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

Taken together, our findings indicate that hyperinsulinemia is required for excess adiposity in Lepob/ob mice and sufficient insulin production is necessary to maintain euglycemia in the absence of leptin.

Leptin expressing (Lepwt/wt) mice lacking 3 insulin alleles were crossed with Lepob/ob mice to generate Lepob/ob and Lepwt/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.

Hyperinsulinemia is commonly associated with obesity. Mice deficient in the adipose-derived hormone leptin (Lepob/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 Lepob/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 Lepob/ob mice on circulating insulin, body composition, and glucose homeostasis.

We found that in young Lepob/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+/-;Lepob/ob mice. This corresponded with ∼30% and ∼50% reduced total body fat in Ins1+/+;Ins2-/-;Lepob/ob and Ins1+/-;Ins2-/-;Lepob/ob mice, respectively. Loss of 2 or 3 insulin alleles in young Lepob/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 Lepwt/wt mice did not significantly alter plasma insulin levels, body weight, fat mass, fasting glycemia, or glucose tolerance.