Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of mouse small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J strain.

ABSTRACT: Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. To gain more insight in the role of the small intestine in the etiology of these metabolic disorders, a microarray study was performed on small intestines (SI) of C57BL/6J mice that were fed a high fat diet mimicking the fatty acid composition of a Western-style human diet. The mice became obese and developed dietary fat-induced glucose intolerance. For gene expression profiling, the small intestines were subdivided in three equal parts along the longitudinal axis. The most pronounced effects of dietary fat were detected in part 2 of the small intestine. The biological processes that were most extensively modulated on a high fat diet were related to lipid metabolism, especially Î²- and Ï-fatty acid oxidation seemed to play an important role, cell cycle and inflammation/immune response. An additional secretome analysis revealed differentially expressed secreted proteins, such as Il18, Ffgf15, Mif, Igfbp3 and Angptl4, which might provoke systemic effects in peripheral organs by influencing their metabolic homeostasis. Furthermore, many of the dietary fat-modulated genes and biological processes in small intestine were previously already associated with obesity and/or insulin resistance. Together, the data of this exploratory study provided various leads for an essential role of the small intestine in development of obesity and/or insulin resistance. Experiment Overall Design: After a run-in period of 3 weeks on a low-fat diet, 9 weeks old mice were fed a high- (HF) or a low-fat (LF) purified diet for 2, 4, and 8 weeks (n=6 per diet, per time point). Body weight was recorded weekly and after 7 weeks of diet intervention an oral glucose tolerance test was performed. At the end of the experiment, mice were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%). The small intestines were excised and the adhering fat and pancreatic tissue were carefully removed. The small intestines were divided in three equal parts along the proximal to distal axis (SI 1, SI 2 and SI 3).

ORGANISM(S): Mus musculus

SUBMITTER: Guido Hooiveld

PROVIDER: E-GEOD-8582 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice.

de Wit Nicole Jw NJ Bosch-Vermeulen Hanneke H de Groot Philip J PJ Hooiveld Guido Jej GJ Bromhaar Mechteld M Grootte MM Jansen Jenny J Müller Michael M van der Meer Roelof R

BMC medical genomics 20080506

<h4>Background</h4>Obesity and insulin resistance are two major risk factors underlying the metabolic syndrome. The development of these metabolic disorders is frequently studied, but mainly in liver, skeletal muscle, and adipose tissue. To gain more insight in the role of the small intestine in development of obesity and insulin resistance, dietary fat-induced differential gene expression was determined along the longitudinal axis of small intestines of C57BL/6J mice.<h4>Methods</h4>Male C57BL/ ...[more]

PMID: 18457598

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Project description:We studied the effect of dietary fat type, varying in polyunsaturated/saturated fatty acid ratio's (P/S) on development of metabolic syndrome. C57Bl/6J mice were fed purified high-fat diets (45E% fat) containing palm oil (HF-PO; P/S 0.4), olive oil (HF-OO; P/S 1.1) or safflower oil (HF-SO; P/S 7.8) for 8 weeks. A low-fat palm oil diet (LF-PO; 10E% fat) was used as a reference. Additionally, we analyzed diet-induced changes in gut microbiota composition and mucosal gene expression. The HF-PO diet induced a higher body weight gain and liver triglyceride content compared to the HF-OO, HF-SO or LF-PO diet. In the intestine, the HF-PO diet reduced microbial diversity and increased the Firmicutes/Bacteroidetes ratio. Although this fits a typical obesity profile, our data clearly indicate that an overflow of the HF-PO diet to the distal intestine, rather than obesity itself, is the main trigger for these gut microbiota changes. A HF-PO diet-induced elevation of lipid metabolism-related genes in the distal small intestine confirmed the overflow of palm oil to the distal intestine. Some of these lipid metabolism-related genes were previously already associated with the metabolic syndrome. In conclusion, our data indicate that saturated fat (HF-PO) has a more stimulatory effect on weight gain and hepatic lipid accumulation than unsaturated fat (HF-OO and HF-SO). The overflow of fat to the distal intestine on the HF-PO diet induced changes in gut microbiota composition and mucosal gene expression. We speculate that both are directly or indirectly contributive to the saturated fat-induced development of obesity and hepatic steatosis. Keywords: Diet intervention study Nine-week-old C57Bl/6J mice were fed a low-fat diet (LF-PO) and three different types of high-fat diet, based on palm oil (HF-PO; P/S1.0), olive oil (HF-OO; P/S4.6) and safflower oil (HF-SO; P/S10.1) for 8 weeks. Body weight was recorded weekly and after 7 weeks of diet intervention an oral glucose tolerance test was performed. After 2 weeks of diet intervention, 6 mice per high-fat diet group were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%) and the small intestines were excised. Adhering fat and pancreatic tissue were carefully removed. The small intestines were divided in three equal parts along the proximal to distal axis (SI 1, SI 2 and SI 3) and microarray analysis was performed on mucosal scrapings.

Project description:There is increased interest in the potential protective role of dietary Ca in the development of metabolic disorders related to the metabolic syndrome. Ca-induced intestinal precipitation of fatty acids and bile acids as well as systemic metabolic effects of Ca on adipose tissue is proposed to play a causal role. In this experiment, we have studied all these aspects to validate the suggested protective effect of Ca supplementation, independent of other dietary changes, on the development of diet-induced obesity and insulin resistance. In our diet intervention study, C57BL/6J mice were fed high-fat diets differing in Ca concentrations (50 v. 150 mmol/kg). Faecal excretion analyses showed an elevated precipitation of intestinal fatty acids (2·3-fold; P < 0·01) and bile acids (2-fold; P < 0·01) on the high-Ca diet. However, this only led to a slight reduction in fat absorption (from 98 to 95 %; P < 0·01), mainly in the distal small intestine as indicated by gene expression changes. We found no effect on body-weight gain. Lipolysis and lipogenesis-related parameters in adipose tissue also showed no significant changes on the high-Ca diet, indicating no systemic effects of dietary Ca on adiposity. Furthermore, early gene expression changes of intestinal signaling molecules predicted no protective effect of dietary Ca on the development of insulin resistance, which was confirmed by equal values for insulin sensitivity on both diets. Taken together, our data do not support the proposed protective effect of dietary Ca on the development of obesity and/or insulin resistance, despite a significant increase in fecal excretion of fatty acids and bile acids. Keywords: Diet intervention study Nine-week-old mice were fed a high fat purified diet with a low calcium concentration of 50mmol/kg (LCa diet) or a high calcium concentration of 150mmol/kg (HCa diet) for 8 weeks. Body weight was recorded weekly and after 7 weeks of diet intervention an oral glucose tolerance test was performed. For microarray analysis, after 2 weeks of diet intervention, 6 mice per diet group were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%) and the small intestines were excised. Adhering fat and pancreatic tissue were carefully removed. The small intestines were divided in three equal parts along the proximal to distal axis (SI 1, SI 2 and SI 3) and microarray analysis was performed on pooled mucosal scrapings.

Project description:By regulating digestion and absorption of nutrients and providing a barrier against the external environment the intestine provides a crucial contribution to the maintenance of health. To what extent aging-related changes in the intestinal system contribute to the impaired health of the aging body is still under debate. Young (4 months) and old (21 months) male C57BL/6J mice were fed a control low-fat (10E%) or a high-fat diet (45E%) for 2 weeks. During the intervention gross energy intake and energy excretion in the feces were measured. After sacrifice the small and large intestine were isolated whereby the small intestine was divided in three equal parts. Of each of the isolated segments Swiss rolls were prepared for histological analysis and the luminal content was isolated to examine alterations in the microflora with 16S rRNA Q-PCR. Furthermore, mucosal scrapings were isolated from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing. Digestible energy intake was similar between the two age groups on both the control and the high-fat diet implying that macronutrient metabolism is not affected in 21-month-old mice. This observation was supported by the fact that the microarray analysis on RNA from intestinal scrapings showed no marked changes in expression of genes involved in metabolic processes. Decreased expression of Cubilin was observed in the intestine of 21-month-old mice, which might contribute to aging-induced vitamin B12 deficiency. Furthermore, microarray data analysis revealed enhanced expression of a high number of genes involved in immune response and inflammation in the colon, but not in the small intestine of the 21-month-old mice. Aging-induced global hypomethylation was observed in the colon and the distal part of the small intestine, but not in the first two sections of the small intestine. In 21-month old mice the most pronounced effects of aging was observed in the colon, limited changes were observed in the small intestine. Young (4 months) and old (21 months) C57BL/6J mice were fed a low-fat (10E%) diet or high-fat (45%E) diet for 2 weeks. After the diet intervention period, the animals were killed and scrapings were made of the proximal, middle and distal part of the small intestine. Total RNA was isolated, pooled and subjected to gene expression profiling.

Project description:An 8-week high fat palm oil diet causes obesity and insulin resistance in C57BL/6J mice, but induces only small changes in the muscle transcriptome. Introduction: The metabolic syndrome (MS) is a cluster of metabolic abnormalities linked to an increased risk of type 2 diabetes and cardiovascular diseases. Two major characteristics of the MS are obesity and insulin resistance. In the present study we investigated the effect of obesity and insulin resistance on the mouse muscle transcriptome. Methods: C57BL/6J mice were fed a palm oil-based low fat diet (LFD) or high fat diet (HFD) for eight weeks. Microarray analysis was performed by using two complementary strategies: (1) 8-week HFD transcriptome versus 8-week LFD transcriptome and (2) transcriptome of mice sacrificed at the start of the intervention versus 8-week LFD transcriptome and 8-week HFD transcriptome, respectively. Results: HFD mice develop obesity and whole-body insulin resistance. Despite these metabolic disturbances we found that HFD induces relatively small changes in gene expression (< 1.3 fold). Only the up-regulation of FA oxidation and the down-regulation of the MAPK cascade were specific for the HFD intervention. Eight-weeks of aging induced more changed gene expression levels than the HFD, including genes involved in cell-cell interaction and development. Conclusion: Eight weeks of aging induce more pronounced changes in the muscle transcriptome than an HFD. Since only one strategy revealed the transcriptional down-regulation of the MAPK cascade, whereas both strategies showed the up-regulation of FA oxidation we suggest the use of complementary analysis strategies by the genome-wide search of gene expression changes induced by mild interventions, such as an HFD. Keywords: diet intervention and time course In this study, C57BL/6J mice were fed a high fat (HF) diet for 8 weeks to induce obesity and insulin resistance. Plasma levels of the adipokines leptin and adiponectin were measured. To investigate how these metabolic disturbances will influence the skeletal muscle transcriptome we performed whole-genome microarray analysis. Functional implications were assessed by analyses of predefined gene sets based on Gene Ontology, biochemical, metabolic and signaling pathways.

Project description:By regulating digestion and absorption of nutrients and providing a barrier against the external environment the intestine provides a crucial contribution to the maintenance of health. To what extent aging-related changes in the intestinal system contribute to the impaired health of the aging body is still under debate. Young (4 months) and old (21 months) male C57BL/6J mice were fed a control low-fat (10E%) or a high-fat diet (45E%) for 2 weeks. During the intervention gross energy intake and energy excretion in the feces were measured. After sacrifice the small and large intestine were isolated whereby the small intestine was divided in three equal parts. Of each of the isolated segments Swiss rolls were prepared for histological analysis and the luminal content was isolated to examine alterations in the microflora with 16S rRNA Q-PCR. Furthermore, mucosal scrapings were isolated from each segment to determine differential gene expression by microarray analysis and global DNA methylation by pyrosequencing. Digestible energy intake was similar between the two age groups on both the control and the high-fat diet implying that macronutrient metabolism is not affected in 21-month-old mice. This observation was supported by the fact that the microarray analysis on RNA from intestinal scrapings showed no marked changes in expression of genes involved in metabolic processes. Decreased expression of Cubilin was observed in the intestine of 21-month-old mice, which might contribute to aging-induced vitamin B12 deficiency. Furthermore, microarray data analysis revealed enhanced expression of a high number of genes involved in immune response and inflammation in the colon, but not in the small intestine of the 21-month-old mice. Aging-induced global hypomethylation was observed in the colon and the distal part of the small intestine, but not in the first two sections of the small intestine. In 21-month old mice the most pronounced effects of aging was observed in the colon, limited changes were observed in the small intestine. Young (4M) and old (21M) wild type C57BL/6J mice were fed a low-fat diet or high-fat diet for 2 weeks. After the diet intervention period, the animals were killed and scrapings were made of the colon. Total RNA was isolated and subjected to gene expression profiling.

Dataset Information

Transcription profiling of mouse small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J strain.

Publications

The role of the small intestine in the development of dietary fat-induced obesity and insulin resistance in C57BL/6J mice.

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