Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference.
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.
Wortley
Katherine E
KE
Regeneron Pharmaceuticals, Inc., 777 Old Saw Mill River Road, Tarrytown, NY 10591, USA.
Anderson
Keith D
KD
Garcia
Karen
K
Murray
Jane D
JD
Malinova
Lubomira
L
Liu
Rong
R
Moncrieffe
Marshena
M
Thabet
Karen
K
Cox
Hilary J
HJ
Yancopoulos
George D
GD
Wiegand
Stanley J
SJ
Sleeman
Mark W
MW
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
D005223:Fats; D054439:Ghrelin; D036361:Peptide Hormones