Mice lacking ghrelin receptors resist the development of diet-induced obesity
Mice lacking ghrelin receptors resist the development of diet-induced obesity
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DOI：
10.1172/jci26002
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发表时间：
2005-12-01
影响因子：
15.9
通讯作者：
Elmquist, JK
中科院分区：
文献类型：
--
作者：
Zigman, JM;Nakano, Y;Elmquist, JK
胃饥饿素是生长激素促分泌素受体（GHSR; Ghrelin receptor）的内源性配体。自发现以来，越来越多的证据表明，胃饥饿素可能在能量不足的信号传导和逆转状态中发挥作用。例如，饥饿素水平在食物匮乏后上升，而饥饿素的摄入刺激了进食，增加了体重和肥胖。然而，最近的功能丧失研究提出了关于胃饥饿素在调节这些过程中的生理意义的问题。在这里，我们展示了一项使用新型GHSR-null小鼠模型的研究结果，在该模型中，ghrelin不能急性刺激食物摄入或激活弓状核神经元。我们发现，当喂食高脂肪食物时，雌性和雄性GHSR-null小鼠吃的食物更少，储存的卡路里更少，优先利用脂肪作为能量基质，并且比对照组小鼠积累的体重和脂肪更少。在喂食标准食物的GHSR-null小鼠中，雌性（而非雄性）也观察到体重和肥胖的类似影响。GHSR缺失也影响运动活动和血糖水平。这些发现支持了生长素反应途径是协调体重控制的重要组成部分的假设。此外，我们的数据表明，饥饿素信号传导是饮食引起的肥胖的完整表型发展所必需的。
Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.