Functional and genetic studies of the NPY system

In mammals, NPY stimulates appetite primarily via receptor subtypes Y1 and Y5, whereas the related gut endocrine peptide PYY reduces appetite via receptor Y2 and pancreatic polypeptide (PP) inhibits appetite via Y4. Future drugs might therefore be agonists acting on Y2 and Y4. We investigate the ligand-binding properties of the human Y2 receptor using a large panel of receptor mutants generated by site-directed mutagenesis and expressed in cultured mammalian cells. We have identified important interaction sites between peptides and receptors, and are now exploring the selectivity of the peptides to the receptor subtypes. The results will help improve structural models for facilitating development of receptor subtype-selective drugs for reducing appetite. We are also starting to investigate how relatives of the NPY receptors, such as PRLH receptors and QRFP receptors, have evolved selectivity after duplication from a common ancestral receptor gene.

Recent studies have shown that the PP receptor Y4 is associated with childhood obesity and adult body weight. Our functional studies in vitro have shown that one receptor variant (allele) displayed reduced functional coupling to signal transduction pathways. We are now resolving the complicated inheritance of this gene which displays both copy number variation (CNV) and single nucleotide polymorphisms (SNPs). The hypothesis is that a lower number of gene copies leads to reduced satiety, resulting in increased food intake and eventually obesity.



Bo Xu
Jasna Pruner
Kataryna Lapshyna
Christina Bergqvist
Nina Mohell
Ingrid Lundell