High-fat-diet induced development of increased fasting glucose levels and impaired response to intraperitoneal glucose challenge in the collaborative cross mouse genetic reference population

Abstract

BackgroundThe prevalence of Type 2 Diabetes (T2D) mellitus in the past decades, has reached epidemic proportions. Several lines of evidence support the role of genetic variation in the pathogenesis of T2D and insulin resistance. Elucidating these factors could contribute to developing new medical treatments and tools to identify those most at risk. The aim of this study was to characterize the phenotypic response of the Collaborative Cross (CC) mouse genetic resource population to high-fat diet (HFD) induced T2D-like disease to evluate its suitability for this purpose.ResultsWe studied 683 mice of 21 different lines of the CC population. Of these, 265 mice (149 males and 116 females) were challenged by HFD (42 % fat); and 384 mice (239 males and145 females) of 17 of the 21 lines were reared as control group on standard Chow diet (18 % fat). Briefly, 8 week old mice were maintained on HFD until 20 weeks of age, and subsequently assessed by intraperitoneal glucose tolerance test (IPGTT). Biweekly body weight (BW), body length (BL), waist circumstance (WC), and body mass index (BMI) were measured. On statistical analysis, trait measurements taken at 20 weeks of age showed significant sex by diet interaction across the different lines and traits. Consequently, males and females were analyzed, separately. Differences among lines were analyzed by ANOVA and shown to be significant (P <0.05), for BW, WC, BMI, fasting blood glucose, and IPGTT-AUC. We use these data to infer broad sense heritability adjusted for number of mice tested in each line; coefficient of genetic variation; genetic correlations between the same trait in the two sexes, and phenotypic correlations between different traits in the same sex.ConclusionsThese results are consistent with the hypothesis that host susceptibility to HFD-induced T2D is a complex trait and controlled by multiple genetic factors and sex, and that the CC population can be a powerful tool for genetic dissection of this trait.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0321-x) contains supplementary material, which is available to authorized users.

Collaborative Cross Mouse Population for Studying Alveolar Bone Changes and Impaired Glucose Tolerance Comorbidity After High‐Fat Diet Consumption

“…These findings validate the power of the CC lines population for studying genetic susceptibility toward comorbidity of the two or more complex diseases simultaneously, representing, to the best of the authors’ knowledge, a novel mouse model that enables exploring co‐ and multi‐morbidity phenomena in wide aspects within a short period of time. The present findings are in agreement with previous reports using this mouse model, which demonstrated the power of the CC population for dissecting host susceptibility to complex diseases with complex etiologies 6,21,22,24,25,28‐30 …”

“…Blood glucose levels were measured at 0, 15, 30, 60, 120, and 180 minutes after glucose injection, followed by overnight recovery. The glucose area under the curve (AUC) value between 0 and 180 minutes (total AUC) was calculated as previously reported 6 …”

“…Type 2 diabetes mellitus (t2DM) is a complex metabolic disease that is characterized by hyperglycemia resulting from insulin resistance. The disease is strongly affected by environmental factors, including a sedentary lifestyle, obesity, HFD consumption independent of obesity, 5 and genetic background of the host 6 …”

“…This unique genetic reference population comprises a set of hundreds of recombinant inbred lines created from full reciprocal mating of eight divergent mice strains: 1) A/J; 2) C57BL/6J; 3) 129S1/SvImJ; 4) NOD/LtJ; 5) NZO/HiLtJ; 6) CAST/Ei; 7) PWK/PhJ; and 8) WSB/EiJ. Controlled randomization was performed during the breeding process to break up large linkage disequilibrium blocks and to recombine the natural genetic variation, resulting in production of an inexhaustible source of recombinant inbred lines exhibiting a wide spectrum of phenotypic and genetic diversity 6,17‐20 . Previous studies have validated the power of CC lines to map QTLs to small genomic intervals, even <0.75 Mb 21–25 …”

Extract of the Microalga Nitzschia laevis Prevents High‐Fat‐Diet‐Induced Obesity in Mice by Modulating the Composition of Gut Microbiota

“…Apart from lipid and cholesterol metabolism, HFD has also been reported to influence physiological response to glucose challenge . Intraperitoneal glucose challenge and insulin tolerance tests after 8 weeks of the dietary regimen, however, did not support a functional role of NLE in this regard (Figure E and F).…”