title: Neuropeptide Y family receptors traffic via the Bardet-Biedl syndrome pathway to signal in neuronal primary cilia.
abstract: Human monogenic obesity syndromes, including Bardet-Biedl syndrome (BBS), implicate neuronal primary cilia in regulation of energy homeostasis. Cilia in hypothalamic neurons have been hypothesized to sense and regulate systemic energy status, but the molecular mechanism of this signaling remains unknown. Here, we report a comprehensive localization screen of 42 G-protein-coupled receptors (GPCR) revealing seven ciliary GPCRs, including the neuropeptide Y (NPY) receptors NPY2R and NPY5R. We show that mice modeling BBS disease or obese tubby mice fail to localize NPY2R to cilia in the hypothalamus and that BBS mutant mice fail to activate c-fos or decrease food intake in response to the NPY2R ligand PYY3-36. We find that cells with ciliary NPY2R show augmented PYY3-36-dependent cAMP signaling. Our data demonstrate that ciliary targeting of NPY receptors is important for controlling energy balance in mammals, revealing a physiologically defined ligand-receptor pathway signaling within neuronal cilia.
authors: Research Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Alexander V
authors: AV
authors: Loktev
authors: Research Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: pjackson@stanford.edu.
authors: Peter K
authors: PK
authors: Jackson
mesh_terms: D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D020788:Bardet-Biedl Syndrome / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D019894:Peptide YY / Q000494:pharmacology; D021381:Protein Transport; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001067:Appetite Depressants; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; C100568:neuropeptide Y5 receptor; D019894:Peptide YY; C061785:peptide YY (3-36); D000242:Cyclic AMP