A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Lepr

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-LeprL536Hfs∗6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin binding site. Compared to C57BL/6N mice, LeprL536Hfs∗6 develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the LeprL536Hfs∗6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared to C57BL/6N mice. Crossing Leprdb/wt with LeprL536Hfs∗6/wt mice results in compound heterozygous LeprL536Hfs∗6/db mice, which develop even higher body weight and fat mass than both homozygous Leprdb/db and LeprL536Hfs∗6 mice. Our study suggests that the phenotype of monogenic Lepr deficient mice depends on the molecular localization of the Lepr mutation. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.