Effects of high-fat diet feeding on Znt8-null mice: differences between β-cell and global knockout of Znt8
Effects of high-fat diet feeding on Znt8-null mice: differences between β-cell and global knockout of Znt8
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DOI：
10.1152/ajpendo.00448.2011
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发表时间：
2012-05-01
影响因子：
5.1
通讯作者：
Wheeler, M. B.
中科院分区：
文献类型：
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作者：
Hardy, A. B.;Wijesekara, N.;Wheeler, M. B.
哈代AB，Wijesekara N，Genkin I，普伦蒂斯KJ，Bhattacharjee A，Kong D，Chimienti F，惠勒MB.高脂饮食喂养对Znt 8基因敲除小鼠的影响：Znt 8基因β细胞敲除和整体敲除之间的差异。Am J Physiol Endocrinol Metab 302：E1084-E1096，2012.首次发表于2012年2月14日; doi：10.1152/ajpendo.00448.2011。全基因组关联研究已经将锌转运蛋白8（Znt 8）基因的多态性与2型糖尿病的高风险联系起来。Znt 8在胰腺β-细胞中高度表达，其中其参与锌转运到颗粒中的调节。然而，Znt 8也在其他组织中表达，包括β细胞，其功能尚不清楚。先前的工作表明，总体上缺乏Znt 8的小鼠更易患饮食诱导的肥胖症（Lemaire等人，Proc Natl Acad Sci USA 106：14872-14877，2009; Nicolson等人，Diabetes 58：2070-2083，2009）。因此，本研究的主要目标是检查在高脂肪高热量（HFHC）饮食喂养期间小鼠中β细胞特异性Znt 8缺乏的生理影响。对于这些研究，我们使用β-细胞特异性Znt 8敲除（Ins 2Cre：Znt 8loxP/loxP）和全身Znt 8敲除（Cre-：Znt 8（-/-））小鼠，将其置于HFHC饮食16周。与同窝对照Ins 2Cre小鼠相比，HFHC饮食的Ins 2Cre：Znt 8loxP/loxP小鼠在整个研究中具有相似的体重，但显示出受损的胰岛素生物合成和分泌，并且是葡萄糖不耐受的。相反，与同窝对照Cre-小鼠相比，Cre-：Znt 8（-/-）小鼠变得显著肥胖、高血糖、高胰岛素血症、胰岛素抵抗和葡萄糖不耐受。这些数据表明，在HFHC饮食施加的代谢应激期间，单独的β-细胞Znt 8不会显著加重体重增加和葡萄糖耐受不良。然而，Znt 8的整体损失涉及加剧饮食诱导的肥胖症和导致的胰岛素抵抗，这可能是由于除了β细胞之外的组织中Znt 8活性的损失。因此，我们的数据表明，Znt 8通过β细胞和非β细胞特异性作用促进发展2型糖尿病的风险。
Hardy AB, Wijesekara N, Genkin I, Prentice KJ, Bhattacharjee A, Kong D, Chimienti F, Wheeler MB. Effects of high-fat diet feeding on Znt8-null mice: differences between beta-cell and global knockout of Znt8. Am J Physiol Endocrinol Metab 302: E1084-E1096, 2012. First published February 14, 2012; doi:10.1152/ajpendo.00448.2011.-Genomewide association studies have linked a polymorphism in the zinc transporter 8 (Znt8) gene to higher risk of developing type 2 diabetes. Znt8 is highly expressed in pancreatic beta-cells where it is involved in the regulation of zinc transport into granules. However, Znt8 is also expressed in other tissues including beta-cells, where its function is as yet unknown. Previous work demonstrated that mice lacking Znt8 globally were more susceptible to diet-induced obesity (Lemaire et al., Proc Natl Acad Sci USA 106: 14872-14877, 2009; Nicolson et al., Diabetes 58: 2070-2083, 2009). Therefore, the main goal of this study was to examine the physiological impact of beta-cell-specific Znt8 deficiency in mice during high-fat high-calorie (HFHC) diet feeding. For these studies, we used beta-cell-specific Znt8 knockout (Ins2Cre: Znt8loxP/loxP) and whole body Znt8 knockout (Cre-:Znt8(-/-)) mice placed on a HFHC diet for 16 wk. Ins2Cre:Znt8loxP/loxP mice on HFHC diet had similar body weights throughout the study but displayed impaired insulin biosynthesis and secretion and were glucose intolerant compared with littermate control Ins2Cre mice. In contrast, Cre-:Znt8(-/-) mice became remarkably obese, hyperglycemic, hyper-insulinemic, insulin resistant, and glucose intolerant compared with littermate control Cre- mice. These data show that beta-cell Znt8 alone does not considerably aggravate weight gain and glucose intolerance during metabolic stress imposed by an HFHC diet. However, global loss of Znt8 is involved in exacerbating diet-induced obesity and resulting insulin resistance, and this may be due to the loss of Znt8 activity in a tissue other than the beta-cell. Thus, our data suggest that Znt8 contributes to the risk of developing type 2 diabetes through beta-cell- and non-beta-cell-specific effects.