PRL2 links magnesium flux and sex-dependent circadian metabolic rhythms.
PRL2 links magnesium flux and sex-dependent circadian metabolic rhythms.
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PRL2 将镁通量和性别依赖性昼夜节律代谢节律联系起来。
作者：
N. Uetani;S. Hardy;Simon;Silke Kiessling;Adam Pietrobon;N. Wong;Valérie Chénard;N. Cermakian;J. St;M. Tremblay
镁（Mg 2+）在细胞生物学中起着多效性作用，是所有生物体所必需的。虽然先前的研究表明细胞内Mg ~（2+）水平受再生肝磷酸酶2（PRL 2）和细胞周期蛋白M的Mg ~（2+）转运蛋白（CNNMs）复合物的调节，但PRL 2在整个动物中的生理功能尚不清楚。有趣的是，镁离子最近被确定为昼夜节律依赖性代谢的调节剂;然而，没有发现任何机制来解释时钟依赖性镁离子振荡。在此，我们报告PRL 2作为性别和代谢之间的缺失环节，以及时钟基因和每日Mg 2+通量的周期。我们的研究结果揭示，PRL-2无效的动物显示性别依赖性的身体组成的变化，和表达的PRL和CNNM的性别和昼夜节律的时间依赖性调节棕色脂肪组织。同样，PRL 2-KO小鼠在产热和昼夜能量代谢方面表现出性别依赖性改变。这些生理变化与PRL 2-KO细胞中低细胞内Mg 2+的解偶联呼吸速率增加相关。此外，PRL 2缺乏导致ATP柠檬酸裂解酶轴的抑制，这是参与脂肪酸合成。总的来说，我们的研究结果支持性别和昼夜节律依赖的PRL 2表达改变细胞内Mg 2+水平，从而控制能量代谢状态。
Magnesium (Mg2+) plays pleiotropic roles in cellular biology, and it is essentially required for all living organisms. Although previous studies demonstrated intracellular Mg2+ levels were regulated by the complex of phosphatase of regenerating liver 2 (PRL2) and Mg2+ transporter of cyclin M (CNNMs), physiological functions of PRL2 in whole animals remain unclear. Interestingly, Mg2+ was recently identified as a regulator of circadian rhythm-dependent metabolism; however, no mechanism was found to explain the clock-dependent Mg2+ oscillation. Herein, we report PRL2 as a missing link between sex and metabolism, as well as clock genes and daily cycles of Mg2+ fluxes. Our results unveil that PRL2-null animals displayed sex-dependent alterations in body composition, and expression of PRLs and CNNMs were sex- and circadian time-dependently regulated in brown adipose tissues. Consistently, PRL2-KO mice showed sex-dependent alterations in thermogenesis and in circadian energy metabolism. These physiological changes were associated with an increased rate of uncoupled respiration with lower intracellular Mg2+ in PRL2-KO cells. Moreover, PRL2 deficiency causes inhibition of the ATP citrate lyase axis, which is involved in fatty acid synthesis. Overall, our findings support that sex- and circadian-dependent PRL2 expression alter intracellular Mg2+ levels, which accordingly controls energy metabolism status.
DOI：
10.1056/nejmoa0810780
发表时间：
2009-04-09
期刊：
The New England journal of medicine
影响因子：
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作者：
Cypess AM;Lehman S;Williams G;Tal I;Rodman D;Goldfine AB;Kuo FC;Palmer EL;Tseng YH;Doria A;Kolodny GM;Kahn CR
通讯作者：
Kahn CR