Phosphatidylinositol 3-kinase is an upstream regulator of the phosphodiesterase 3B pathway of leptin signalling that may not involve activation of Akt in the rat hypothalamus.
Phosphatidylinositol 3-kinase is an upstream regulator of the phosphodiesterase 3B pathway of leptin signalling that may not involve activation of Akt in the rat hypothalamus.
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DOI：
10.1111/j.1365-2826.2012.02386.x
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发表时间：
2013-02
影响因子：
3.2
通讯作者：
Sahu M
中科院分区：
文献类型：
--
作者：
Sahu A;Koshinaka K;Sahu M
瘦素是肥胖基因的产物，主要通过在下丘脑水平上起作用来调节能量稳态。瘦素通过其受体参与多种途径，包括中枢神经系统和外周组织中的信号转导和转录激活因子（STAT3）、磷脂酰肌醇3-激酶（PI3K）和磷酸二酯酶3B (PDE3B)-cAMP信号转导。在下丘脑，瘦素刺激STAT3激活，诱导PI3K和PDE3B活性等。我们之前已经证明，PDE3B在下丘脑的激活对于瘦素的厌食和体重减轻作用的转导至关重要。同样，PI3K也被认为在下丘脑瘦素信号传导中起关键作用。在胰岛素信号通路中，已知PI3K在非神经元组织中是PDE3B的上游调节因子，但下丘脑中瘦素信号通路是否也是如此尚不清楚。为了研究这种可能性，我们研究了一种特异性PI3K抑制剂wortmannin对瘦素诱导的雄性大鼠下丘脑PDE3B活性的影响。脑室内注射瘦素（4 μg）可使下丘脑PDE3B活性增加2倍。然而，先前给药wortmannin完全逆转了瘦素对下丘脑PDE3B活性的刺激作用。为了证明瘦素是否通过PDE3B可能的上游调节因子刺激p-Akt水平，我们研究了icv瘦素对下丘脑p-Akt水平的影响，并将其与已知的胰岛素对p-Akt的刺激作用进行了比较。我们观察到胰岛素增加了p-Akt水平，而瘦素没有这样做，尽管它增加了大鼠下丘脑的p-STAT3水平。免疫细胞化学证实了生化发现，瘦素失效，而胰岛素增加了下丘脑各核中p-Akt阳性细胞的数量。总之，这些结果暗示PI3K而不是Akt是大鼠下丘脑中瘦素信号PDE3B途径的上游调节因子。
Leptin, the product of the obese gene, regulates energy homeostasis by acting primarily at the level of the hypothalamus. Leptin action through its receptor involves various pathways including the signal transducer and activator of transcription (STAT3), phosphatidylinositol 3-kinase (PI3K), and phosphodiesterase 3B (PDE3B)-cAMP signaling in the CNS and peripheral tissues. In the hypothalamus, leptin stimulates STAT3 activation, and induces PI3K and PDE3B activities, among others. We have previously demonstrated that PDE3B activation in the hypothalamus is critical for transducing anorectic and body weight reducing effects of leptin. Similarly, PI3K has been implicated toplay a critical role in leptin signaling in the hypothalamus. Whereas in insulin signaling pathway, PI3K is known to be an upstream regulator of PDE3B in non-neuronal tissues, it is still unknown whether this is also the case for leptin signaling in the hypothalamus. To address this possibility, the effect of wortmannin, a specific PI3K inhibitor, was examined on the leptin-induced PDE3B activity in the hypothalamus of male rats. Intracerebroventricular (icv) injection of leptin (4 μg) significantly increased PDE3B activity by 2-fold in the hypothalamus as expected. However, prior administration of wortmannin completely reversed the stimulatory effect of leptin on PDE3B activity in the hypothalamus. To demonstrate whether leptin stimulates p-Akt levels and there by a possible upstream regulator of PDE3B, we examined the effects of icv leptin on p-Akt levels in the hypothalamus and compared that with the known stimulatory effect of insulin on p-Akt. We observed that insulin increased p-Akt levels but leptin failed to do so although it increased p-STAT3 levels in the rat hypothalamus. Immunocytochemistry confirmed the biochemical finding in that leptin failed but insulin increased the number of p-Akt positive cells in various hypothalamic nuclei. Altogether these results implicate PI3K but not Akt as an upstream regulator of the PDE3B pathway of leptin signaling in the rat hypothalamus.
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影响因子：
56.9
作者：
Cota, D;Proulx, K;Seeley, RJ
通讯作者：
Seeley, RJ
DOI：
10.1038/oby.2005.7
发表时间：
2005-01-01
期刊：
OBESITY RESEARCH
影响因子：
--
作者：
Carvalheira, JBC;Torsoni, MA;Saad, MJA
通讯作者：
Saad, MJA
影响因子：
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作者：
Bhaskar, Prashanth T.;Nogueira, Veronique;Hay, Nissim
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Hay, Nissim
影响因子：
64.5
作者：
Jacinto, Estela;Facchinetti, Valeria;Su, Bing
通讯作者：
Su, Bing
影响因子：
2.5
作者：
Caron, Emilie;Sachot, Christelle;Bouret, Sebastien G.
通讯作者：
Bouret, Sebastien G.