Obesity: An appetizing target

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Obestatin and its orphan G protein-coupled receptor GPR39 oppose the action of the appetite-inducing hormone ghrelin.

The discovery of hormones regulating appetite — specifically the appetite-suppressant leptin and the appetite-stimulant ghrelin — generated optimism that drugs for the treatment of obesity would soon follow. But extensive research on the roles of these peptide hormones in the pathways that control body weight has not led to an effective drug therapy. The identification of a new appetite-suppressing hormone, obestatin, and its receptor described by Zhang and colleagues provides new insights into how appetite-regulation hormones elicit their effects that could be key in the development of a treatment for obesity.

Ghrelin, which is produced in the gut by the posttranslational modification of a prohormone, was thought to be the last of the key genes involved in the regulation of body weight. However, while searching databases of known peptide hormones for potential hormone derivatives, Zhang and co-workers concluded that processing of proghrelin produces a second peptide hormone. They subsequently isolated this ghrelin-associated hormone from rat stomach and named it obestatin. To investigate the effect of obestatin on food intake, a synthetic obestatin peptide was injected into rat brain and gut. After treatment with obestatin, rats consumed $sim$ 50% less food. Obestatin also suppressed weight gain and slowed the passage of digested food from the stomach.

Zhang and colleagues then went on to identify the cognate receptor of obestatin. Ghrelin binds to growth hormone secretagogue receptor (GHSR), a G-protein-coupled receptor (GPCR), and the authors therefore proposed that the target of obestatin would be an orphan GPCR. Indeed, using I¹²⁵-radiolabelled obestatin the authors identified the target of obestatin to be GPR39.

The isolation of obestatin also sheds light on the mechanisms that underlie hormonal regulation of body weight. Deletion of the gene encoding ghrelin would be expected to suppress appetite; however, knockout of this gene has almost no effect on growth and appetite. It is now clear that knockout of the gene encoding ghrelin also deletes obestatin, which suggests an intricate balance in the activities of these two hormones in weight regulation.

The prevalence of obesity is on the increase worldwide. Understanding how obestatin and ghrelin interact to regulate weight could lead not only to an effective treatment for obesity, but also for other eating disorders such as anorexia nervosa.

Samantha Barton

References

Zhang, J. V. et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 310, 996–999 (2005) | Article | PubMed |
Crowley, V. E. F., Yeo, G. S. H. & O'Rahilly, S. Obesity therapy: altering the energy intake-and-expenditure balance sheet. Nature Rev. Drug Discov. 1, 276–286 (2002) | Article | PubMed |