title: Suppression of hyperinsulinaemia in growing female mice provides long-term protection against obesity.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3.
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Templeman
authors.affiliation: Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3.
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Clee
authors.affiliation: Diabetes Research Group, Life Sciences Institute, Department of Cellular and Physiological Sciences, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, Canada, V6T 1Z3. james.d.johnson@ubc.ca.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001823:Body Composition / Q000235:genetics; D059305:Diet, High-Fat; D005260:Female; D005947:Glucose / Q000378:metabolism; D006946:Hyperinsulinism / Q000235:genetics* / Q000378:metabolism; D007328:Insulin / Q000235:genetics* / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics* / Q000378:metabolism
chemical_list: C514817:Ins1 protein, mouse; C561967:Ins2 protein, mouse; D007328:Insulin; D005947:Glucose
keywords: Adolescence; Diet-induced obesity; Glucose homeostasis; Insulin; Knockout mice; Type 2 diabetes