Genetic background and diet induce hepatic gene expression of different regulatory pathways associated with obesity in the Collaborative Cross
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE185547 | GEO | 2022/08/24
REPOSITORIES: GEO
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Project description:High-protein diets are known to reduce adiposity in the context of high carbohydrate and Western diets. However, few studies have investigated the specific high-protein effect on lipogenesis induced by a high-sucrose (HS) diet or fat deposition induced by high-fat feeding. We aimed to determine the effects of high protein intake on the development of fat deposition and partitioning in response to high-fat and/or HS feeding. A total of thirty adult male Wistar rats were assigned to one of the six dietary regimens with low and high protein, sucrose and fat contents for 5 weeks. Body weight (BW) and food intake were measured weekly. Oral glucose tolerance tests and meal tolerance tests were performed after 4th and 5th weeks of the regimen, respectively. At the end of the study, the rats were killed 2 h after ingestion of a calibrated meal. Blood, tissues and organs were collected for analysis of circulating metabolites and hormones, body composition and mRNA expression in the liver and adipose tissues. No changes were observed in cumulative energy intake and BW gain after 5 weeks of dietary treatment. However, high-protein diets reduced by 20 % the adiposity gain induced by HS and high-sucrose high-fat (HS-HF) diets. Gene expression and transcriptomic analysis suggested that high protein intake reduced liver capacity for lipogenesis by reducing mRNA expressions of fatty acid synthase (fasn), acetyl-CoA carboxylase a and b (Acaca and Acacb) and sterol regulatory element binding transcription factor 1c (Srebf-1c). Moreover, ketogenesis, as indicated by plasma β-hydroxybutyrate levels, was higher in HS-HF-fed mice that were also fed high protein levels. Taken together, these results suggest that high-protein diets may reduce adiposity by inhibiting lipogenesis and stimulating ketogenesis in the liver. Adult male Wistar rats were fed diets with varying amounts of protein, carbohydrates and fat for 5 weeks. At the end of the experiment, rats were killed and tanscriptome analysis was performed on pooled liver samples.
2015-09-01 | E-GEOD-47570 | biostudies-arrayexpress
Project description:High-protein diets are known to reduce adiposity in the context of high carbohydrate and Western diets. However, few studies have investigated the specific high-protein effect on lipogenesis induced by a high-sucrose (HS) diet or fat deposition induced by high-fat feeding. We aimed to determine the effects of high protein intake on the development of fat deposition and partitioning in response to high-fat and/or HS feeding. A total of thirty adult male Wistar rats were assigned to one of the six dietary regimens with low and high protein, sucrose and fat contents for 5 weeks. Body weight (BW) and food intake were measured weekly. Oral glucose tolerance tests and meal tolerance tests were performed after 4th and 5th weeks of the regimen, respectively. At the end of the study, the rats were killed 2 h after ingestion of a calibrated meal. Blood, tissues and organs were collected for analysis of circulating metabolites and hormones, body composition and mRNA expression in the liver and adipose tissues. No changes were observed in cumulative energy intake and BW gain after 5 weeks of dietary treatment. However, high-protein diets reduced by 20 % the adiposity gain induced by HS and high-sucrose high-fat (HS-HF) diets. Gene expression and transcriptomic analysis suggested that high protein intake reduced liver capacity for lipogenesis by reducing mRNA expressions of fatty acid synthase (fasn), acetyl-CoA carboxylase a and b (Acaca and Acacb) and sterol regulatory element binding transcription factor 1c (Srebf-1c). Moreover, ketogenesis, as indicated by plasma β-hydroxybutyrate levels, was higher in HS-HF-fed mice that were also fed high protein levels. Taken together, these results suggest that high-protein diets may reduce adiposity by inhibiting lipogenesis and stimulating ketogenesis in the liver.
2015-09-01 | GSE47570 | GEO
Project description:Defined as chronic excessive accumulation of adiposity, obesity results from long-term imbalance between energy intake and expenditure. The mechanisms behind how caloric imbalance occurs are complex and influenced by numerous biological and environmental factors, especially genetics and diet. Population-based diet recommendations have had limited success partly due to the wide variation in physiological responses across individuals when they consume the same diet. Thus, it is necessary to broaden our understanding of how individual genetics and diet interact relative to the development of obesity for improving weight loss treatment. To determine how consumption of diets with different macronutrient composition alter adiposity and other obesity-related traits in a genetically diverse population, we analyzed body composition, metabolic rate, clinical blood chemistries, and circulating metabolites in 22 strains of mice from the Collaborative Cross (CC), a highly diverse recombinant inbred mouse population, before and after 8 weeks of feeding either a high protein or high fat high sucrose diet. At both baseline and post-diet, adiposity and other obesity-related traits exhibited a broad range of phenotypic variation based on CC strain; diet-induced changes in adiposity and other traits also depended largely on CC strain. In addition to estimating heritability at baseline, we also quantified the effect size of diet for each trait, which varied by trait and experimental diet. Our findings identified CC strains prone to developing obesity, demonstrate the genotypic and phenotypic diversity of the CC for studying complex traits, and highlight the importance of accounting for genetic differences when making dietary recommendations.
2020-11-05 | ST001607 | MetabolomicsWorkbench
Project description:Identification of molecular determinants of the inter-individual and sex variability in the development of nonalcoholic fatty liver disease (NAFLD) is of great importance. Next-generation sequencing (NGS) derived transcriptome profiling (RNA-seq) is a powerful technique to investigate gene transcripts and gene variants for the systems-based analysis of molecular and cellular pathways. The goal of this study was to determine transcriptomic profiles in the livers of male and female Collaborative Cross (CC) mice fed a high-fat and high-sucrose (HF/HS) diet or a control diet for 12 weeks and to identify inter-individual- and sex-specific gene expression differences during the development of NAFLD. Liver mRNA profiles of 10 CC mouse strains (CC003/Unc, CC011/Unc, CC013/GeniUnc, CC019/TauUnc, CC032/GeniUnc, CC040/TauUnc, CC041/TauUnc, CC042/GeniUnc, CC043/GeniUnc, and CC060/Unc) fed an HF/HS diet were generated by deep sequencing, in triplicate, using Illumina NextSeq 500 NGS system. The sequence reads that passed quality filters were analyzed at the transcript level using TopHat followed by Cufflinks. The total number of differentially expressed genes identified by RNA-seq varied between sexes and individual mouse strains and correlated with the severity of liver steatosis. Pathway analysis of differentially expressed genes showed dysregulation of genes involved in lipid metabolism, cell proliferation and death, inflammation, and fibrogenesis pathways in the livers of males and females CC mice. The RNA-seq data were validated and confirmed by qRT-PCR analysis of 27 selected genes associated with lipid metabolism and fibrogenesis using TaqMan assays. Our results show that RNA-seq based transcriptome analysis offers a comprehensive, quantitative, and qualitative evaluation of whole-genome expression that can be used for the identification of unique genes associated with the inter-individual and sex differences in susceptibility to NAFLD at the population level.
2020-05-05 | GSE149863 | GEO
Project description:The Collaborative Cross (CC) recombinant inbred panel was conceived as an ideal resource for mammalian system genetics. The pre-CC is a proof-of-concept experiment involving CC lines that have undergone at least five generations of inbreeding. Siblings from these lines were each involved in one of four distinct phenotyping arms, then genotyped on a high-density Affymetrix platform. The genetic profile of these emerging lines reveals high diversity, balanced allele frequencies, and well-distributed recombination – all ideal qualities for a mapping panel. We have mapped white spot, a discrete trait; body weight, a highly polygenic complex trait; and more than 11,000 liver gene expression traits. These analyses provide a glimpse of the potential mapping power and resolution of the CC. The goal of this project was to identify eQTLs for genome-wide gene expression from liver tissue in pre-CC mice. Gene expression profiling from liver tissue from pre-CC males. Pre-Collaborative Cross (CC) mice are partially inbred strains created by intercrossing eight founder (parental) strains: 129S1/SvImJ, (129S1), A/J (AJ), C57BL/6J (B6), CAST/Ei (CAST), NOD/LtJ (NOD), NZO/H1LtJ (NZO), PWK/Ph (PWK), and WSB/Ei (WSB). Sister-brother mating in 220 families was done for 4-11 generations. One animal was sampled from 157 pre-CC strain. Hybridizations were performed at the Gene Expression Core Facility at The Jackson Laboratory. Samples were divided in six batches of about 11 to 24 samples. Two batches were performed per day. Probe-level data was summarized by a custom CDF file based on Ensembl genes (NCBI 37, Ensembl 49; htttp://brainarray.mbni.med.umich.edu). The parental strains are not part of this submission.
2010-12-01 | E-GEOD-22297 | biostudies-arrayexpress
Project description:Obesity and associated increased prevalence of non-alcoholic fatty liver (NAFLD) disease is suggested to be positively modulated by a high protein (HP) diet in humans and rodents. The aim was to detect mechanisms by which a HP diet prevents hepatic lipid accumulation by means of transcriptomics. To study the acute and long term effect of a high protein ingestion on hepatic lipid accumulation under both low and high fat (HF) conditions, mice were fed combinations of high (35%) or low (10%) fat and high (50%) or normal (15%) protein diets for 1 or 12 weeks. Body composition, liver fat, VLDL production rate and gene expression were investigated. Differences in metabolic processes and functions in the liver were identified using gene set enrichment analysis on microarray data. Mice fed the HP diets developed less adiposity and decreased hepatic lipid accumulation due a combination of induced processes mainly involved in protein catabolism such as transamination, TCA cycle and oxidative phosphorylation. Feeding a HP diet can successfully prevent the development of NAFLD by using ingested energy for oxidation instead of storage.
2012-11-21 | GSE37897 | GEO
Project description:Obesity and associated increased prevalence of non-alcoholic fatty liver (NAFLD) disease is suggested to be positively modulated by a high protein (HP) diet in humans and rodents. The aim was to detect mechanisms by which a HP diet prevents hepatic lipid accumulation by means of transcriptomics. To study the acute and long term effect of a high protein ingestion on hepatic lipid accumulation under both low and high fat (HF) conditions, mice were fed combinations of high (35%) or low (10%) fat and high (50%) or normal (15%) protein diets for 1 or 12 weeks. Body composition, liver fat, VLDL production rate and gene expression were investigated. Differences in metabolic processes and functions in the liver were identified using gene set enrichment analysis on microarray data. Mice fed the HP diets developed less adiposity and decreased hepatic lipid accumulation due a combination of induced processes mainly involved in protein catabolism such as transamination, TCA cycle and oxidative phosphorylation. Feeding a HP diet can successfully prevent the development of NAFLD by using ingested energy for oxidation instead of storage. Wild type mice were fed combinations of high (35%) or low (10%) fat and high (50%) or normal (15%) protein diets for 1 or 12 weeks. After the diet intervention period, the animals were killed and liver tissue was removed. Total RNA was isolated, pooled and subjected to gene expression profiling.
2012-11-21 | E-GEOD-37897 | biostudies-arrayexpress
Project description:The Collaborative Cross (CC) recombinant inbred panel was conceived as an ideal resource for mammalian system genetics. The pre-CC is a proof-of-concept experiment involving CC lines that have undergone at least five generations of inbreeding. Siblings from these lines were each involved in one of four distinct phenotyping arms, then genotyped on a high-density Affymetrix platform. The genetic profile of these emerging lines reveals high diversity, balanced allele frequencies, and well-distributed recombination – all ideal qualities for a mapping panel. We have mapped white spot, a discrete trait; body weight, a highly polygenic complex trait; and more than 11,000 liver gene expression traits. These analyses provide a glimpse of the potential mapping power and resolution of the CC. The goal of this project was to identify eQTLs for genome-wide gene expression from liver tissue in pre-CC mice.
2010-12-01 | GSE22297 | GEO
Project description:Transcriptomic profiling of non-alcoholic fatty liver induced by a high-fat and high-sucrose diet in the genetically diverse Collaborative Cross mice.
| PRJNA630290 | ENA
Project description:We report that the HF/HS-mediated functional enrichment of genes of immunity and inflammation is driven toward normal by the AOF supplementation Obesity may not constantly associate with metabolic disorders and mortality later in life, raising the challenging concept of healthy obesity. Here, high fat-high sucrose (HF/HS) feeding produces hyperglycaemia and hypercholesterolemia, increases oxidative stress, elevates endotoxemia, expands adipose tissue (with enlarged adipocytes, macrophage infiltration and accumulation of cholesterol and oxysterols), and reduces lifespan of obese mice. Despite persistence of obesity, supplementation with an antioxidant formulation normalizes plasma lipids and endotoxemia, prevents macrophage recruitment in adipose tissue, reduces adipose accumulation of cholesterol and cholesterol oxides, and extends lifespan. The HF/HS-mediated functional enrichment of genes of immunity and inflammation (in particular response to lipopolysaccharides) is driven towards normal by the antioxidant formulation. It is concluded that the limitation of immune cell infiltration in adipose tissue on the long term by an antioxidant formulation can increase lifespan independently of body weight and fat storage. It constitutes the hallmark of a healthy adiposity trait.
2019-07-09 | GSE120748 | GEO