Analysis of feeding and lipid metabolism regulation by bombesin-like peptide receptors.

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To clarify the mechanism underlying modulation of feeding and metabolism by BRS-3, we investigated the relationship between BRS-3 and other feeding-regulating peptides and their receptors. In BRS-3-deficient mice, we found hyperphagia, subsequent hyperleptinemia and brain leptin resistance. Among orexigenic neuropeptides, the hyperphagic response to melanin-concentrating hormone (MCH) was significantly enhanced in BRS-3-deficient mice. In addition, the levels of MCH-R and MCH mRNAs in the hypothalamus were significantly elevated. From these results, we assume that the BRS-3 regulate the mechanism by which leptin decreases the MCH/MCH-R signaling. To generate mouse line conditionally expressing BRS-3, we constructed the vector and introduced it into ES cells and obtained the chimeric mice. We also have successfully cloned two bombesin-like peptide receptors, chGRP-R and chBRS-3.5 from chick brain. ChGRP-R is highly identical with mammalian and amphibian GRP-R, and this receptor showed high affinity for both GRP and bombesin. ChBRS-3.5, having sequence similarities to both mammalian BRS-3 and amphibian BB4, showed moderate affinity for bombesin, but low affinity for both GRP and NMB. In chick brain, chGRP-R is expressed predominantly in the hypothalamus whereas chBRS-3.5 is distributed widely in the pallium. These results recapitulate important roles of bombesin peptide receptors in vertebrates.