Department of Adipose Tissue Biology, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Int J Obes (Lond). 2020 Jan;44(1):235-244. doi: 10.1038/s41366-018-0281-0. Epub 2018 Dec 11.
BACKGROUND/OBJECTIVE: Adaptation to the extrauterine environment depends on a switch from glycolysis to catabolism of fatty acids (FA) provided as milk lipids. We sought to learn whether the postnatal induction of muscle FA oxidation in mice could reflect propensity to obesity and to characterize the mechanisms controlling this induction.
Experiments were conducted using obesity-resistant A/J and obesity-prone C57BL/6J (B6) mice maintained at 30 °C, from 5 to 28 days after birth. At day 10, both A/J and B6 mice with genetic ablation (KO) of α2 subunit of AMP-activated protein kinase (AMPK) were also used. In skeletal muscle, expression of selected genes was determined using quantitative real-time PCR, and AMPK subunits content was evaluated using Western blotting. Activities of both AMPK and pyruvate dehydrogenase (PDH), as well as acylcarnitine levels in the muscle were measured.
Acylcarnitine levels and gene expression indicated transient increase in FA oxidation during the first 2 weeks after birth, with a stronger increase in A/J mice. These data correlated with (i) the surge in plasma leptin levels, which peaked at day 10 and was higher in A/J mice, and (ii) relatively low activity of PDH linked with up-regulation of PDH kinase 4 gene (Pdk4) expression in the 10-day-old A/J mice. In contrast with the Pdk4 expression, transient up-regulation of uncoupling protein 3 gene was observed in B6 but not A/J mice. AMPK activity changed during the development, without major differences between A/J and B6 mice. Expression of neither Pdk4 nor other muscle genes was affected by AMPK-KO.
Our results indicate a relatively strong postnatal induction of FA oxidation in skeletal muscle of the obesity-resistant A/J mice. This induction is transient and probably results from suppression of PDH activity, linked with a postnatal surge in plasma leptin levels, independent of AMPK.
背景/目的：适应子宫外环境取决于从糖酵解到提供的乳脂中脂肪酸（FA）分解代谢的转变。我们试图了解小鼠肌肉 FA 氧化的产后诱导是否可以反映肥胖倾向，并描述控制这种诱导的机制。
使用肥胖抵抗的 A/J 和肥胖易感的 C57BL/6J（B6）小鼠进行实验，这些小鼠在出生后 5 至 28 天内保持在 30°C。在第 10 天，还使用了 AMP 激活的蛋白激酶（AMPK）α2 亚基基因缺失（KO）的 A/J 和 B6 小鼠。在骨骼肌中，使用定量实时 PCR 确定选定基因的表达，并用 Western 印迹法评估 AMPK 亚基含量。还测量了肌肉中的 AMPK 和丙酮酸脱氢酶（PDH）的活性以及酰基辅酶 A 水平。
在出生后的前 2 周内，FA 氧化的酰基辅酶 A 水平和基因表达表明发生了短暂增加，A/J 小鼠的增加更为明显。这些数据与以下因素相关：（i）血浆瘦素水平的激增，该水平在第 10 天达到峰值，并且在 A/J 小鼠中更高；（ii）与 10 日龄 A/J 小鼠中 PDH 激酶 4 基因（Pdk4）表达上调相关的 PDH 活性相对较低。与 Pdk4 表达相反，在 B6 但不在 A/J 小鼠中观察到解偶联蛋白 3 基因的短暂上调。AMPK 活性在发育过程中发生变化，A/J 和 B6 小鼠之间没有明显差异。Pdk4 或其他肌肉基因的表达不受 AMPK-KO 的影响。
我们的结果表明肥胖抵抗的 A/J 小鼠骨骼肌中 FA 氧化的产后诱导相对较强。这种诱导是短暂的，可能是由于 PDH 活性受到抑制所致，与血浆瘦素水平的产后激增有关，与 AMPK 无关。
