAc转移酶（OGT）负责将GlcNAc部分添加到靶蛋白。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， OGT的转基因过表达促进饮食诱导的肥胖。此外，来自OGT缺陷脂肪细胞的条件培养基在体外调节前脂肪细胞增殖和分化。为了说明营养感应OGT如何影响脂肪组织稳态，我们假设成熟脂肪细胞中的OGT通过旁分泌调节前脂肪细胞增殖和分化来控制脂肪生成。目的1将评估脂肪特异性OGT敲除和敲入小鼠体内脂肪形成。目的2：研究脂肪OGT对脂肪形成和全身代谢的影响。目的3将确定OGT在成熟脂肪细胞中如何以旁分泌方式调节前脂肪细胞的增殖和分化。完成拟议的研究将定义脂肪细胞OGT作为营养传感器，介导脂肪生成的旁分泌调节，并控制肥胖和合并症的发展。

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.