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This version published online on December 30, 2003
Endocrinology, doi:10.1210/en.2003-1509
A more recent version of this article appeared on April 1, 2004
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Submitted on November 6, 2003
Accepted on December 23, 2003

Physiological studies of transgenic mice over-expressing Growth Hormone Secretagogue Receptor-1A in GHRH neurones

Sabrina Lall1, Nina Balthasar1, Danielle Carmignac1, Charamboulos Magoulas1, Abdul Sesay1, Pamela Houston1, Kathleen Mathers1, and Iain Robinson1*

1 Division of Molecular Neuroendocrinology, National Institute for Medical Research, Mill Hill, London

* To whom correspondence should be addressed. E-mail: irobins{at}nimr.mrc.ac.uk.

The type 1A growth hormone secretagogue receptor (GHSR) has been proposed to mediate the effects of ghrelin on growth hormone (GH) release, food intake and body composition. We have overexpressed GHSR in GH-producing GC cells and in GHRH neurons in an attempt to enhance signaling via this pathway selectively, in the GH axis. Constitutive overexpression of the human GHSR (hGHSR) in rat GC cell lines resulted in increased basal phosphoinositol (PI) turnover and rendered them responsive to GHS ligands. We then generated transgenic mice overexpressing hGHSR in GHRH neurons using a 38kb rat GHRH cosmid promoter. The GHRH-GHSR transgenic mice showed increased hypothalamic GHRH expression, pituitary GH contents and post-weaning growth rates. Body weights of the transgenic mice became similar in adulthood, while adipose mass was reduced, particularly so in female GHRH-GHSR mice. Organ and muscle weights of transgenics were increased despite chronic exposure to a high fat diet. These results suggest that constitutive overexpression of GHSR in GHRH neurons upregulates basal activity in the GHRH-GH axis. However, GHRH-GHSR mice showed no evidence of an increased sensitivity to acute or chronic treatment with exogenous GHS ligands. Food intake and adipose tissue responses to chronic high fat feeding and treatment with growth hormone secretagogue (GHS) ligands were unaffected as were locomotor and anxiety behaviors though GHRH-GHSR mice remained significantly leaner than wild-type littermates. Thus constitutive overexpression of GHSR can up-regulate basal signaling activity in the GHRH/GH axis and reduce adiposity, without affecting other GHSR-mediated signals.
Key words: growth hormone releasing hormone • ghrelin receptors • transgenic mice • arcuate nucleus




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