title: Hyperinsulinemia drives diet-induced obesity independently of brain insulin production.
abstract: Hyperinsulinemia is associated with obesity and pancreatic islet hyperplasia, but whether insulin causes these phenomena or is a compensatory response has remained unsettled for decades. We examined the role of insulin hypersecretion in diet-induced obesity by varying the pancreas-specific Ins1 gene dosage in mice lacking Ins2 gene expression in the pancreas, thymus, and brain. Age-dependent increases in fasting insulin and β cell mass were absent in Ins1(+/-):Ins2(-/-) mice fed a high-fat diet when compared to Ins1(+/+):Ins2(-/-) littermate controls. Remarkably, Ins1(+/-):Ins2(-/-) mice were completely protected from diet-induced obesity. Genetic prevention of chronic hyperinsulinemia in this model reprogrammed white adipose tissue to express uncoupling protein 1 and increase energy expenditure. Normalization of adipocyte size and activation of energy expenditure genes in white adipose tissue was associated with reduced inflammation, reduced fatty acid spillover, and reduced hepatic steatosis. Thus, we provide genetic evidence that pathological circulating hyperinsulinemia drives diet-induced obesity and its complications.
authors.affiliation: Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
authors.forename: Arya E
authors.initials: AE
authors.lastname: Mehran
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Templeman
authors.forename: G Stefano
authors.initials: GS
authors.lastname: Brigidi
authors.forename: Gareth E
authors.initials: GE
authors.lastname: Lim
authors.forename: Kwan-Yi
authors.initials: KY
authors.lastname: Chu
authors.forename: Xiaoke
authors.initials: X
authors.lastname: Hu
authors.forename: Jose Diego
authors.initials: JD
authors.lastname: Botezelli
authors.forename: Ali
authors.initials: A
authors.lastname: Asadi
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hoffman
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
authors.forename: Shernaz X
authors.initials: SX
authors.lastname: Bamji
authors.forename: Susanne M
authors.initials: SM
authors.lastname: Clee
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism; D018628:Gene Dosage; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism* / Q000473:pathology; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D000071256:Uncoupling Protein 1
chemical_list: D005227:Fatty Acids; C514817:Ins1 protein, mouse; C561967:Ins2 protein, mouse; D007328:Insulin; D007473:Ion Channels; D024101:Mitochondrial Proteins; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D005947:Glucose