Lim Jae-Min, Sherling Dan, Teo Chin Fen, Hausman Dorothy B, Lin Dawei, Wells Lance
Complex Carbohydrate Research Center, University of Georgia, Athens, Georgia 30602, USA.
J Proteome Res. 2008 Mar;7(3):1251-63. doi: 10.1021/pr7006945. Epub 2008 Feb 1.
Insulin resistance defines the metabolic syndrome and precedes, as well is the hallmark of, type II diabetes. Adipocytes, besides being a major site for energy storage, are endocrine in nature and secrete a variety of proteins, adipocytokines (adipokines), that can modulate insulin sensitivity, inflammation, obesity, hypertension, food intake (anorexigenic and orexigenic), and general energy homeostasis. Recent data demonstrates that increased intracellular glycosylation of proteins via O-GlcNAc can induce insulin resistance and that a rodent model with genetically elevated O-GlcNAc levels in muscle and fat displays hyperleptinemia. The link between O-GlcNAc levels, insulin resistance, and adipocytokine secretion is further explored here. First, with the use of immortalized and primary rodent adipocytes, the secreted proteome of differentiated adipocytes is more fully elucidated by the identification of 97 and 203 secreted proteins, respectively. Mapping of more than 80 N-linked glycosylation sites on adipocytokines from the cell lines further defines this proteome. Importantly, adipocytokines that are modulated when cells are shifted from insulin responsive to insulin resistant conditions are determined. By the use of two protocols for inducing insulin resistance, classical hyperglycemia with chronic insulin exposure and pharmacological elevation of O-GlcNAc levels, several proteins are identified that are regulated in a similar fashion under both conditions including HCNP, Quiescin Q6, Angiotensin, lipoprotein lipase, matrix metalloproteinase 2, and slit homologue 3. Detection of these potential prognostic/diagnostic biomarkers for metabolic syndrome, type II diabetes, and the resulting complications of both diseases further establishes the central role of the O-GlcNAc modification of intracellular proteins in the pathophysiology of these conditions.
胰岛素抵抗是代谢综合征的特征，也是2型糖尿病的先兆和标志性特征。脂肪细胞不仅是能量储存的主要场所，本质上还是内分泌细胞，能分泌多种蛋白质，即脂肪细胞因子，这些因子可调节胰岛素敏感性、炎症反应、肥胖、高血压、食物摄入（厌食性和促食欲性）以及整体能量平衡。最近的数据表明，通过O - GlcNAc增加蛋白质的细胞内糖基化可诱导胰岛素抵抗，并且在肌肉和脂肪中O - GlcNAc水平基因上调的啮齿动物模型表现出高瘦素血症。本文进一步探讨了O - GlcNAc水平、胰岛素抵抗和脂肪细胞因子分泌之间的联系。首先，利用永生化和原代啮齿动物脂肪细胞，分别通过鉴定97种和203种分泌蛋白，更全面地阐明了分化脂肪细胞的分泌蛋白质组。对细胞系中脂肪细胞因子上80多个N - 糖基化位点的定位进一步明确了该蛋白质组。重要的是，确定了细胞从胰岛素敏感状态转变为胰岛素抵抗状态时被调节的脂肪细胞因子。通过使用两种诱导胰岛素抵抗的方案，即慢性胰岛素暴露导致的经典高血糖和O - GlcNAc水平的药理学升高，鉴定出了几种在两种情况下均以相似方式调节的蛋白质，包括HCNP、Quiescin Q6、血管紧张素、脂蛋白脂肪酶、基质金属蛋白酶2和缝隙同源物3。对这些代谢综合征、2型糖尿病以及这两种疾病所致并发症的潜在预后/诊断生物标志物的检测，进一步确立了细胞内蛋白质的O - GlcNAc修饰在这些病症病理生理学中的核心作用。
