Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity

Aims/hypothesis Hyperinsulinaemia is associated with obesity but its causal role in the onset of obesity remains controversial. In this study, we tested the hypothesis that transient attenuation of diet-induced insulin hypersecretion in young mice can provide sustained protection against obesity throughout adult life. Methods Using 'genetically humanised' mice lacking both alleles of rodent-specific Ins1, we compared mice heterozygous for the ancestral insulin gene Ins2 with Ins2 (+/+) controls. Female Ins1 (-/-):Ins2 (+/-) and Ins1 (-/-):Ins2 (+/+) littermates were fed chow or high-fat diet (HFD). Insulin secretion, metabolic health variables and body mass/composition were tracked for over 1 year. We examined islet function and adipose transcript levels of adipogenic, lipogenic and lipolytic genes at two time points. Results In control Ins1 (-/-):Ins2 (+/+) mice, HFD resulted in elevated fasting and glucose-stimulated insulin secretion between 8 weeks and 27 weeks of age. Hyperinsulinaemia was reduced by nearly 50% in Ins1 (-/-):Ins2 (+/-) mice during this period, without lasting adverse effects on glucose homeostasis. This corresponded with attenuated weight gain and adiposity. White adipose tissue from Ins1 (-/-):Ins2 (+/-) mice had fewer large lipid droplets, although transcriptional changes were not detected. Importantly, Ins1 (-/-):Ins2 (+/-) mice remained lighter than Ins1 (-/-):Ins2 (+/+) littermates despite reaching an equivalent degree of hyperinsulinaemia on HFD by 52 weeks. Conclusions/interpretation These data demonstrate that attenuation of hyperinsulinaemia in young, growing female mice provides a long-lasting protection against obesity. This protection persists despite a late-onset emergence of hyperinsulinaemia in HFD-fed Ins1 (-/-):Ins2 (+/-) mice. Given the evolutionary conserved roles of insulin, it is possible that suppressing hyperinsulinaemia early in life may have far-reaching consequences on obesity in full-grown adult humans.