A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Lepr^db/db mice

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-Lepr^{L536Hfs*6-1NKB}), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, Lepr^L536Hfs*6 develop early onset obesity and their body weight exceeds that of Lepr^db/db mice at an age of 30 weeks. Similar to Lepr^db/db mice, the Lepr^L536Hfs*6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Lepr^db/wt with Lepr^L536Hfs*6/wt mice results in compound heterozygous Lepr^L536Hfs*6/db mice, which develop even higher body weight and fat mass than both homozygous Lepr^db/db and Lepr^L536Hfs*6 mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.