Downregulation of peroxisome proliferator-activated receptor α and its coactivators in liver and skeletal muscle mediates the metabolic adaptations during lactation in mice
Downregulation of peroxisome proliferator-activated receptor α and its coactivators in liver and skeletal muscle mediates the metabolic adaptations during lactation in mice
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DOI：
10.1677/jme-09-0064
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发表时间：
2009-11-01
影响因子：
3.5
通讯作者：
Eder, Klaus
中科院分区：
文献类型：
--
作者：
Gutgesell, Anke;Ringseis, Robert;Eder, Klaus
先前的研究表明，在哺乳期间，大鼠肝脏和骨骼肌中参与脂肪酸摄取、脂肪酸氧化和产热的基因下调。然而，哺乳期间这些重要代谢适应的生化机制尚未阐明。由于所有这些基因都受过氧化物酶体增殖物激活受体α (Ppar α)的转录调控，我们假设它们的下调是由哺乳期间Ppar α的抑制介导的。为了验证这一假设，我们对哺乳期和非哺乳期Ppar α敲除小鼠以及相应的野生型小鼠进行了实验。在野生型小鼠中，哺乳导致Ppar α、Ppar共激活因子Pgc1 α和Pgc1 β以及肝脏和骨骼肌中参与脂肪酸摄取、脂肪酸氧化和产热的Ppar α靶基因显著下调（P < 0.05）。Ppar α敲除小鼠的肝脏和骨骼肌中所有这些Ppar α靶基因的表达通常较低。然而，在这些小鼠中，哺乳并没有降低肝脏和骨骼肌中脂肪酸利用和产热相关基因的表达。Ppar α靶基因在哺乳期野生型小鼠中的表达水平与哺乳期和非哺乳期Ppar α敲除小鼠相似。综上所述，目前的研究结果表明，Ppar α及其辅激活因子在脂肪酸分解代谢率高的组织中的下调是导致哺乳动物肝脏和骨骼肌中脂肪酸利用率降低和产热减少的原因，而产热是为了在乳腺中保存能量和代谢底物以产奶。
Previous studies have shown that genes involved in fatty acid uptake, fatty acid oxidation, and thermogenesis are downregulated in liver and skeletal muscle of rats during lactation. However, biochemical mechanisms underlying these important metabolic adaptations during lactation have not yet been elucidated. As all these genes are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (Ppar alpha), we hypothesized that their downregulation is mediated by a suppression of Ppar alpha during lactation. In order to investigate this hypothesis, we performed an experiment with lactating and nonlactating Ppar alpha knockout and corresponding wild-type mice. In wild-type mice, lactation led to a considerable downregulation of Ppar alpha, Ppar coactivators Pgc1 alpha and Pgc1 beta, and Ppar alpha target genes involved in fatty acid uptake, fatty acid oxidation, and thermogenesis in liver and skeletal muscle (P < 0.05). Ppar alpha knockout mice had generally a lower expression of all these Ppar alpha target genes in liver and skeletal muscle. However, in those mice, lactation did not lower the expression of genes involved in fatty acid utilization and thermogenesis in liver and skeletal muscle. Expression levels of Ppar alpha target genes in lactating wild-type mice were similar than in lactating or nonlactating Ppar alpha knockout mice. In conclusion, the present findings suggest that downregulation of Ppar alpha and its coactivators in tissues with high rates of fatty acid catabolism is responsible for the reduced utilization of fatty acids in liver and skeletal muscle and the reduced thermogenesis occurring in the lactating animal, which aim to conserve energy and metabolic substrates for milk production in the mammary gland.