Quantitative trait loci for obesity and insulin resistance (Nob1, Nob2) and their interaction with the leptin receptor allele (LeprA720T/T1044I) in New Zealand obese mice

Abstract

Aims/hypothesis. To locate genes responsible for obesity and insulin resistance, a backcross model of New Zealand obese (NZO) mice with the lean Swiss/Jackson Laboratory (SJL) strain was stablished. Results. In female NZO x F1 backcross mice, two major quantitative trait loci for variables of obesity (body weight, body mass index, total body fat) and insulin resistance (hyperinsulinaemia) were identified on chromosomes 5 (Nob1) and 19 (Nob2) close to the markers D5Mit392 and D19Mit91. The aberrant alleles have presumably contributed by the NZO genome. Whereas Nob1 contributed mainly to higher body weight, Nob2 seemed to mainly aggravate insulin resistance independent of obesity. The leptin receptor variant of NZO (Lepr ^A720T/T1044I) failed to alter any of the variables of obesity. It seemed, however, to enhance the effect of Nob1 on body weight and that of Nob2 on serum insulin concentration. When expressed in COS-7 cells, Lepr ^A720T/T1044I produced a normal basal and maximum activation with a minor increase in the EC₅₀ of leptin. Conclusions/interpretation. The data identify two new quantitative trait loci that are responsible for a major part of obesity and hyperinsulinaemia as produced by recessive genes in NZO mice. Lepr ^A720T/T1044I alone cannot produce obesity, but may enhance the effects of other obesity/insulin resistance genes in this mouse model. [Diabetologia (2000) 43: 1565–1572]