Experiment
Three different BSB crosses were used to map obesity QTLs and assess the role of Lipc as an obesity gene.
Cross 1: (C57BL/6J-Lipc-/- x SPRET/Ei)F1 x C57BL/6J-Lipc-/-
Cross 2: (C57BL/6J-Lipc-/- x SPRET/Ei)F1 x C57BL/6J
Cross 3: (C57BL/6J x SPRET/Ei)F1 x C57BL/6J-Lipc-/-
(Note: The C57BL/6J-Lipc-/- strain carries 129P2/OlaHsd-derive DNA around the region of Lipc.)
In Cross 1, significant linkage to total cholesterol was detected on mouse Chromosome 9 between Lipc (39 cM) and D9Mit8 (42 cM). InCross 2, significant linkage to hepatic lipase activity, total cholesterol, and percent body fat was detected on mouse Chromosome 9 between Lipc (39 cM) and D9Mit8 (42 cM). In Cross 3, significant linkage was detected on mouse Chromosome 9 between D9Mit104 (35 cM) and D9Mit8 (42 cM). Animals with the LipcC57BL/6J/- genotype are considerably lean whereas animals with the LipcSPRET/Ei/- genotype are the fattest. Animals with the LipcSPRET/Ei/- genotype also exhibit a 25% increase in fasting triglycerides compared to LipcC57BL/6J/- animals.
Sequence analysis of Lipc revealed 7 polymorphisms between C57BL/6J and SPRET/Ei, 4 of which result in amino acid substitutions. SPRET/Ei also exhibits a 1.8-fold increase in Lipc mRNA expression compared to C57BL/6J.
Previously identified QTL Mob1 (62 cM on mouse Chromosome 7 near D7Mit8) was detected with significant linkage to percent body fat in Cross 2 and Cross 3. The SPRET/Ei-derived allele confers increased body fat percentage compared to animals homozygous for C57BL/6J-derived alleles. The SPRET/Ei allele at Mob1 also confers increased body length, hepatic lipase activity, food intake, total cholesterol levels, and reduced rectal temperature.
Together, Lipc and Mob1 account for 17% and 27% of the variance in percent body fat in Cross 2 and Cross 3, respectively.