Abstract
ABSTRACTObesity has reached pandemic levels worldwide. The current models of diet-induced obesity in rodents use predominantly high-fat based diets that do not take into account the consumption of variety of highly palatable, energy-dense foods that are prevalent in Western society. We and others have shown that the cafeteria (CAF) diet is a robust and reproducible model of human metabolic syndrome with tissue inflammation in the rat. We have previously shown that inbred rat strains such as Wistar Kyoto (WKY) and Lewis (LEW) show different susceptibilities to CAF diets with distinct metabolic and morphometric profiles. Here, we show a difference in plasma MCP-1 levels and investigate the effect of the CAF diet on peripheral blood monocyte transcriptome, as powerful stress-sensing immune cells, in WKY and LEW rats. We found that 75.5% of the differentially expressed transcripts under the CAF diet were upregulated in WKY rats and were functionally related to the activation of the immune response. Using a gene co-expression network constructed from the genes differentially expressed between CAF diet-fed LEW and WKY rats, we identified acyl-CoA synthetase short-chain family member 2 (Acss2) as a hub gene for a nutrient-sensing cluster of transcripts in monocytes. The Acss2 genomic region is significantly enriched for previously established metabolism quantitative trait loci in the rat. Notably, monocyte expression levels of Acss2 significantly correlated with plasma glucose, triglyceride, leptin and non-esterified fatty acid (NEFA) levels as well as morphometric measurements such as body weight and the total fat following feeding with the CAF diet in the rat. These results show the importance of the genetic background in nutritional genomics and identify inbred rat strains as potential models for CAF-diet-induced obesity.
Highlights
IntroductionObesity represents an important health problem in human populations and there is need for new animal models that mimic optimally the main characteristics of human obesity
The metabolic response of LEW and Wistar Kyoto (WKY) rats to CAF diet is strain dependent We have previously shown in detail strain-specific phenotypic differences in CAF-diet-induced obesity in LEW and WKY rats (Martínez-Micaelo et al, 2016)
The CAF diet provoked a significant increase in the levels of MCP-1 in LEW rats (241.29±13.0 versus 297.97±11.9, mean±s.d., n=5, P=0.017), no dietary effects were observed in the circulating MCP-1 levels in WKY rats (273.57±22.0 versus 305.10±10.9, P=0.263)
Summary
Obesity represents an important health problem in human populations and there is need for new animal models that mimic optimally the main characteristics of human obesity. LEW rats display a typical obesity phenotype, characterised by an increase in body weight, adiposity and dyslipidaemic and hyperglycaemic profiles, accompanied by a preferential metabolisation of carbohydrates, as opposed to WKY rats, which preferentially metabolised lipids. Despite their body weight and adiposity gain, WKY rats maintained metabolic homeostasis as a result of the obesogenic diet showing a differential regulation in the leptin axis
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