A High-Fat Diet Induces Bone Loss in Mice Lacking the Alox5 Gene
A High-Fat Diet Induces Bone Loss in Mice Lacking the Alox5 Gene
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DOI：
10.1210/en.2011-0082
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发表时间：
2012-01-01
期刊：
影响因子：
4.8
通讯作者：
Rosen, Clifford J.
中科院分区：
文献类型：
--
作者：
Le, Phuong;Kawai, Masanobu;Rosen, Clifford J.
5-脂氧合酶催化花生四烯酸生成白三烯。编码5-脂氧合酶的基因Alox 5已在全基因组关联和小鼠数量性状基因座研究中被鉴定为肥胖和低骨量的候选基因。因此，我们测试了Alox 5（-/-）小鼠在受到高脂饮食（HFD）挑战时会表现出代谢和骨骼变化的假设。在常规饮食下，Alox 5（-/-）小鼠与野生型（WT）对照相比在总体重、脂肪质量百分比或骨矿物质密度方面没有差异（P < 0.05）。然而，当放置在HFD上时，Alox 5（-/-）与WT相比获得了更多的脂肪量并且损失了更大的面积骨量（P < 0.05）。微结构分析显示，与WT对照组相比，WT组皮质面积（P < 0.01）和骨小梁厚度（P < 0.01）增加，而Alox 5（-/-）组皮质参数无变化，但骨小梁数量（P < 0.05）和骨体积分数（P < 0.05）减少。通过组织形态计量学，HFD没有改变两种品系的骨形成率，但在Alox 5（-/-）小鼠中每骨周长的破骨细胞数量增加（P < 0.03）。在体外，骨髓基质细胞的破骨细胞生成增强突变体，但不是野生型小鼠喂食HFD。Rankl、Pparg和考克斯-2的基因表达在HFD的Alox 5（-/-）小鼠的股骨中比WT小鼠更高（P < 0.01），但在用塞来昔布（一种环氧合酶-2抑制剂）治疗8周后，这些增加在Alox 5（-/-）小鼠中被抑制。总之，当缺乏Alox 5基因的小鼠被喂食HFD时，存在对骨量的强基因与环境相互作用。（内分泌学153：6-16，2012）
5-Lipoxygenase catalyzes leukotriene generation from arachidonic acid. The gene that encodes 5-lipoxygenase, Alox5, has been identified in genome-wide association and mouse Quantitative Trait Locus studies as a candidate gene for obesity and low bone mass. Thus, we tested the hypothesis that Alox5(-/-) mice would exhibit metabolic and skeletal changes when challenged by a high-fat diet (HFD). On a regular diet, Alox5(-/-) mice did not differ in total body weight, percent fat mass, or bone mineral density compared with wild-type (WT) controls (P < 0.05). However, when placed on a HFD, Alox5(-/-) gained more fat mass and lost greater areal bone mass vs. WT (P < 0.05). Microarchitectural analyses revealed that on a HFD, WT showed increases in cortical area (P < 0.01) and trabecular thickness (P < 0.01), whereas Alox5(-/-) showed no change in cortical parameters but a decrease in trabecular number (P < 0.05) and bone volume fraction compared with WT controls (P < 0.05). By histomorphometry, a HFD did not change bone formation rates of either strain but produced an increase in osteoclast number per bone perimeter in Alox5(-/-) mice (P < 0.03). In vitro, osteoclastogenesis of marrow stromal cells was enhanced in mutant but not WT mice fed a HFD. Gene expression for Rankl, Pparg, and Cox-2 was greater in the femur of Alox5(-/-) than WT mice on a HFD (P < 0.01), but these increases were suppressed in the Alox5(-/-) mice after 8 wk of treatment with celecoxib, a cyclooxygenase-2 inhibitor. In sum, there is a strong gene by environmental interaction for bone mass when mice lacking the Alox5 gene are fed a HFD. (Endocrinology 153: 6-16, 2012)