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

ABSTRACT: BACKGROUND: 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. METHODS: Male C57BL/6J mice were fed a low-fat or a high-fat diet that mimicked the fatty acid composition of a Western-style human diet. After 2, 4 and 8 weeks of diet intervention small intestines were isolated and divided in three equal parts. Differential gene expression was determined in mucosal scrapings using Mouse genome 430 2.0 arrays. RESULTS: The high-fat diet significantly increased body weight and decreased oral glucose tolerance, indicating insulin resistance. Microarray analysis showed that dietary fat had the most pronounced effect on differential gene expression in the middle part of the small intestine. By overrepresentation analysis we found that the most modulated biological processes on a high-fat diet were related to lipid metabolism, cell cycle and inflammation. Our results further indicated that the nuclear receptors Ppars, Lxrs and Fxr play an important regulatory role in the response of the small intestine to the high-fat diet. Next to these more local dietary fat effects, a secretome analysis revealed differential gene expression of secreted proteins, such as Il18, Fgf15, Mif, Igfbp3 and Angptl4. Finally, we linked the fat-induced molecular changes in the small intestine to development of obesity and insulin resistance. CONCLUSION: During dietary fat-induced development of obesity and insulin resistance, we found substantial changes in gene expression in the small intestine, indicating modulations of biological processes, especially related to lipid metabolism. Moreover, we found differential expression of potential signaling molecules that can provoke systemic effects in peripheral organs by influencing their metabolic homeostasis. Many of these fat-modulated genes could be linked to obesity and/or insulin resistance. Together, our data provided various leads for a causal role of the small intestine in the etiology of obesity and/or insulin resistance.

SUBMITTER: de Wit NJ

PROVIDER: S-EPMC2396659 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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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:A high caloric diet, in conjunction with low levels of physical activity, promotes obesity. Many studies are available regarding the relation between dietary saturated fats and the etiology of obesity, but most focus on liver, muscle and white adipose tissue. Furthermore, the majority of transcriptomic studies seek to identify linear effects of an external stimulus on gene expression, although such an assumption does not necessarily hold. Our work assesses the dose-dependent effects of dietary fat intake on differential gene expression in the proximal, middle and distal sections of the small intestine in C57BL/6J mice. Gene expression is analyzed in terms of either linear or nonlinear responses to fat intake.The highest number of differentially expressed genes was observed in the middle section. In all intestine sections, most of the identified processes exhibited a linear response to increasing fat intake. The relative importance of logarithmic and exponential responses was higher in the proximal and distal sections, respectively. Functional enrichment analysis highlighted a constantly linear regulation of acute-phase response along the whole small intestine, with up-regulation of Serpina1b. The study of gene expression showed that exponential down-regulation of cholesterol transport in the middle section is coupled with logarithmic up-regulation of cholesterol homeostasis. A shift from linear to exponential response was observed in genes involved in the negative regulation of caspase activity, from middle to distal section (e.g., Birc5, up-regulated).The transcriptomic signature associated with inflammatory processes preserved a linear response in the whole small intestine (e.g., up-regulation of Serpina1b). Processes related to cholesterol homeostasis were particularly active in the middle small intestine and only the highest fat intake down-regulated cholesterol transport and efflux (with a key role played by the down-regulation of ATP binding cassette transporters). Characterization of nonlinear patterns of gene expression triggered by different levels of dietary fat is an absolute novelty in intestinal studies. This approach helps identifying which processes are overloaded (i.e., positive, logarithmic regulation) or arrested (i.e., negative, exponential regulation) in response to excessive fat intake, and can shed light on the relationships linking lipid intake to obesity and its associated molecular disturbances.

Project description: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).

Project description:BackgroundTo date, there is only scare evidence characterizing the temporal features and progression of metabolic dysfunction in high-fat diet (HFD)-fed obese mice. Hence, its specific pathogenesis remains unclear.MethodsSixty 6-week-old male C57BL/6J mice were randomly divided into HFD and control diet (CD) groups and sacrificed at 1, 5, 9, 13, 17, and 21 weeks, respectively. At weekly intervals, intraperitoneal glucose tolerance testing (IPGTT) and intraperitoneal insulin tolerance testing (IPITT) were performed in both groups. A detailed time course in HFD-fed mice was investigated by evaluating the initiation of glucose homeostasis impairment, dyslipidemia, systemic insulin sensitivity, monocyte chemoattractant protein-1 (MCP-1) levels, epididymal white adipose tissue (eWAT) expansion, macrophage content changes, pro-inflammatory (M1)/anti-inflammatory (M2) macrophage imbalance, lipid accumulation in the liver, and β-cell morphometry in the pancreas.ResultsIn the HFD group, progressive weight gain and impairments in glucose metabolism (elevated fasting blood glucose and area under the curve (AUC) of IPGTT) were observed from the 3rd week, and a significantly elevated AUC of IPITT was first detected after week 7 of HFD feeding. As for dyslipidemia, after 9 weeks of feeding, the low-density lipoprotein cholesterol level and total cholesterol level in HFD group were significantly higher than those in the CD group (all P < 0.05), whereas no significant differences were shown in triglyceride level. Adipocyte size increased significantly in the HFD group in the 1st week, a phenotypic switch in eWAT from anti-inflammatory (M2) to pro-inflammatory (M1) macrophages was observed in the 5th week, and the metabolic inflammation was distinct in eWAT in the 9th week. Additionally, liver steatosis was considerably obvious at the 17th week and pancreatic β-cell morphometry did not change during 21 weeks of HFD feeding.ConclusionThe eWAT expansion was detected early in HFD-induced obese mice, which occurred prior to obvious insulin resistance.

Dataset Information

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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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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