Mice with hyperghrelinemia are hyperphagic and glucose intolerant and have reduced leptin sensitivity.
OBJECTIVE
Ghrelin is the only known peripheral hormone to increase ingestive behavior. However, its role in the physiological regulation of energy homeostasis is unclear because deletion of ghrelin or its receptor does not alter food intake or body weight in mice fed a normal chow diet. We hypothesized that overexpression of ghrelin in its physiological tissues would increase food intake and body weight.


METHODS
We used bacterial artificial chromosome transgenesis to generate a mouse model with increased ghrelin expression and production in the stomach and brain. We investigated the effect of ghrelin overexpression on food intake and body weight. We also measured energy expenditure and determined glucose tolerance, glucose stimulated insulin release, and peripheral insulin sensitivity.


RESULTS
Ghrelin transgenic (Tg) mice exhibited increased circulating bioactive ghrelin, which was associated with hyperphagia, increased energy expenditure, glucose intolerance, decreased glucose stimulated insulin secretion, and reduced leptin sensitivity.


CONCLUSIONS
This is the first report of a Tg approach suggesting that ghrelin regulates appetite under normal feeding conditions and provides evidence that ghrelin plays a fundamental role in regulating beta-cell function.
Bewick
Gavin A
GA
Department of Investigative Medicine, Hammersmith Campus, Imperial College London, London, UK.
Kent
Aysha
A
Campbell
Daniel
D
Patterson
Michael
M
Ghatei
Mohammed A
MA
Bloom
Stephen R
SR
Gardiner
James V
JV
D000818:Animals; D001066:Appetite / Q000235:genetics / Q000502:physiology; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000378:metabolism; D022202:Chromosomes, Artificial, Bacterial; D005753:Gastric Mucosa / Q000378:metabolism; D005786:Gene Expression Regulation; D054439:Ghrelin / Q000235:genetics*; D006963:Hyperphagia / Q000235:genetics* / Q000378:metabolism; D020738:Leptin / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic
D001786:Blood Glucose; D054439:Ghrelin; D020738:Leptin