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This version published online on October 9, 2003
Endocrinology, doi:10.1210/en.2003-0899
A more recent version of this article appeared on January 1, 2004
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Submitted on July 18, 2003
Accepted on October 2, 2003

Ghrelin and des-octanoyl ghrelin promote adipogenesis directlyin vivo by a mechanism independent of GHS-R1a

Nichola M Thompson1, Dave AS Gill1, Rhos Davies1, Nigel Loveridge1, Pamela A Houston1, Iain CAF Robinson1, and Timothy Wells1*

1 School of Biosciences, Cardiff University, PO Box 911, Museum Avenue, Cardiff CF10 3US, U.K.; MRC Bone Research Group, University of Cambridge, Department of Medicine, Addenbrookes Hospital, Cambridge, CB2 2QQ, U.K.; Department of Neuroendocrinology, Division of Neuroscience & Psychological Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, U.K.; Division of Molecular Neuroendocrinology, National Institute for Medical Research, Mill Hill, London NW7 1AA, U.K.

* To whom correspondence should be addressed. E-mail: wellst{at}cardiff.ac.uk.

Ghrelin promotes fat accumulation, despite potent stimulation of the lipolytic hormone, growth hormone (GH). The function of the major circulating isoform of ghrelin, des-octanoyl ghrelin, is unclear, since it does not activate the GH secretagogue receptor (GHS-R1a), and lacks the endocrine activities of ghrelin. We have now addressed these issues by infusing ghrelin, des-octanoyl ghrelin or synthetic GHS-R1a agonists into three rat models with moderate, severe or total GH deficiency. We show that, in the context of significant GH secretion, the adipogenic effect of systemic ghrelin infusion is pattern-dependent. However, this adipogenic action is not mediated by the pituitary hormones. Using a novel unilateral local infusion strategy, we demonstrate that ghrelin promotes bone marrow adipogenesis in vivo by a direct peripheral action. Surprisingly, this effect was also observed with des-octanoyl ghrelin, while a potent synthetic GHS-R1a agonist was ineffective. Thus, these adipogenic effects are mediated by a receptor other than GHS-R1a. This is the first in vivo demonstration of a direct adipogenic effect of des-octanoyl ghrelin, a major circulating form of ghrelin that lacks GH-releasing activity. We suggest that the ratio of ghrelin and des-octanoyl ghrelin production could help regulate the balance between adipogenesis and lipolysis in response to nutritional status.
Key words: ghrelin • Adiposity • bone marrow adipocytes • growth hormone • starvation




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