The Hyperphagic Effect of Ghrelin Is Inhibited in Mice by a Diet High in Fat

TY - JOUR

T1 - The Hyperphagic Effect of Ghrelin Is Inhibited in Mice by a Diet High in Fat

AU - Gardiner, James V.

AU - Campbell, Daniel

AU - Patterson, Michael

AU - Kent, Aysha

AU - Ghatei, Mohammed A.

AU - Bloom, Stephen R.

AU - Bewick, Gavin

PY - 2010/6

Y1 - 2010/6

N2 - BACKGROUND & AIMS: Ghrelin is the only peripheral hormone known to increase food intake. It is released from the stomach and is thought to function as a signal of energy deficit and a meal initiator. We generated transgenic mice in which levels of bioactive ghrelin are increased in the stomach and circulation. These mice, as expected, are hyperphagic and glucose intolerant. We investigated whether exposure to a high-fat diet (HFD) would exacerbate this phenotype.  METHODS: We investigated the effect of HFD on energy and glucose homeostasis in ghrelin transgenic mice. We determined dietary preference; expression of hypothalamic neuropeptides that control food intake; and, using fast-performance liquid chromatography, the circulating forms of ghrelin. We measured food intake during continuous administration of ghrelin in wild-type mice fed either regular chow or an HFD.  RESULTS: Ghrelin transgenic mice were resistant to diet-induced obesity because of their reduced food intake. This was not caused by alterations to food preference, hypothalamic signaling of neuropeptides that control food intake, or the form of circulating acylated ghrelin. Long-term administration of ghrelin to wild-type mice failed to increase ingestion of an HFD but, as expected, increased intake of regular chow.  CONCLUSIONS: This is the first report that diets high in fat inhibit the hyperphagic effect of ghrelin; these findings indicate that features of the diet are important determinants of ghrelin's function. This information is important for the development of anti-obesity drugs that target ghrelin signaling.

AB - BACKGROUND & AIMS: Ghrelin is the only peripheral hormone known to increase food intake. It is released from the stomach and is thought to function as a signal of energy deficit and a meal initiator. We generated transgenic mice in which levels of bioactive ghrelin are increased in the stomach and circulation. These mice, as expected, are hyperphagic and glucose intolerant. We investigated whether exposure to a high-fat diet (HFD) would exacerbate this phenotype.  METHODS: We investigated the effect of HFD on energy and glucose homeostasis in ghrelin transgenic mice. We determined dietary preference; expression of hypothalamic neuropeptides that control food intake; and, using fast-performance liquid chromatography, the circulating forms of ghrelin. We measured food intake during continuous administration of ghrelin in wild-type mice fed either regular chow or an HFD.  RESULTS: Ghrelin transgenic mice were resistant to diet-induced obesity because of their reduced food intake. This was not caused by alterations to food preference, hypothalamic signaling of neuropeptides that control food intake, or the form of circulating acylated ghrelin. Long-term administration of ghrelin to wild-type mice failed to increase ingestion of an HFD but, as expected, increased intake of regular chow.  CONCLUSIONS: This is the first report that diets high in fat inhibit the hyperphagic effect of ghrelin; these findings indicate that features of the diet are important determinants of ghrelin's function. This information is important for the development of anti-obesity drugs that target ghrelin signaling.

KW - Transgenic

KW - Appetite Regulation

KW - Diabetes

KW - Leptin

KW - Hypothalamus

KW - AGOUTI-RELATED PROTEIN

KW - RECEPTOR GENE POLYMORPHISMS

KW - PANCREATIC-ISLETS

KW - ENERGY-BALANCE

KW - INSULIN-RELEASE

KW - NEUROPEPTIDE-Y

KW - FOOD-INTAKE

KW - OBESITY

KW - HORMONE

KW - APPETITE

U2 - 10.1053/j.gastro.2010.02.012

DO - 10.1053/j.gastro.2010.02.012

M3 - Article

SN - 0016-5085

VL - 138

SP - 2468-2476.e1

JO - Gastroenterology

JF - Gastroenterology

IS - 7

M1 - N/A

ER -