Suppressing hyperinsulinemia prevents obesity but causes rapid onset of diabetes in leptin-deficient Lep(ob/ob) mice

OBJECTIVE: Hyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin (Lep(ob/ob)) develop hyperinsulinemia prior to onset of obesity and glucose intolerance. Whether the excess of circulating insulin is a major contributor to obesity and impaired glucose homeostasis in Lep(ob/ob) mice is unclear. It has been reported previously that diet-induced obesity in mice can be prevented by reducing insulin gene dosage. In the present study, we examined the effects of genetic insulin reduction in Lep(ob/ob) mice on circulating insulin, body composition, and glucose homeostasis. METHODS: Leptin expressing (Lep(wt/wt)) mice lacking 3 insulin alleles were crossed with Lep(ob/ob) mice to generate Lep(ob/ob) and Lep(wt/wt) littermates lacking 1 (Ins1(+/+);Ins2(+/−)), 2 (Ins1(+/+);Ins2(−/−)) or 3 (Ins1(+/−);Ins2(−/−)) insulin alleles. Animals were assessed for body weight gain, body composition, glucose homeostasis, and islet morphology. RESULTS: We found that in young Lep(ob/ob) mice, loss of 2 or 3 insulin alleles reduced plasma insulin levels by 75–95% and attenuated body weight gain by 50–90% compared to Ins1(+/+);Ins2(+/−);Lep(ob/ob) mice. This corresponded with ∼30% and ∼50% reduced total body fat in Ins1(+/+);Ins2(−/−);Lep(ob/ob) and Ins1(+/−);Ins2(−/−);Lep(ob/ob) mice, respectively. Loss of 2 or 3 insulin alleles in young Lep(ob/ob) mice resulted in onset of fasting hyperglycemia by 4 weeks of age, exacerbated glucose intolerance, and abnormal islet morphology. In contrast, loss of 1,2 or 3 insulin alleles in Lep(wt/wt) mice did not significantly alter plasma insulin levels, body weight, fat mass, fasting glycemia, or glucose tolerance. CONCLUSION: Taken together, our findings indicate that hyperinsulinemia is required for excess adiposity in Lep(ob/ob) mice and sufficient insulin production is necessary to maintain euglycemia in the absence of leptin.