Pnlip encoding pancreatic lipase is possible candidate for obesity QTL in the OLETF rat

Abstract

The Otsuka Long–Evans Tokushima Fatty (OLETF) rat exhibits polygenic obesity, and one of quantitative trait loci (QTLs) responsible for a susceptibility to obesity in the OLETF, Nidd6/of, has been mapped to the ∼10-cM genomic region between D1Rat166 and D1Rat90 on chromosome 1 in (OLETF × normal) F 2 intercross. In this study, we have attempted to identify the causal gene for the Nidd6/of QTL. A Nidd6/of congenic strain, constructed by introgressing the OLETF allele on the mapped Nidd6/of region in the normal F344 rat strain, confirmed the existence of the Nidd6/of as obesity QTL. The Nidd6/of region was refined to a ∼2.3-cM genomic region between D1Rat225 and D1Rat90, using informative recombinants selected from ( Nidd6/of congenic × F344) F 1 × Nidd6/of congenic backcross progenies. Among 46 genes located within the ∼ 2.3-cM region, pancreatic lipase gene, Pnlip, was regarded as the most prominent and physiologically relevant positional candidate for the Nidd6/of QTL. We found that Pnlip possesses an OLETF allele-specific increase of mRNA levels in the pancreas, and that the OLETF allele is longer in variable number of tandem repeat (VNTR) within the 5′-flanking region than normal alleles. We further showed that the Nidd6/of QTL completely cosegregates with Pnlip VNTR in the informative recombinants from ( Nidd6/of congenic × F344) F 1 × Nidd6/of congenic backcross progenies. These results suggest that Pnlip is possible candidate for the Nidd6/of QTL.