FIAT Deletion Increases Bone Mass But Does Not Prevent High-Fat-Diet-Induced Metabolic Complications.
FIAT Deletion Increases Bone Mass But Does Not Prevent High-Fat-Diet-Induced Metabolic Complications.
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DOI：
10.1210/en.2016-1867
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发表时间：
2017-02-01
期刊：
影响因子：
4.8
通讯作者：
St-Arnaud R
中科院分区：
文献类型：
--
作者：
Hekmatnejad B;Yu VW;Addison W;Mandic V;Pellicelli M;Arabian A;St-Arnaud R
抑制转录激活因子4（ATF 4）介导的转录（FIAT）的因子与ATF 4相互作用以抑制其转录活性。我们对8周龄和16周龄的Fiat缺陷雄性小鼠（Fiat −/Y）进行了表型分析。股骨远端的显微计算机断层扫描分析表明，Fiat −/Y小鼠的骨小梁体积和厚度分别增加了46%和13%。股骨中段的皮质骨测量显示，老年Fiat-/Y小鼠的皮质厚度大幅增加。骨增量与增加的矿物质沉积率和增加的成骨细胞功能有关。与野生型（WT）小鼠相比，Fiat −/Y小鼠的股骨刚度和强度显著增加。我们还研究了FIAT是否有助于代谢功能。当喂食标准小鼠食物时，Fiat −/Y动物具有葡萄糖耐受性。然而，当喂食高脂饮食（HFD）8周时，Fiat-/Y小鼠的体重比对照小鼠增加更多，特别是白色脂肪组织脂肪量增加。脂肪量的增加是由于能量消耗减少，这与突变小鼠脂肪组织中脂肪酸氧化和脂解减少有关。参与脂肪生成的Scd1基因的表达在Fiat −/Y小鼠的皮下脂肪组织中上调。此外，与WT小鼠相比，HFD喂养的Fiat −/Y小鼠表现出循环瘦素和胰岛素水平升高，表明内分泌异常与能量平衡紊乱有关。我们的结论是，Fiat −/Y小鼠表现出合成代谢骨表型，但在食用HFD时表现出对代谢相关疾病的易感性增加。
Factor inhibiting activating transcription factor 4 (ATF4)-mediated transcription (FIAT) interacts with ATF4 to repress its transcriptional activity. We performed a phenotypic analysis of Fiat-deficient male mice (Fiat−/Y) at 8 and 16 weeks of age. Microcomputed tomography analysis of the distal femur demonstrated 46% and 13% age-dependent increases in trabecular bone volume and thickness, respectively, in Fiat−/Y mice. Cortical bone measurements at the femoral midshaft revealed a substantial increase in cortical thickness in older Fiat−/Y mice. Bone gain was related to increased mineral apposition rate and increased osteoblast function. Femoral stiffness and strength were substantially increased in Fiat−/Y compared with wild-type (WT) mice. We also investigated whether FIAT contributes to metabolic function. When fed standard mouse chow, Fiat−/Y animals were glucose-tolerant. However, when fed a high-fat diet (HFD) for 8 weeks, Fiat−/Y mice gained more weight than control mice, with a specific increase in white adipose tissue fat mass. The increase in fat mass was due to reduced energy expenditure, which correlated with reduced fatty acid oxidation and lipolysis in the adipose tissue of mutant mice. The expression of the Scd1 gene, involved in lipogenesis, was upregulated in the subcutaneous adipose tissue of Fiat−/Y mice. Moreover, HFD-fed Fiat−/Y mice exhibited increased circulating leptin and insulin levels relative to WT mice, demonstrating that endocrine abnormalities are associated with the disturbance in energy balance. We conclude that Fiat−/Y mice exhibited an anabolic bone phenotype but displayed increased susceptibility to developing metabolic-related disorders when consuming an HFD.