The Yin and Yang of Appetite Hormones

J.V. Zhang, P-G Ren, O. Avsian-Kretchmer, C-W Luo, R. Rauch, C. Klein, A.J. Hsueh. Science, 310, pg. 996-999 (November 11, 2005).

A bioinformatics analysis of genes coding for prohormones identified several with unexplored regions that are conserved across species. One, for a 117-amino acid prepropeptide that yields the appetite stimulating hormone ghrelin, also encodes a 23-amino acid peptide that reduces food intake. The authors named the new protein obestatin. Isolation of the peptide from rat stomach extract found that obestatin is amidated at the C terminus, much as ghrelin is acylated.

Binding studies found that amidation is needed for obestatin to bind to the G protein-coupled receptor GPR39, a member of the ghrelin receptor subfamily, and to stimulate c-AMP production. In vivo experiments found that amidated human obestatin reduced food intake in a time- and dose-dependent manner in mice and significantly reduced the body weight of rats when given alone. When combined with ghrelin, which increases body mass, obestatin inhibited weight gain. Similarly, an in vitro analysis of ghrelin and obestatin on jejunum muscle contraction confirmed ghrelin's stimulatory effect and found that obestatin reduced contractile activity when used alone and antagonized ghrelin's affect when the two are present together.

These findings illuminate further the pathways regulating energy balance. They also explain why mice lacking the ghrelin gene have normal food intake and body weight - both the appetite stimulant ghrelin and the anorexic hormone obestatin are lost. Moreover, the discovery of obestatin may eventually lead to a new therapeutic approach to weight control. Johnson & Johnson, which sponsored this research, has licensed rights to the hormone.

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