O-GlcNAc modification in metabolic homeostasis

肥胖症已经成为一种全球流行病，在世界范围内造成了巨大的经济和公共卫生负担。脂肪组织对营养的可获得性有巨大的可塑性。进入氨基己糖生物合成途径的营养物质流量导致核蛋白、细胞质蛋白和线粒体蛋白被O-连接的β-N-乙酰氨基葡萄糖(O-GlcNAc)部分翻译后修饰。O-GlcNAc转移酶(OGT)负责将GlcNAc部分加到靶蛋白上。我们的初步结果表明，OGT在成熟脂肪细胞中的缺失会导致脂肪营养不良和 转基因过表达OGT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液在体外调节前脂肪细胞的增殖和分化。为了阐明营养感知OGT如何影响脂肪组织的动态平衡，我们假设成熟脂肪细胞中的OGT通过旁分泌调节前体脂肪细胞的增殖和分化来控制脂肪的生成。目的1将评估体内脂肪特异性OGT基因敲除和敲除小鼠的成脂作用。目的2确定脂肪OGT对膳食脂肪生成和全身代谢的调节作用。目的3研究OGT在成熟脂肪细胞中如何旁分泌调节前脂肪细胞的增殖和分化。拟议的研究完成后，脂肪细胞OGT将被定义为一种营养感受器，介导脂肪生成的旁分泌调节，并控制肥胖和共病的发展。

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.