How can loss of ghrelin receptor function lead to obesity?
It can rather easily be rationalized that loss-of-function mutations in the ghrelin receptor would lead to the development of short stature through reduced activity at the hypothalamic-pituitary-GH axis — although, in the present case, the precise mechanism of this is not entirely clear (6). In contrast, with respect to the control of appetite and energy expenditure, it would be expected that loss-of-function mutations in the ghrelin receptor would lead to a lean and not an obese phenotype, because ghrelin is a potent hunger signal. In accordance with this inference, recent studies in mice have shown that knockout of either the ghrelin hormone or the ghrelin receptor protects against obesity induced by a high-fat diet (11, 17, 18). Frequently, knockout of molecular elements in complex, redundant physiological systems will lead to compensatory changes in related pathways as a compensation for the lost function. Normally, such compensation will result in a diminished or total lack of the
