Below is an abstract of a paper just published in the Proceedings of the National Academy of Sciences (PNAS) discussing a new mouse model in which they have completely deleted the ghrelin gene. (you'll recall that individuals with PWS frequently have high levels of this hormone in their blood, and that ghrelin stimulates food intake).
This is the second mouse model that has been produced with ghrelin system is disrupted. The ghrelin deficient mice actually look very normal - they eat, grow, and behave like normal mice (consistent with the findings of a mouse deficient in the ghrelin receptor). This suggests that the food-seeking pathway is redundant (ie, there are other peptides that will stimulate food intake in the absence of ghrelin). This really seems to be the case with control of food intake -- these systems are highly redundant (the neuropeptides NPY and AgRP also stimulate appetite, and if you knock them out the mice appear pretty normal also).
One new interesting finding is that the ghrelin deficient mice burn fat much more efficiently than mice that have ghrelin - so on a high fat diet, they are more lean than normal mice. So, the presence of ghrelin may help fat to stay around (from an evolutionary standpoint, it was important to build and keep fat reserves so that they would be there during the hard times). Although it's not been tested yet, it is possible that the high ghrelin that is common in PWS contributes to the fact that our kids have a higher body fat than normal.
Abstract Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference . Wortley KE, Anderson KD, Garcia K, Murray JD, Malinova L, Liu R, Moncrieffe M, Thabet K, Cox HJ, Yancopoulos GD, Wiegand SJ, Sleeman MW. Proc Natl Acad Sci U S A. 101(21):8227-32, 2004 Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl-/-) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl-/- mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl-/- mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.
Theresa Strong
Theresa V. Strong, Ph.D., received a B.S. from Rutgers University and a Ph.D. in Medical Genetics from the University of Alabama at Birmingham (UAB). After postdoctoral studies with Dr. Francis Collins at the University of Michigan, she joined the UAB faculty, leading a research lab focused on gene therapy for cancer and directing UAB’s Vector Production Facility. Theresa is one of the founding members of FPWR and has directed FPWR’s grant program since its inception. In 2016, she transitioned to a full-time position as Director of Research Programs at FPWR. She remains an Adjunct Professor in the Department of Genetics at UAB. She and her husband Jim have four children, including a son with PWS.
