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.

Genetic control of plasma lipid levels in a cross derived from normoglycaemic Brown Norway and spontaneously diabetic Goto–Kakizaki rats

“…The QTL Tchol/gk1 contains numerous candidates, including the sterol carrier protein 2 (Scp2) and clusters of cytochrome P450 and phospholipase A2 genes involved in the synthesis and transport of lipids [36]. A mutation found in both the GK and OLETF strains [37], which prevents the translation of a G-protein-coupled receptor (Gpr10) and is believed to cause hyperphagia, obesity and dyslipidaemia in OLETF rats, may account for at least part of the QTL Pl/ gk1. As outlined above, the existence of this variant in GK and OLETF rats supports its aetiological role in diabetes and obesity in these strains.…”

The role of RFamide peptides in feeding

“…The anorexic actions of PrRP appear to be related to satiety, as administration of the peptide does not invoke a conditioned taste aversion, or disrupt the normal behavioural satiety sequence (Lawrence et al 2002). The anorexic actions of PrRP are attenuated in mice (Bechtold & Luckman 2006) and rats (Watanabe et al 2005) that lack functional expression of GPR10, the putative receptor for PrRP. The significance of endogenous PrRP-GPR10 signalling in the regulation of feeding behaviour is also demonstrated by the fact that GPR10-knockout mice become heavier than congenetic wild types, due primarily to an increased accumulation of fat stores (Gu et al 2004).…”

Prolylcarboxypeptidase regulates food intake by inactivating α-MSH in rodents

“…Congenic mouse strain analyses have successfully identified several positional candidate obesity genes (1)(2)(3). The identification of novel aspects of known metabolic pathways is a particularly valuable outcome of positional genetics approaches.…”