Identification of Susceptibility Loci for Obesity, Insulin Resistance, and Hyperglycemia in a Backcross Model of New Zealand Obese (NZO) and Lean SJL Mice

Abstract

New Zealand Obese (NZO) mice exhibit several characteristics that resemble the human metabolic syndrome or syndrome X. A backcross model of New Zealand Obese (NZO) mice with the lean SJL strain was established in order to locate genes responsible for obesity, insulin resistance, and type 2 diabetes-like hyperglycemia. In male NZOxFl backcross mice, a major susceptibility locus for the development of severe hyperglycemia (Nidd/SJL) was identified on chromosome 4. The diabetogenic allele appeared to be contributed by the SJL genome and was responsible for approximately 60% of the total prevalence of diabetes in the total male backcross population. In female NZOxF1 animals, a significant quantitative trait locus for parameters of obesity (body weight, body mass index, total body fat) and insulin resistance (hyperinsulinemia) (Nob1) was detected on chromosome 5. The aberrant allele was presumably contributed by the NZO genome. Phenotypic effects of this locus were also observed in the male population. Nidd/SJL and Nob1 showed additional effects on the development of insulin resistance and diabetes and were responsible for a major part of obesity, hyperinsulinemia and hyperglycemia in the backcross population.