Regulation of AMP-activated protein kinase by cAMP in adipocytes: roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis.
Regulation of AMP-activated protein kinase by cAMP in adipocytes: roles for phosphodiesterases, protein kinase B, protein kinase A, Epac and lipolysis.
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DOI：
10.1016/j.cellsig.2009.01.015
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发表时间：
2009-05
影响因子：
4.8
通讯作者：
Degerman E
中科院分区：
文献类型：
--
作者：
Omar B;Zmuda-Trzebiatowska E;Manganiello V;Göransson O;Degerman E
AMP活化蛋白激酶(AMPK)是细胞能量状态的重要调节因子。在脂肪细胞中，增加细胞内环磷酸腺苷(CAMP)的刺激也被证明增加了AMPK的活性。CAMP诱导AMPK激活的确切分子机制尚不清楚。磷酸二酯酶3B(PDE3B)是脂肪细胞内cAMP信号的关键调节因子。在此，我们研究了PDE3B、PDE4、蛋白激酶B(PKB)和cAMP 1激活的交换蛋白(Epac1)以及脂解作用在调节原代大鼠脂肪细胞AMPK中的作用。我们证明了由肾上腺素能激动剂异丙肾上腺素引起的T172位AMPK的磷酸化增加可以通过与胰岛素共同孵育来减弱。PDE3B特异性抑制剂OPC3911可逆转胰岛素对AMPK活性的抑制作用，但PDE4抑制剂罗利普兰不能逆转这种作用。腺病毒介导的PDE3B和固有活性PKB的过表达均显著降低了异丙肾上腺素诱导的AMPK在T172的磷酸化。脂肪细胞与异丙肾上腺素和PKA抑制剂H89共同孵育后，脂肪细胞的脂解作用被完全消除，AMPK的磷酸化/活化水平降低。用Epac1激动剂8-PCPT-2‘O-Me-cAMP刺激脂肪细胞后，AMPK在T172的磷酸化增加。普通脂肪酶抑制剂奥利司他降低了异丙肾上腺素诱导的AMPK在T172的磷酸化。这一下降与脂肪细胞的脂肪分解减少相对应。综上所述，这些数据表明，PDE3B和PDE4调节cAMP池，从而影响AMPK的激活/磷酸化状态，环AMP对AMPK的影响涉及Epac1、PKA和脂解。
AMP-activated protein kinase (AMPK) is an important regulator of cellular energy status. In adipocytes, stimuli that increase intracellular cyclic AMP (cAMP) have also been shown to increase the activity of AMPK. The precise molecular mechanisms responsible for cAMP-induced AMPK activation are not clear. Phosphodiesterase 3B (PDE3B) is a critical regulator of cAMP signalling in adipocytes. Here we investigated the roles of PDE3B, PDE4, protein kinase B (PKB) and the exchange protein activated by cAMP 1 (Epac1), as well as lipolysis, in the regulation of AMPK in primary rat adipocytes. We demonstrate that the increase in phosphorylation of AMPK at T172 induced by the adrenergic agonist isoproterenol can be diminished by co-incubation with insulin. The diminishing effect of insulin on AMPK activation was reversed upon treatment with the PDE3B specific inhibitor OPC3911 but not with the PDE4 inhibitor Rolipram. Adenovirus-mediated overexpression of PDE3B and constitutively active PKB both resulted in greatly reduced isoproterenol-induced phosphorylation of AMPK at T172. Co-incubation of adipocytes with isoproterenol and the PKA inhibitor H89 resulted in a total ablation of lipolysis and a reduction in AMPK phosphorylation/activation. Stimulation of adipocytes with the Epac1 agonist 8-pCPT-2’O-Me-cAMP led to increased phosphorylation of AMPK at T172. The general lipase inhibitor Orlistat decreased isoproterenol-induced phosphorylation of AMPK at T172. This decrease corresponded to a reduction of lipolysis from adipocytes. Taken together, these data suggest that PDE3B and PDE4 regulate cAMP pools that affect the activation/phosphorylation state of AMPK and that the effects of cyclic AMP on AMPK involve Epac1, PKA and lipolysis.
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影响因子：
--
作者：
Hawley SA;Boudeau J;Reid JL;Mustard KJ;Udd L;Mäkelä TP;Alessi DR;Hardie DG
通讯作者：
Hardie DG
影响因子：
15.9
作者：
Choi, Young Hun;Park, Sunhee;Manganiello, Vincent C.
通讯作者：
Manganiello, Vincent C.
影响因子：
3.5
作者：
CARLING, D;ZAMMIT, VA;HARDIE, DG
通讯作者：
HARDIE, DG
影响因子：
5.3
作者：
Petersen, Rasmus Koefoed;Madsen, Lise;Kristiansen, Karsten
通讯作者：
Kristiansen, Karsten
DOI：
10.1111/j.1432-1033.1994.tb19001.x
发表时间：
1994-07-15
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
DAVIES, SP;HAWLEY, SA;HARDIE, DG
通讯作者：
HARDIE, DG