Intracellular Signals Mediating the Food Intake-Suppressive Effects of Hindbrain Glucagon-like Peptide-1 Receptor Activation
Intracellular Signals Mediating the Food Intake-Suppressive Effects of Hindbrain Glucagon-like Peptide-1 Receptor Activation
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DOI：
10.1016/j.cmet.2011.02.001
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发表时间：
2011-03-02
期刊：
影响因子：
29
通讯作者：
Bence, Kendra K.
中科院分区：
文献类型：
--
作者：
Hayes, Matthew R.;Leichner, Theresa M.;Bence, Kendra K.
孤束核（NTS）内的胰高血糖素样肽-1受体（GLP-1 R）激活可抑制摄食量和体重（BW），但介导这些效应的细胞内信号尚不清楚。这里，后脑（第四次i. c. v.）Exendin-4（Ex-4）激活GLP-1 R可增加NTS中PKA和MAPK活性，并降低AMPK磷酸化。PKA和MAPK信号传导有助于Ex-4的食物摄入和BW抑制，作为抑制剂RpcAMP和U 0126（第四次i. c. v.），分别减弱了Ex-4的作用。后脑GLP-1 R激活通过减少进食次数而非进食量来抑制进食。通过AICAR（第四次i. c. v.）刺激AMPK活性，这种作用减弱。Ex-4的PKA、MAPK和AMPK信号传导反应存在于永生化GLP-1 R表达神经元（GT 1 -7）中。总之，后脑GLP-1 R激活通过协调PKA介导的AMPK抑制和MAPK激活抑制摄食量和BW。靶向这些信号通路（介导CNS GLP-1 R活化的摄入抑制作用）的药物治疗可能被证明在治疗肥胖方面有效。
Glucagon-like peptide-1 receptor (GLP-1R) activation within the nucleus tractus solitarius (NTS) suppresses food intake and body weight (BW), but the intracellular signals mediating these effects are unknown. Here, hindbrain (fourth i.c.v.) GLP-1R activation by Exendin-4 (Ex-4) increased PKA and MAPK activity and decreased phosphorylation of AMPK in NTS. PKA and MAPK signaling contribute to food intake and BW suppression by Ex-4, as inhibitors RpcAMP and U0126 (fourth i.c.v.), respectively, attenuated Ex-4's effects. Hindbrain GLP-1R activation inhibited feeding by reducing meal number, not meal size. This effect was attenuated with stimulation of AMPK activity by AICAR (fourth i.c.v.). The PKA, MAPK, and AMPK signaling responses by Ex-4 were present in immortalized GLP-1R-expressing neurons (GT1-7). In conclusion, hindbrain GLP-1R activation suppresses food intake and BW through coordinated PKA-mediated suppression of AMPK and activation of MAPK. Pharmacotherapies targeting these signaling pathways, which mediate intake-suppressive effects of CNS GLP-1R activation, may prove efficacious in treating obesity.