Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity.
Diabetologia
; 58(10): 2392-402, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26155745
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Hiperinsulinismo
/
Insulina
/
Obesidade
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article