Orphan GPCR Ligands Related to Obesity

Yukio      Fujisawa; Masaaki      Mori; Tetsuya      Ohtaki; Shuji      Hinuma; Masahiko      Fujino

Abstract

In this article, we describe recent advances in the study of novel orphan GPCR ligands related to obesity, focusing on melanin-concentrating hormone (MCH), neuropeptide W (NPW), neuropeptide B (NPB) and galanin-like peptide (GALP). An endogenous ligand of orphan G-protein-coupled receptor (GPCR), SLC-1 (MCH-R1), was isolated from rat brain and revealed to be MCH. Phenotypic analyses of genetically engineered animals indicated that the MCH-SLC-1 / MCH-R1 axis is relevant to feeding behavior and energy homeostasis. We developed MCH receptor antagonists and found that they could inhibit food intake stimulated by central administration of MCH. NPW was isolated from porcine hypothalamus as a ligand for orphan GPR8 and found to bind to both GPR7 and GPR8 at similar effective doses. Results of intracerebroventricular administration of NPW to rats suggested that it regulated feeding behavior and the neuroendocrine system, although further study is required to confirm the physiological functions of NPW.In addition, we isolated NPB, which was closely related to NPW in structure, from bovine hypothalamus as a GPR7 ligand and found that it was modified with bromine at position C-6 of the indole ring of the N-terminal Trp residue. From the distribution of the NPB mRNA in the rat brain, NPB was suggested to be involved in the regulation of feeding and the neuroendocrine system as well as memory and learning. GALP was isolated from porcine small intestines as a ligand for galanin subtype receptor GALR2. The most interesting feature was that GALP-neurons were specifically localized to the arcuate nucleus in rats and under the positive regulation of leptin, suggesting that GALP mediates the anorexic activity of leptin.

Keywords: gpcr ligands, Obesity, galanin-like peptide, gpcr, mch-r1, galp-neurons, anorexic activity