High-fat feeding rapidly induces obesity and lipid derangements in C57BL/6N mice.
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ABSTRACT:
SUBMITTER: Podrini C
PROVIDER: S-EPMC3685703 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundRegulation of the endoplasmic reticulum (ER) stress pathway is critical to mammary epithelial cell function throughout pregnancy, lactation, and involution. Treatment with trans-10, cis-12 conjugated linoleic acid (t10c12CLA) suppresses mammary lipogenesis and stimulates the ER stress pathway. The ER stress pathway includes tribbles pseudokinase 3 (TRB3), a protein that regulates cellular energy and insulin signaling.ObjectivesOur objective was to describe the effect of TRB3 deficiency on milk fat synthesis and determine if TRB3 deficiency protects against suppression of mammary lipogenesis.MethodsFirst, mammary Trb3 expression was observed throughout pregnancy and lactation using ancillary microarray data (n = 4/time point). Second, intake, litter growth, and milk clot fatty acid (FA) profile of Trb3 knockout (KO) C57BL/6N mice were compared with wild-type (WT) and heterozygous (HET) mice throughout first (n ≥ 8/group) and second (n ≥ 6/group) lactation. Lastly, the interaction between Trb3 genotype and 2 treatments that suppress mammary lipogenesis, t10c12CLA and high safflower oil (HO) diet, was investigated in a 2 × 2 factorial design (n ≥ 6/group).ResultsTrb3 expression was higher during late pregnancy and lactation. Trb3 KO and HET mice had lower feed intake, dam weight, and litter growth throughout first, but not second, lactation than WT mice. Treatment with t10c12CLA decreased litter growth (28%; P < 0.0001) and feed intake (8%; P < 0.0001) regardless of Trb3 genotype. When fed the HO diet, Trb3 KO mice had 17% higher mammary de novo synthesized FAs (<16 carbons; P int = 0.002) than WT mice. Mammary ER stress and lipogenic genes were mostly unaltered by Trb3 deficiency.ConclusionsOverall, TRB3 plays a minor role in regulating mammary lipogenesis, because Trb3 deficiency had only a limited protective effect against diet-induced suppression of lipogenesis.
| S-EPMC8791759 | biostudies-literature
Project description:BackgroundExcessive gestational weight gain (EGWG) closely associates with postpartum obesity. However, the causal role of EGWG in postpartum obesity has not been experimentally verified. The objective of this study was to determine whether and how EGWG causes long-term postpartum obesity.MethodsC57BL/6 mice were fed with high-fat diet during gestation (HFFDG) or control chow, then their body composition and energy metabolism were monitored after delivery.ResultsWe found that HFFDG significantly increased gestational weight gain. After delivery, adiposity of HFFDG-treated mice (Preg-HF) quickly recovered to the levels of controls. However, 3 months after parturition, Preg-HF mice started to gain significantly more body fat even with regular chow. The increase of body fat of Preg-HF mice was progressive with aging and by 9 months after delivery had increased 2-fold above the levels of controls. The expansion of white adipose tissue (WAT) of Preg-HF mice was manifested by hyperplasia in visceral fat and hypertrophy in subcutaneous fat. Preg-HF mice developed low energy expenditure and UCP1 expression in interscapular brown adipose tissue (iBAT) in later life. Although blood estrogen concentrations were similar between Preg-HF and control mice, a significant decrease in estrogen receptor α (ERα) expression and hypermethylation of the ERα promoter was detected in the fat of Preg-HF mice 9 months after delivery. Interestingly, hypermethylation of ERα promoter and low ERα expression were only detected in adipocyte progenitor cells in both iBAT and WAT of Preg-HF mice at the end of gestation.ConclusionsThese results demonstrate that HFFDG causes long-term postpartum obesity independent of early postpartum fat retention. This study also suggests that HFFDG adversely programs long-term postpartum energy metabolism by epigenetically reducing estrogen signaling in both BAT and WAT.
| S-EPMC6614019 | biostudies-literature
Project description:High salt (HS) dietary intake leads to impaired vascular endothelium-dependent responses to various physiological stimuli, some of which are mediated by arachidonic acid (AA) metabolites. Transgenic Tff3-/- gene knockout mice (Tff3-/-/C57BL/6N) have changes in lipid metabolism which may affect vascular function and outcomes of stroke. We aimed to study the effects of one week of HS diet (4% NaCl) on vascular function and stroke induced by transient occlusion of middle cerebral artery in Tff3-/- and wild type (WT/C57BL/6N) mice. Flow-induced dilation (FID) of carotid artery was reduced in WT-HS mice, but not affected in Tff3-/--HS mice. Nitric oxide (NO) mediated FID. NO production was decreased with HS diet. On the contrary, acetylcholine-induced dilation was significantly decreased in Tff3-/- mice on both diets and WT-HS mice. HS intake and Tff3 gene depletion affected the structural components of the vessels. Proteomic analysis revealed a significant effect of Tff3 gene deficiency on HS diet-induced changes in neuronal structural proteins and acute innate immune response proteins' expression and Tff3 depletion, but HS diet did not increase the stroke volume, which is related to proteome modification and upregulation of genes involved mainly in cellular antioxidative defense. In conclusion, Tff3 depletion seems to partially impair vascular function and worsen the outcomes of stroke, which is moderately affected by HS diet.
| S-EPMC6829871 | biostudies-literature
Project description:BackgroundMetabolic disorders are commonly investigated using knockout and transgenic mouse models on the C57BL/6N genetic background due to its genetic susceptibility to the deleterious metabolic effects of high-fat diet (HFD). There is growing awareness of the need to consider sex in disease progression, but limited attention has been paid to sexual dimorphism in mouse models and its impact in metabolic phenotypes. We assessed the effect of HFD and the impact of sex on metabolic variables in this strain.MethodsWe generated a reference data set encompassing glucose tolerance, body composition and plasma chemistry data from 586 C57BL/6N mice fed a standard chow and 733 fed a HFD collected as part of a high-throughput phenotyping pipeline. Linear mixed model regression analysis was used in a dual analysis to assess the effect of HFD as an absolute change in phenotype, but also as a relative change accounting for the potential confounding effect of body weight.ResultsHFD had a significant impact on all variables tested with an average absolute effect size of 29%. For the majority of variables (78%), the treatment effect was modified by sex and this was dominated by male-specific or a male stronger effect. On average, there was a 13.2% difference in the effect size between the male and female mice for sexually dimorphic variables. HFD led to a significant body weight phenotype (24% increase), which acts as a confounding effect on the other analysed variables. For 79% of the variables, body weight was found to be a significant source of variation, but even after accounting for this confounding effect, similar HFD-induced phenotypic changes were found to when not accounting for weight.ConclusionHFD and sex are powerful modifiers of metabolic parameters in C57BL/6N mice. We also demonstrate the value of considering body size as a covariate to obtain a richer understanding of metabolic phenotypes.
| S-EPMC5436097 | biostudies-literature
Project description:To evaluate the antiobesity effects of yellow and black soybean, C57BL/6 mice were provided with a normal diet, high-fat diet, HFD-containing yellow soybean powder (YS), and black soybean powder (BS) for six weeks. Compared with the HFD group, both YS and BS decreased body weight by 30.1% and 37.2% and fat in tissue by 33.3% and 55.8%, respectively. Simultaneously, both soybeans significantly reduced the serum triglyceride and total cholesterol levels and regulated the lipogenic mRNA expressions of Pparγ, Acc, and Fas genes in the liver, supporting reduced body adiposity. Furthermore, BS significantly increased Pgc-1α and Ucp1 mRNA expression levels in epididymal adipose tissue, indicating thermogenesis is the key mechanism of BS. Taken together, our findings suggest that both soybeans prevent high-fat diet-induced obesity in mice by regulating lipid metabolism, and BS, in particular, has a greater antiobesity potential than YS.
| S-EPMC10129420 | biostudies-literature
Project description:Fetal/neonatal exposure to the endocrine disruptor bisphenol A (BPA) has induced obesity and increased glucose intolerance. We hypothesized that chronic BPA exposure would worsen the obesity and glucose intolerance induced by a high fat diet (HFD). The drinking water of C57bl/6n dams was treated with vehicle (VEH) or BPA (25 ng/ml) from gestation day 11.5 to postnatal day 21. Another group was treated with oral diethylstilbestrol (DES, 1 ?g/kg/day) during gestation. Progeny were treated with VEH (VEH and DES groups) or BPA (2.5 ng/ml) in the drinking water and fed either a control diet (CD) or HFD from weaning until euthanasia at 4 months of age. CD-fed mice were similar in size; however HFD-BPA males and HFD-DES mice were smaller than HFD-VEH mice. No CD-fed mice were glucose intolerant. All HFD-fed mice were glucose intolerant. Cholesterol and triglyceride were increased in HFD-VEH mice and HFD-BPA males. Total fat weight and adipocyte area were similar in HFD-VEH and HFD-BPA mice and reduced in HFD-DES mice. HFD-BPA females increased perirenal and reduced gonadal fat weights. Reduced leptin and increased IL-6 in CD-BPA and CD-DES mice were not found in their HFD-cohorts. Adiponectin levels were similar. Thus, although chronic BPA exposure did not increase body size or increase glucose intolerance, it induced an adipokine imbalance in CD-fed mice and sex-specifically altered the lipid response and adipose deposition when fed the HFD.
| S-EPMC5598494 | biostudies-literature
Project description:The C57BL/6N inbred lines of mice are widely used in genetic research. They are particularly favoured in large scale studies such as the International Mouse Phenotyping Consortium (IMPC), where C57BL/6N mice are genetically altered to generate a collection of null alleles (currently more than 8500 null alleles have been generated). In this project, mice carrying null alleles are subjected to a pipeline of broad-based phenotyping tests to produce wide ranging phenotyping data on each model. We have previously described the development of a Home Cage Analysis system that automatically tracks the activity of group housed mice from a microchip inserted in the groin. This platform allows assessment of multiple biologically relevant phenotypes over long periods of time without experimenter interference, and therefore is particularly suited for high through-put studies. To investigate the impact of microchips on other tests carried out in the IMPC pipeline, we inserted microchips in 12 male and 12 female C57BL/6Ntac mice at seven weeks of age. Starting at nine weeks of age these mice underwent standard phenotyping tests, concurrently with 20 unchipped C57BL/6Ntac mice (10 females, 10 males). Tissues from a subset of the microchipped mice (six males and six females), chosen at random, were also sent for histopathological examination at the end of the phenotyping pipeline. No significant impact of insertion of microchip was observed in any of the phenotyping tests apart from bone mineral density measurement at DEXA due to the nature of the microchip. We therefore recommend that the microchip be inserted during the DEXA procedure, after the measurement is taken but before the mouse has recovered from the anaesthetic. This would avoid multiple anaesthetic exposures and prevent the potential variability in DEXA analysis output.
| S-EPMC7194481 | biostudies-literature
Project description:Aging is a risk factor for adipose tissue dysfunction, which is associated with inflammatory innate immune mechanisms. Since the adipose tissue/liver axis contributes to hepatosteatosis, we sought to determine age-related adipose tissue dysfunction in the context of the activation of the innate immune system fostering fatty liver phenotypes. Using wildtype and immune-deficient mice, we compared visceral adipose tissue and liver mass as well as hepatic lipid storage in young (ca. 14 weeks) and adult (ca. 30 weeks) mice. Adipocyte size was determined as an indicator of adipocyte function and liver steatosis was quantified by hepatic lipid content. Further, lipid storage was investigated under normal and steatosis-inducing culture conditions in isolated hepatocytes. The physiological age-related increase in body weight was associated with a disproportionate increase in adipose tissue mass in immune-deficient mice, which coincided with higher triglyceride storage in the liver. Lipid storage was similar in isolated hepatocytes from wildtype and immune-deficient mice under normal culture conditions but was significantly higher in immune-deficient than in wildtype hepatocytes under steatosis-inducing culture conditions. Immune-deficient mice also displayed increased inflammatory, adipogenic, and lipogenic markers in serum and adipose tissue. Thus, the age-related increase in body weight coincided with an increase in adipose tissue mass and hepatic steatosis. In association with a (pro-)inflammatory milieu, aging thus promotes hepatosteatosis, especially in immune-deficient mice.
| S-EPMC6721582 | biostudies-literature
Project description:The C57BL/6J and C57BL/6N mice have well-documented phenotypic and genotypic differences, including the infamous nicotinamide nucleotide transhydrogenase (Nnt) null mutation in the C57BL/6J substrain, which has been linked to cardiovascular traits in mice and cardiomyopathy in humans. To assess whether Nnt loss alone causes a cardiovascular phenotype, we investigated the C57BL/6N, C57BL/6J mice and a C57BL/6J-BAC transgenic rescuing NNT expression, at 3, 12, and 18 mo. We identified a modest dilated cardiomyopathy in the C57BL/6N mice, absent in the two B6J substrains. Immunofluorescent staining of cardiomyocytes revealed eccentric hypertrophy in these mice, with defects in sarcomere organisation. RNAseq analysis identified differential expression of a number of cardiac remodelling genes commonly associated with cardiac disease segregating with the phenotype. Variant calling from RNAseq data identified a myosin light chain kinase 3 (Mylk3) mutation in C57BL/6N mice, which abolishes MYLK3 protein expression. These results indicate the C57BL/6J Nnt-null mice do not develop cardiomyopathy; however, we identified a null mutation in Mylk3 as a credible cause of the cardiomyopathy phenotype in the C57BL/6N.
| S-EPMC7103425 | biostudies-literature
Project description:BackgroundHigh-fat diets promote hepatic lipid accumulation. Paradoxically, these diets also induce lipogenic gene expression in rodent liver. Whether high expression of these genes actually results in an increased flux through the de novo lipogenic pathway in vivo has not been demonstrated.Methodology/principal findingsTo interrogate this apparent paradox, we have quantified de novo lipogenesis in C57Bl/6J mice fed either chow, a high-fat or a n-3 polyunsaturated fatty acid (PUFA)-enriched high-fat diet. A novel approach based on mass isotopomer distribution analysis (MIDA) following 1-(13)C acetate infusion was applied to simultaneously determine de novo lipogenesis, fatty acid elongation as well as cholesterol synthesis. Furthermore, we measured very low density lipoprotein-triglyceride (VLDL-TG) production rates. High-fat feeding promoted hepatic lipid accumulation and induced the expression of lipogenic and cholesterogenic genes compared to chow-fed mice: induction of gene expression was found to translate into increased oleate synthesis. Interestingly, this higher lipogenic flux (+74 microg/g/h for oleic acid) in mice fed the high-fat diet was mainly due to an increased hepatic elongation of unlabeled palmitate (+66 microg/g/h) rather than to elongation of de novo synthesized palmitate. In addition, fractional cholesterol synthesis was increased, i.e. 5.8+/-0.4% vs. 8.1+/-0.6% for control and high fat-fed animals, respectively. Hepatic VLDL-TG production was not affected by high-fat feeding. Partial replacement of saturated fat by fish oil completely reversed the lipogenic effects of high-fat feeding: hepatic lipogenic and cholesterogenic gene expression levels as well as fatty acid and cholesterol synthesis rates were normalized.Conclusions/significanceHigh-fat feeding induces hepatic fatty acid synthesis in mice, by chain elongation and subsequent desaturation rather than de novo synthesis, while VLDL-TG output remains unaffected. Suppression of lipogenic fluxes by fish oil prevents from high fat diet-induced hepatic steatosis in mice.
| S-EPMC2699051 | biostudies-literature