Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure
Simultaneous deletion of ghrelin and its receptor increases motor activity and energy expenditure
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DOI：
10.1152/ajpgi.00321.2007
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发表时间：
2008-03-01
影响因子：
4.5
通讯作者：
Tschoep, Matthias H.
中科院分区：
文献类型：
--
作者：
Pfluger, Paul T.;Kirchner, Henriette;Tschoep, Matthias H.
化学合成的生长素释放肽（Ghr）肽的管理已被证明会增加大多数物种的食物摄入量和身体肥胖。然而，内源性Ghr在能量代谢的分子控制中的生物学作用远未被理解。缺乏Ghr或其受体（生长激素促分泌素受体，GHS-R1 a）的小鼠似乎表现出对高脂饮食诱导的肥胖的增强保护，但在标准饮食中没有表现出实质性的代谢表型。在这里，我们提出了第一个缺乏GHR和GHR受体的小鼠突变体。我们证明，同时遗传破坏的两个基因的GHR系统导致增强的能量代谢表型。Ghr/Ghr受体双敲除（dKO）小鼠在不暴露于高热量环境的情况下在标准饮食下表现出体重减轻、能量消耗增加和运动活动增加。缺乏Ghr或Ghr受体基因的相同遗传背景的小鼠在标准食物中没有表现出这种表型，从而证实了早期的报道。在dKO、Ghr缺陷、Ghr受体缺陷和野生型（WT）对照小鼠之间未观察到摄食量、膳食模式或瘦体重差异。只有dKO显示体长略有下降。总之，与WT小鼠相比，Ghr及其受体的同时缺失增强了单基因缺陷小鼠的代谢表型，这可能表明存在额外的（迄今未知的）内源性Ghr系统的分子组分。
Administration of chemically synthesized ghrelin (Ghr) peptide has been shown to increase food intake and body adiposity in most species. However, the biological role of endogenous Ghr in the molecular control of energy metabolism is far less understood. Mice deficient for either Ghr or its receptor ( the growth hormone secretagogue receptor, GHS-R1a) seem to exhibit enhanced protection against high-fat diet-induced obesity but do not show a substantial metabolic phenotype on a standard diet. Here we present the first mouse mutant lacking both Ghr and the Ghr receptor. We demonstrate that simultaneous genetic disruption of both genes of the Ghr system leads to an enhanced energy metabolism phenotype. Ghr/Ghr receptor double knockout (dKO) mice exhibit decreased body weight, increased energy expenditure, and increased motor activity on a standard diet without exposure to a high caloric environment. Mice on the same genetic background lacking either the Ghr or the Ghr receptor gene did not exhibit such a phenotype on standard chow, thereby confirming earlier reports. No differences in food intake, meal pattern, or lean mass were observed between dKO, Ghr-deficient, Ghr receptor-deficient, and wild-type (WT) control mice. Only dKO showed a slight decrease in body length. In summary, simultaneous deletion of Ghr and its receptor enhances the metabolic phenotype of single gene-deficient mice compared with WT mice, possibly suggesting the existence of additional, as of yet unknown, molecular components of the endogenous Ghr system.