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http://purl.uniprot.org/citations/26155745http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
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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."xsd:string
http://purl.uniprot.org/citations/26155745http://purl.org/dc/terms/identifier"doi:10.1007/s00125-015-3676-7"xsd:string
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/author"Clee S.M."xsd:string
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/author"Johnson J.D."xsd:string
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/author"Templeman N.M."xsd:string
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/date"2015"xsd:gYear
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/name"Diabetologia"xsd:string
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/pages"2392-2402"xsd:string
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/title"Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity."xsd:string
http://purl.uniprot.org/citations/26155745http://purl.uniprot.org/core/volume"58"xsd:string
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