title: Divergent compensatory responses to high-fat diet between C57BL6/J and C57BLKS/J inbred mouse strains.
abstract: Impaired glucose tolerance (IGT) and type 2 diabetes (T2DM) are polygenic disorders with complex pathophysiologies; recapitulating them with mouse models is challenging. Despite 70% genetic homology, C57BL/6J (BL6) and C57BLKS/J (BLKS) inbred mouse strains differ in response to diet- and genetic-induced obesity. We hypothesized these differences would yield insight into IGT and T2DM susceptibility and response to pharmacological therapies. To this end, male 8-wk-old BL6 and BLKS mice were fed normal chow (18% kcal from fat), high-fat diet (HFD; 42% kcal from fat), or HFD supplemented with the PPARγ agonist pioglitazone (PIO; 140 mg PIO/kg diet) for 16 wk. Assessments of body composition, glucose homeostasis, insulin production, and energy metabolism, as well as histological analyses of pancreata were undertaken. BL6 mice gained weight and adiposity in response to HFD, leading to peripheral insulin resistance that was met with increased β-cell proliferation and insulin production. By contrast, BLKS mice responded to HFD by restricting food intake and increasing activity. These behavioral responses limited weight gain and protected against HFD-induced glucose intolerance, which in this strain was primarily due to β-cell dysfunction. PIO treatment did not affect HFD-induced weight gain in BL6 mice, and decreased visceral fat mass, whereas in BLKS mice PIO increased total fat mass without improving visceral fat mass. Differences in these responses to HFD and effects of PIO reflect divergent human responses to a Western lifestyle and underscore the careful consideration needed when choosing mouse models of diet-induced obesity and diabetes treatment.
authors.affiliation: Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana;
authors.forename: Emily K
authors.initials: EK
authors.lastname: Sims
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hatanaka
authors.forename: David L
authors.initials: DL
authors.lastname: Morris
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Tersey
authors.forename: Tatsuyoshi
authors.initials: T
authors.lastname: Kono
authors.forename: Zunaira Z
authors.initials: ZZ
authors.lastname: Chaudry
authors.forename: Kathleen H
authors.initials: KH
authors.lastname: Day
authors.forename: Dan R
authors.initials: DR
authors.lastname: Moss
authors.forename: Natalie D
authors.initials: ND
authors.lastname: Stull
authors.forename: Raghavendra G
authors.initials: RG
authors.lastname: Mirmira
authors.forename: Carmella
authors.initials: C
authors.lastname: Evans-Molina
mesh_terms: D050154:Adiposity / Q000187:drug effects / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000494:pharmacology; D004198:Disease Susceptibility; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics*; D018149:Glucose Intolerance / Q000139:chemically induced / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics; D050152:Intra-Abdominal Fat / Q000187:drug effects / Q000254:growth & development; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D009765:Obesity / Q000209:etiology*; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics
chemical_list: D004041:Dietary Fats
keywords: C57BL/6J; C57BLKS/J; diet-induced obesity; mouse models of T2DM; pioglitazone