Directed antisense expression moderates feeding and weight gain

Rats receiving the hormone ghrelin as a direct injection into the hypothalamus respond with vigorous feeding and reduced fat metabolism. Ghrelin stimulates the growth hormone (GH) secretogogue receptor (GHS-R) on hypothalamic and pituitary neurons, promoting GH release, and leaving the treated animals in a state of positive energy balance, where they become obese when supplied unlimited food. To test the possibility that hypothalamic ghrelin-responsive neurons mediate the behavioral and metabolic effects of this hormone, Shuto and colleagues generated transgenic rats in which an antisense to the GHS-R mRNA is produced specifically in these cells. The resulting transgenic animals are smaller than controls, even at birth, and females show blunted expression of GH. Surprisingly, although males are apparently normal for GH synthesis and show the normal daily fluctuations in GH release, animals of both sexes are significantly reduced in food intake and body adiposity. The same authors have previously shown that a synthetic GHS-R agonist, also stimulates food consumption and increases adiposity in wild type animals, but they find that this drug has no such effects in their transgenic lines. While the relationship between GH production and energy balance remains uncertain, this work clearly supports a crucial role for ghrelin or other GHS receptor ligands in the central control of energy balance.

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