Physiological Roles of circulating ghrelin on food intake and energy homeostasis

生长激素释放肽具有强有力的促食欲作用，并且当外源性施用时诱导肥胖。由于血浆ghrelin水平在饭前升高，ghrelin被认为在调节食欲中起着至关重要的作用。相比之下，缺乏生长素释放肽或其受体GHS-R的小鼠并没有吃得更少，这就对生长素释放肽在调节能量稳态中的作用提出了质疑。由于这些小鼠从受孕开始就缺乏生长激素释放肽或GHS-R，因此不能排除在发育过程中可能出现补偿机制的可能性。在这项研究中，我们使用了一个转基因小鼠，表达人白喉毒素（DT）受体cDNA的生长激素释放肽启动子的控制下（GPDTR-Tg小鼠）。正如我们以前报道的，DT注射到这只小鼠中消融了胃中的生长素释放肽分泌细胞，但没有消融下丘脑中的生长素释放肽分泌细胞，导致循环中生长素释放肽水平降低。我们使用这个模型系统来评估循环ghrelin在调节食物摄入中的生理作用。DT处理的GPDTR-Tg小鼠的膳食模式、昼夜膳食量和累积食物摄入量未受影响，尽管即使在禁食后循环ghrelin水平也显著降低。这些小鼠也表现出对饥饿的正常反应，但增加了它们对脂肪的使用，并且在维持高脂肪饮食时表现出较慢的体重增加。总之，这些数据表明，循环ghrelin在摄食行为中并不起关键作用，而是参与维持体重。

Ghrelin has a potent orexigenic effect and induces adiposity when administered exogenously. Because plasma ghrelin levels rise before meals, ghrelin has been thought to play a crucial role in the regulation of appetite. By contrast, mice deficient in the production of ghrelin or its receptor, GHS-R, do not eat less, throwing into question the role of ghrelin in the regulation of energy homeostasis. Since these mice lack ghrelin or GHS-R from conception, one cannot rule out the possibility that compensatory mechanisms may have arisen during development. In this study, we used a transgenic mouse that expresses human diphtheria toxin (DT) receptor cDNA under control of the ghrelin promoter (GPDTR-Tg mice). As we previously reported, an injection of DT into this mouse ablates ghrelin-secreting cells in the stomach but not in the hypothalamus, resulting in a reduction in circulating ghrelin levels. We used this model system to evaluate the physiological roles of circulating ghrelin in the regulation of food intake. The meal patterns, diurnal and nocturnal meal sizes, and the cumulative food intake of DT-treated GPDTR-Tg mice were not affected, though circulating ghrelin levels were markedly decreased even after fasting. These mice also displayed normal responses to starvation, but increased their use of fat and exhibited slower weight gain when maintained on a high fat diet. Together, these data suggested that circulating ghrelin does not play a crucial role in feeding behavior, but rather is involved in maintaining body weight.