title: Mutated G-protein-coupled receptor GPR10 is responsible for the hyperphagia/dyslipidaemia/obesity locus of Dmo1 in the OLETF rat.
abstract: 1. We have confirmed the Diabetes Mellitus OLETF type I (Dmo1) effect on hyperphagia, dyslipidaemia and obesity in the Otsuka Long-Evans Tokushima Fatty (OLETF) strain. The critical interval was narrowed down to 570 kb between D1Got258 to p162CA1 by segregation analyses using congenic lines. 2. Within the critical 570 kb region of the Dmo1 locus, we identified the G-protein-coupled receptor gene GPR10 as the causative gene mutated in the OLETF strain. The ATG translation initiation codon of GPR10 is changed into ATA in this strain and, so, is unavailable for the initiation of translation. 3. The GPR10 protein has a cognate ligand, namely prolactin-releasing peptide (PrRP). Centrally administered PrRP suppressed the food intake of congenic rats that have a Brown Norway derived Dmo1 region (i.e. with wild-type GPR10), but did not suppress that of the OLETF strain, indicating that GPR10 is without function and could explain hyperphagia in the OLETF strain. 4. Moreover, when restricted in food volume to the same level consumed by the congenic strain, OLETF rats showed few differences in the parameters of dyslipidaemia and obesity compared with congenic strains. 5. Taken together, these results demonstrate that the mutated GPR10 receptor is responsible for the hyperphagia leading to obesity and dyslipidaemia in the obese diabetic strain rat.
authors.affiliation: Otsuka GEN Research Institute, Otsuka Pharmaceutical Co. Ltd, Tokushima, Japan. tkw_watanabe@research.otsuka.co.jp
authors.forename: Takeshi K
authors.initials: TK
authors.lastname: Watanabe
authors.forename: Mikio
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamasaki
authors.forename: Shiro
authors.initials: S
authors.lastname: Okuno
authors.forename: Haretsugu
authors.initials: H
authors.lastname: Hishigaki
authors.forename: Toshihide
authors.initials: T
authors.lastname: Ono
authors.forename: Keiko
authors.initials: K
authors.lastname: Oga
authors.forename: Ayako
authors.initials: A
authors.lastname: Mizoguchi-Miyakita
authors.forename: Atsushi
authors.initials: A
authors.lastname: Tsuji
authors.forename: Naohide
authors.initials: N
authors.lastname: Kanemoto
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Wakitani
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Takagi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Akira
authors.initials: A
authors.lastname: Tanigami
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000235:genetics; D050171:Dyslipidemias / Q000235:genetics*; D005838:Genotype; D006963:Hyperphagia / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D020334:Rats, Inbred OLETF; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D013045:Species Specificity
chemical_list: C112345:PRLHR protein, human; D043562:Receptors, G-Protein-Coupled