Department of Medicine, Endocrine Division, University of California, San Diego, La Jolla, California, USA.
Diabetes. 2009 Nov;58(11):2476-85. doi: 10.2337/db08-1781. Epub 2009 Aug 3.
Tankyrase (TNKS) is a Golgi-associated poly-ADP-ribose polymerase that is implicated in the regulation of GLUT4 trafficking in 3T3-L1 adipocytes. Its chromosomal locus 8p23.1 is linked to monogenic forms of diabetes in certain kindred. We hypothesize that TNKS is involved in energy homeostasis in mammals.
Gene-trap techniques were used to ablate TNKS expression in mice. Homozygous and wild-type littermates maintained on standard chow were compared.
Wild-type mice express the TNKS protein abundantly in adipose tissue, the brain, and the endocrine pancreas but scarcely in the exocrine pancreas and skeletal muscle. TNKS-deficient mice consume increased amounts of food (by 34%) but have decreased plasma leptin levels and a >50% reduction in epididymal and perirenal fat pad size. Their energy expenditure is increased as assessed by metabolic cage studies and core body temperatures. These changes are not attributable to an increase in physical activity or uncoupled respiration (based on oxygraph analyses of mitochondria isolated from brown fat and skeletal muscle). The heightened thermogenesis of TNKS-deficient mice is apparently fueled by increases in both fatty acid oxidation (based on muscle and liver gene expression analyses and plasma ketone levels) and insulin-stimulated glucose utilization (determined by hyperinsulinemic-euglycemic clamps). Although TNKS deficiency does not compromise insulin-stimulated GLUT4 translocation in primary adipocytes, it leads to the post-transcriptional upregulation of GLUT4 and adiponectin in adipocytes and increases plasma adiponectin levels.
TNKS-deficient mice exhibit increases in energy expenditure, fatty acid oxidation, and insulin-stimulated glucose utilization. Despite excessive food intake, their adiposity is substantially decreased.
Tankyrase（TNKS）是一种与高尔基体相关的多聚 ADP-核糖聚合酶，它参与调节 3T3-L1 脂肪细胞中 GLUT4 的运输。其染色体位点 8p23.1 与某些家族中的单基因糖尿病有关。我们假设 TNKS 参与哺乳动物的能量稳态。
使用基因捕获技术在小鼠中敲除 TNKS 表达。比较同窝出生的杂合子和野生型对照。
野生型小鼠在脂肪组织、大脑和内分泌胰腺中大量表达 TNKS 蛋白，但在外分泌胰腺和骨骼肌中几乎不表达。TNKS 缺陷型小鼠摄入的食物量增加（增加 34%），但血浆瘦素水平降低，附睾和肾周脂肪垫大小减少超过 50%。通过代谢笼研究和核心体温评估，它们的能量消耗增加。这些变化不是由于体力活动增加或解偶联呼吸（基于棕色脂肪和骨骼肌分离的线粒体的耗氧分析）引起的。TNKS 缺陷型小鼠的产热增加显然是由脂肪酸氧化增加（基于肌肉和肝脏基因表达分析和血浆酮体水平）和胰岛素刺激的葡萄糖利用增加（通过高胰岛素正常血糖钳夹确定）引起的。尽管 TNKS 缺乏不会损害原代脂肪细胞中胰岛素刺激的 GLUT4 易位，但它会导致脂肪细胞中 GLUT4 和脂联素的转录后上调，并增加血浆脂联素水平。
TNKS 缺陷型小鼠表现出能量消耗、脂肪酸氧化和胰岛素刺激的葡萄糖利用增加。尽管摄入过多的食物，但它们的肥胖程度明显降低。
