MICE LACKING BOMBESIN RECEPTOR SUBTYPE-3 DEVELOP METABOLIC DEFECTS AND OBESITY

Mammalian bombesin-like peptides are widely distributed in the central nervous system as well as in the gastrointestinal tract, where they m odulate smooth-muscle contraction, exocrine and endocrine processes, m etabolism and behaviour(1). They bind to G-protein-coupled receptors o n the cell surface to elicit their effects, Bombesin-like peptide rece ptors cloned so far include, gastrin-releasing peptide receptor (GRP-R )(2,3), neuromedin B receptor (NMB-R)(4,5), and bombesin receptor subt ype-3 (BRS-3)(6,7). However, despite the molecular characterization of BRS-3, determination of its function has been difficult as a result o f its low affinity for bombesin and its lack of an identified natural ligand, We have generated BRS-3-deficient mice in an attempt to determ ine the in vivo function of the receptor, Mice lacking functional BRS- 3 developed a mild obesity, associated with hypertension and impairmen t of glucose metabolism, They also exhibited reduced metabolic rate, i ncreased feeding efficiency and subsequent hyperphagia, Our data sugge st that BRS-3 is required for the regulation of endocrine processes an d metabolism responsible for energy balance and adiposity, BRS-3-defic ient mice provide a useful new model for the investigation of human ob esity and associated diseases.