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首页> 外文期刊>American Journal of Physiology >Hindbrain GLP-1 receptor-mediated suppression of food intake requires a P13K-dependent decrease in phosphorylation of membrane-bound Akt
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Hindbrain GLP-1 receptor-mediated suppression of food intake requires a P13K-dependent decrease in phosphorylation of membrane-bound Akt

机译：Hindbrain GLP-1受体介导的食物摄取抑制需要膜结合Akt磷酸化的P13K依赖性降低

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摘要

Glucagon-like peptide-1 (GLP-1) receptors (GLP-1R) expressed in the nucleus tractus soli-tarius (NTS) are physiologically required for the control of feeding. Recently, NTS GLP-1 R-mediated suppression of feeding was shown to occur via a rapid PKA-induced suppression of AMPK and activation of MAPK signaling. Unknown are the additional intracellular signaling pathways that account for the long-term hypophagic effects of GLP-1R activation. Because cAMP/PKA activity can promote PI3K/PIP3-dependent translocation of Akt to the plasma membrane, we hypothesize that hindbrain GLP-1R-mediated control of feeding involves a PI3K-Akt-dependent pathway. Importantly, the novel evidence presented here challenges the dogmatic view that PI3K phosphorylation results in an obligatory activation of Akt and instead supports a growing body of literature showing that activation of cAMP/PKA can inhibit Akt phosphorylation at the plasma membrane. Behavioral data show that inhibition of hindbrain PI3K activity by a fourth icv administration of LY-294002 (3.07 mug) attenuated the food intake- and body weight-suppressive effects of a fourth icv administration of the GLP-1R agonist exendin-4 (0.3 mug) in rats. Hindbrain administration of triciribine (10 mug), an inhibitor of PIP3-dependent translocation of Akt to the cell membrane, also attenuated the intake-suppressive effects of a fourth icv injection of exendin-4. Immunoblot analyses of ex vivo NTS tissue lysates and in vitro GLP-1 R-expressing neurons (GT1-7) support the behavioral findings and show that GLP-1 R activation decreases phosphorylation of Akt in a time-dependent fashion. Current data reveal the requirement of PI3K activation, PIP3-dependent translocation of Akt to the plasma membrane, and suppression in phosphorylation of membrane-bound Akt to mediate the food intake-suppressive effects of hindbrain GLP-1 R activation.
机译：生理上需要在乳突核（NTS）中表达胰高血糖素样肽-1（GLP-1）受体（GLP-1R）。最近，NTS GLP-1 R介导的摄食抑制作用是通过快速PKA诱导的AMPK抑制和MAPK信号激活而发生的。未知的其他细胞内信号通路解释了GLP-1R激活的长期低吞噬作用。由于cAMP / PKA活性可以促进Akt依赖PI3K / PIP3的质膜转运，我们假设后脑GLP-1R介导的进食控制涉及PI3K-Akt依赖性途径。重要的是，这里提出的新证据挑战了教条主义的观点，即PI3K磷酸化导致Akt的强制性激活，反而支持了越来越多的文献，表明cAMP / PKA的激活可以抑制质膜上的Akt磷酸化。行为数据显示，第四次icv施用LY-294002（3.07杯）对后脑PI3K活性的抑制作用减弱了第四次icv施用GLP-1R激动剂exendin-4（0.3杯）对食物摄入和体重的抑制作用。 ）的老鼠。 Hindbrain给予Triciribine（10杯）（一种Akt依赖PIP3的Akt转运至细胞膜的抑制剂）也减弱了第四次icv注射exendin-4的摄入抑制作用。对离体NTS组织裂解物和体外表达GLP-1 R的神经元（GT1-7）的免疫印迹分析支持了行为学发现，并表明GLP-1 R激活以时间依赖性方式降低了Akt的磷酸化。当前数据表明需要PI3K激活，依赖AIP的Pkt3依赖的Akt易位，以及与膜结合的Akt磷酸化的抑制，以介导后脑GLP-1 R激活的食物摄入抑制作用。

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