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

Abstract

ObjectiveHyperinsulinemia 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.MethodsLeptin 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.ResultsWe 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.ConclusionTaken 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.

Hyperinsulinemia: a Cause of Obesity?

“…These data imply that suppression of HI could provide protection against obesity later in life. Genetic prevention of HI also greatly blunts weight gain and adiposity in leptin-deficient ob/ob mice [16]. These data support the notion that prevention of initial weight gain by reduction of HI may be favorable to reduction of HI as a treatment for obesity.…”

Leptin: A new therapeutic target for treatment of diabetes mellitus

“…It is further explained by the observations in which restriction in caloric intake failed to improve or recover the sensitivity of insulin in all models either genetically leptin-deficient or leptin receptor deficient. 60 Another observation consistent with the above findings is that leptin administration in genetically leptindeficient models lowers plasma insulin and blood glucose levels, even when differences in energy intake are controlled. 47 Deficiency of leptin has also shown to play an…”

Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice

“…Mechanistically, hyperinsulinaemia causes obesity [39], in part by inducing leptin resistance and hyperphagia [40]. Thus, normalisation of food intake can also result from reduced visceral obesity by liver-specific recovery of CEACAM1 expression.…”