Abstract
Aims/hypothesisHyperinsulinaemia 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.MethodsUsing ‘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.ResultsIn 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/interpretationThese 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-015-3676-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
Highlights
Over 40 million children younger than 5 years of age were overweight worldwide in 2011 [1], and being overweight or obese during childhood and adolescence is a predictor of adult obesity [2, 3]
These data demonstrate that reduced Ins2 dosage resulted in lower insulin production, there is potential for age-dependent compensation with high-fat diet (HFD)-feeding
Our objective was to test the hypothesis that reducing insulin secretion by partial disruption of the Ins2 gene would prevent diet-induced obesity
Summary
Over 40 million children younger than 5 years of age were overweight worldwide in 2011 [1], and being overweight or obese during childhood and adolescence is a predictor of adult obesity [2, 3]. Hyperinsulinaemia and insulin resistance are two characteristics of the obese state that have been proposed to contribute to its detrimental effects on health [5, 6]. Drugs that suppress insulin secretion in hyperinsulinaemic obese rodents or humans lead to weight loss [12,13,14]. Obese individuals with the highest insulin levels respond best to diets that reduce postprandial glycaemia and insulinaemia whereas those with less-elevated insulin show equivalent weight loss on low-fat diets [15, 16]. Insulin is known to suppress lipolysis and stimulate lipogenesis in white adipose tissue (WAT) [17], and mouse models with reduced adipose tissue insulin signalling are protected against obesity [18, 19]
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