AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue
AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue
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DOI：
10.1128/mcb.00244-16
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发表时间：
2016-07-01
影响因子：
5.3
通讯作者：
Sul, Hei Sook
中科院分区：
文献类型：
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作者：
Kim, Sun-Joong;Tang, Tianyi;Sul, Hei Sook
AMP激活的蛋白激酶(AMPK)在肝脏和肌肉等多种组织中促进脂肪酸(FA)氧化的作用已为人们所熟知。然而，AMPK在脂肪组织的脂解和FA代谢中的作用一直存在争议。为了研究AMPK在体内脂肪分解调节中的作用，我们用aP2-Cre和Adiponectin-Cre建立了脂肪组织特异性敲除AMPKα1和α2催化亚基的小鼠(AMPK-Asko小鼠)。两种AMPK-ASKO消融模型均未显示Desnutrin/ATGL水平的变化，但S406处Desnutrin/ATGL的磷酸化缺陷降低了其三酰甘油(TAG)水解酶活性，从而降低了脂肪组织的基础脂解。这些小鼠还表现出激素敏感脂肪酶(HSL)在S565位的磷酸化缺陷，蛋白激酶A位S563和S660的磷酸化水平较高，增加了其水解酶活性和异丙肾上腺素刺激的脂解作用。AMPK-Asko小鼠的两种模型都是瘦小的，脂肪细胞较小，TAG较低，细胞内游离脂肪酸水平较高，总体脂肪分解程度较高。此外，来自较高脂解水平的FA激活了过氧化物酶体增殖物激活受体Delta，从而诱导FA氧化基因，增加FA氧化和能量消耗。总体而言，我们第一次提供了AMPK在Desnutrin/ATGL和HSL的磷酸化和调节中的作用的体内证据，从而导致脂肪分解。
The role of AMP-activated protein kinase (AMPK) in promoting fatty acid (FA) oxidation in various tissues, such as liver and muscle, has been well understood. However, the role of AMPK in lipolysis and FA metabolism in adipose tissue has been controversial. To investigate the role of AMPK in the regulation of adipose lipolysis in vivo, we generated mice with adipose-tissue-specific knockout of both the alpha 1 and alpha 2 catalytic subunits of AMPK (AMPK-ASKO mice) by using aP2-Cre and adiponectin-Cre. Both models of AMPK-ASKO ablation show no changes in desnutrin/ATGL levels but have defective phosphorylation of desnutrin/ATGL at S406 to decrease its triacylglycerol (TAG) hydrolase activity, lowering basal lipolysis in adipose tissue. These mice also show defective phosphorylation of hormone-sensitive lipase (HSL) at S565, with higher phosphorylation at protein kinase A sites S563 and S660, increasing its hydrolase activity and isoproterenol-stimulated lipolysis. With higher overall adipose lipolysis, both models of AMPK-ASKO mice are lean, having smaller adipocytes with lower TAG and higher intracellular free-FA levels. Moreover, FAs from higher lipolysis activate peroxisome proliferator-activated receptor delta to induce FA oxidative genes and increase FA oxidation and energy expenditure. Overall, for the first time, we provide in vivo evidence of the role of AMPK in the phosphorylation and regulation of desnutrin/ATGL and HSL and thus adipose lipolysis.