Physiological Roles of circulating ghrelin on food intake and energy homeostasis

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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.