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支持组成型胃饥饿素受体信号在雄性小鼠禁食诱导的食欲亢进中起作用的证据。

Evidence Supporting a Role for Constitutive Ghrelin Receptor Signaling in Fasting-Induced Hyperphagia in Male Mice.

作者信息

Fernandez Gimena, Cabral Agustina, Andreoli María F, Labarthe Alexandra, M'Kadmi Céline, Ramos Jorge G, Marie Jacky, Fehrentz Jean-Alain, Epelbaum Jacques, Tolle Virginie, Perello Mario

机构信息

Laboratory of Neurophysiology of the Multidisciplinary Institute of Cell Biology (Argentine Research Council, Scientific Research Commission of the Province of Buenos Aires and National University of La Plata), La Plata, Buenos Aires, Argentina.

School of Biochemistry and Biological Sciences, National University of Litoral and Institute of Environmental Health, Santa Fe, Argentina.

出版信息

Endocrinology. 2018 Feb 1;159(2):1021-1034. doi: 10.1210/en.2017-03101.

Abstract

Ghrelin is a potent orexigenic peptide hormone that acts through the growth hormone secretagogue receptor (GHSR), a G protein-coupled receptor highly expressed in the hypothalamus. In vitro studies have shown that GHSR displays a high constitutive activity, whose physiological relevance is uncertain. As GHSR gene expression in the hypothalamus is known to increase in fasting conditions, we tested the hypothesis that constitutive GHSR activity at the hypothalamic level drives the fasting-induced hyperphagia. We found that refed wild-type (WT) mice displayed a robust hyperphagia that continued for 5 days after refeeding and changed their food intake daily pattern. Fasted WT mice showed an increase in plasma ghrelin levels, as well as in GHSR expression levels and ghrelin binding sites in the hypothalamic arcuate nucleus. When fasting-refeeding responses were evaluated in ghrelin- or GHSR-deficient mice, only the latter displayed an ∼15% smaller hyperphagia, compared with WT mice. Finally, fasting-induced hyperphagia of WT mice was significantly smaller in mice centrally treated with the GHSR inverse agonist K-(D-1-Nal)-FwLL-NH2, compared with mice treated with vehicle, whereas it was unaffected in mice centrally treated with the GHSR antagonists D-Lys3-growth hormone-releasing peptide 6 or JMV2959. Taken together, genetic models and pharmacological results support the notion that constitutive GHSR activity modulates the magnitude of the compensatory hyperphagia triggered by fasting. Thus, the hypothalamic GHSR signaling system could affect the set point of daily food intake, independently of plasma ghrelin levels, in situations of negative energy balance.

摘要

胃饥饿素是一种强效的促食欲肽激素,它通过生长激素促分泌素受体(GHSR)发挥作用,GHSR是一种在下丘脑中高度表达的G蛋白偶联受体。体外研究表明,GHSR具有较高的组成性活性,但其生理相关性尚不确定。由于已知禁食条件下下丘脑GHSR基因表达会增加,我们测试了下丘脑水平的组成性GHSR活性驱动禁食诱导的食欲亢进这一假设。我们发现,重新喂食的野生型(WT)小鼠出现了强烈的食欲亢进,在重新喂食后持续5天,并改变了它们的每日食物摄入模式。禁食的WT小鼠血浆胃饥饿素水平、下丘脑弓状核中GHSR表达水平和胃饥饿素结合位点均增加。当在胃饥饿素或GHSR缺陷小鼠中评估禁食-再喂养反应时,与WT小鼠相比,只有后者的食欲亢进程度小约15%。最后,与接受载体处理的小鼠相比,用GHSR反向激动剂K-(D-1-Nal)-FwLL-NH2进行中枢处理的WT小鼠,其禁食诱导的食欲亢进明显较小,而用GHSR拮抗剂D-Lys3-生长激素释放肽6或JMV2959进行中枢处理的小鼠则不受影响。综合来看,遗传模型和药理学结果支持组成性GHSR活性调节禁食引发的代偿性食欲亢进程度这一观点。因此,在下丘脑能量负平衡的情况下,下丘脑GHSR信号系统可能会影响每日食物摄入的设定点,而与血浆胃饥饿素水平无关。

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