title: Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference.
abstract: 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.
authors.affiliation: Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Wortley
authors.forename: Keith D
authors.initials: KD
authors.lastname: Anderson
authors.forename: Karen
authors.initials: K
authors.lastname: Garcia
authors.forename: Jane D
authors.initials: JD
authors.lastname: Murray
authors.forename: Lubomira
authors.initials: L
authors.lastname: Malinova
authors.forename: Rong
authors.initials: R
authors.lastname: Liu
authors.forename: Marshena
authors.initials: M
authors.lastname: Moncrieffe
authors.forename: Karen
authors.initials: K
authors.lastname: Thabet
authors.forename: Hilary J
authors.initials: HJ
authors.lastname: Cox
authors.forename: George D
authors.initials: GD
authors.lastname: Yancopoulos
authors.forename: Stanley J
authors.initials: SJ
authors.lastname: Wiegand
authors.forename: Mark W
authors.initials: MW
authors.lastname: Sleeman
mesh_terms: D000818:Animals; D001066:Appetite / Q000502:physiology; D001835:Body Weight; D050260:Carbohydrate Metabolism; D004435:Eating; D004734:Energy Metabolism; D005215:Fasting; D005223:Fats / Q000378:metabolism; D005247:Feeding Behavior / Q000502:physiology*; D017353:Gene Deletion; D054439:Ghrelin; D051379:Mice; D036361:Peptide Hormones / Q000172:deficiency* / Q000235:genetics
chemical_list: D005223:Fats; D054439:Ghrelin; D036361:Peptide Hormones