Dataset Information

An accelerated mouse model for atherosclerosis and adipose tissue inflammation.

ABSTRACT:

Background

Obesity and particularly the metabolic syndrome, which is often associated with obesity, combine a major risk for type 2 diabetes and cardiovascular disease. Emerging evidence indicate obesity-associated subclinical inflammation primarily originating from adipose tissue as a common cause for type 2 diabetes and cardiovascular disease. However, a suitable and well-characterized mouse model to simultaneously study obesity-associated metabolic disorders and atherosclerosis is not available yet. Here we established and characterized a murine model combining diet-induced obesity and associated adipose tissue inflammation and metabolic deteriorations as well as atherosclerosis, hence reflecting the human situation of cardio-metabolic disease.

Methods

We compared a common high-fat diet with 0.15% cholesterol (HFC), and a high-fat, high-sucrose diet with 0.15% cholesterol (HFSC) fed to LDL receptor-deficient (LDLR-/-) mice. Insulin resistance, glucose tolerance, atherosclerotic lesion formation, hepatic lipid accumulation, and inflammatory gene expression in adipose tissue and liver were assessed.

Results

After 12-16 weeks, LDLR-/- mice fed HFSC or HFC developed significant diet-induced obesity, adipose tissue inflammation, insulin resistance, and impaired glucose tolerance compared to lean controls. Notably, HFSC-fed mice developed significantly higher adipose tissue inflammation in parallel with significantly elevated atherosclerotic lesion area compared to those on HFC. Moreover, LDLR-/- mice on HFSC showed increased insulin resistance and impaired glucose tolerance relative to those on HFC. After prolonged feeding (20 weeks), however, no significant differences in inflammatory and metabolic parameters as well as atherosclerotic lesion formation were detectable any more between LDLR-/- mice fed HFSC or HFC.

Conclusion

The use of high sucrose rather than more complex carbohydrates in high-fat diets significantly accelerates development of obesity-driven metabolic complications and atherosclerotic plaque formation parallel to obesity-induced adipose tissue inflammation in LDLR-/- mice. Hence LDLR-/- mice fed high-fat high-sucrose cholesterol-enriched diet appear to be a suitable and time-saving animal model for cardio-metabolic disease. Moreover our results support the suggested interrelation between adipose tissue inflammation and atherosclerotic plaque formation.

SUBMITTER: Neuhofer A

PROVIDER: S-EPMC3902066 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

An accelerated mouse model for atherosclerosis and adipose tissue inflammation.

Neuhofer Angelika A Wernly Bernhard B Leitner Lukas L Sarabi Alisina A Sommer Nicole G NG Staffler Günther G Zeyda Maximilian M Stulnig Thomas M TM

Cardiovascular diabetology 20140117

<h4>Background</h4>Obesity and particularly the metabolic syndrome, which is often associated with obesity, combine a major risk for type 2 diabetes and cardiovascular disease. Emerging evidence indicate obesity-associated subclinical inflammation primarily originating from adipose tissue as a common cause for type 2 diabetes and cardiovascular disease. However, a suitable and well-characterized mouse model to simultaneously study obesity-associated metabolic disorders and atherosclerosis is not ...[more]

PMID: 24438079

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Project description:Fat inflammation may play an important role in comorbidities associated with obesity such as atherosclerosis.To first establish feasibility of fat transplantation, epididymal fat pads were harvested from wild-type C57BL/6J mice and transplanted into leptin-deficient (Lep(ob/ob)) mice. Fat transplantation produced physiological leptin levels and prevented obesity and infertility in Lep(ob/ob) mice. However, the transplanted fat depots were associated with chronically increased macrophage infiltration with characteristics identical to those observed in fat harvested from obese animals. The inflammation in transplanted adipose depots was regulated by the same factors that have been implicated in endogenous fat inflammation such as monocyte chemoattractant protein-1. To determine whether this inflamed adipose depot could affect vascular disease in mice, epididymal fat depots were transplanted into atherosclerosis-prone apolipoprotein E-deficient ApoE(-/-) mice. Plasma from ApoE(-/-) mice receiving fat transplants contained increased leptin, resistin, and monocyte chemoattractant protein-1 compared with plasma from sham-operated ApoE(-/-) mice. Furthermore, mice transplanted with visceral fat developed significantly more atherosclerosis compared with sham-operated animals, whereas transplants with subcutaneous fat did not affect atherosclerosis despite a similar degree of fat inflammation. Treatment of transplanted ApoE(-/-) mice with pioglitazone decreased macrophage content of the transplanted visceral fat pad and reduced plasma monocyte chemoattractant protein-1. Importantly, pioglitazone also reduced atherosclerosis triggered by inflammatory visceral fat but had no protective effect on atherosclerosis in the absence of the visceral fat transplantation.Our results indicate that visceral adipose-related inflammation accelerates atherosclerosis in mice. Drugs such as thiazolidinediones might be a useful strategy to specifically attenuate the vascular disease induced by visceral inflammatory fat.

Project description:Adipose tissue inflammation and atherosclerosis are the main mechanisms behind type 2 diabetes and cardiovascular disease respectively, the major risks associated with the metabolic syndrome. Studies considering more than single factors behind the complexity of the metabolic syndrome are valuable to achieve a better and wider understanding of the metabolic syndrome. In this study common dysregulated pathways between adipose tissue inflammation and atherosclerosis were identified using two different bioinformatic tools to perform pathway analysis. First, we run a gene set enrichment analysis utilizing with data from two microarray experiments done with gonadal white adipose tissue and atherosclerotic aorta. Once the common dysregulated pathways between both tissues were identify, the inflammatory response and the oxidative phosphorylation pathways from the Hallmark geneset were selected to conduct a deeper checkup at the single gene level of these pathways. Second, we carried out a pathway analysis validation with the Pantherâ¢ software combining the microarray data with a published type 2 diabetes mellitus metanalysis and cardiovascular disease metanalysis which included human data. In conclusion, this study provides worthwhile data pointing out and describing several dysregulated and common pathways in adipose tissue inflammation and atherosclerotic aorta with a potential implication in the pathogenesis of type 2 diabetes and atherosclerosis. LDLR-/- on a C57BL/6J background, purchased from Charles River Laboratories (Sulzfeld, Germany) were used. At 9 weeks of age the LDLR-/- were placed for up to 20 weeks on sucrose-enriched high-fat diet (HFSC) (with 17.5 kcal% from sucrose; (D09071704, Research Diets Inc.). Their respective controls were kept on normal chow diet (NC) for up to 20 weeks. After sacrificing the gonadal white adipose tissue (GWAT) from LDLR-/- animals on NC (Samples 22-27) or HFSC (Samples 28-33) was collected as well as the whole aortae from LDLR-/- animals on NC (Samples 13-15) or HFSC (Samples16-18). The collected tissues were immediately snap frozen in liquid nitrogen. RNA was isolated for gene expression microarray analyses at the exon level (GeneChip Mouse Exon 2.0 ST Array, Affymetrix, Santa Clara, CA, USA). To isolate RNA, the frozen tissue samples were homogenized in TRIzolÂ® reagent (Invitrogen/Life Technologies, Carlsbad, CA, USA) and processed based on manufacturerâs instructions. Total RNA (1Î¼g) was then used for GeneChip analysis, individual samples were used in GWAT preparation and three samples were pooled and used for aorta preparations. Terminal-labeled cDNA, hybridization to genome-wide Mouse Gene 2.0 ST Gene Chips and scanning of the arrays were carried out according to the manufactureâs indications (Affymetrix).Output primary row data was analyzed with Expression Console software (Affymetrix).

Dataset Information

An accelerated mouse model for atherosclerosis and adipose tissue inflammation.

Background

Methods

Results

Conclusion

Publications

An accelerated mouse model for atherosclerosis and adipose tissue inflammation.

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