Leptin signal transduction underlies the differential metabolic response of LEW and WKY rats to cafeteria diet

Abstract

Although the effect of genetic background on obesity-related phenotypes is well established, the main objective of this study is to determine the phenotypic responses to cafeteria diet (CAF) of two genetically distinct inbred rat strains and give insight into the molecular mechanisms that might be underlying. Lewis (LEW) and Wistar-Kyoto (WKY) rats were fed with either a standard or a CAF diet. The effects of the diet and the strain in the body weight gain, food intake, respiratory quotient, biochemical parameters in plasma as well as in the expression of genes that regulate leptin signalling were determined. Whereas CAF diet promoted weight gain in LEW and WKY rats, as consequence of increased energy intake, metabolic management of this energy surplus was significantly affected by genetic background. LEW and WKY showed a different metabolic profile, LEW rats showed hyperglycaemia, hypertriglyceridemia and high FFA levels, ketogenesis, high adiposity index and inflammation, but WKY did not. Leptin signalling, and specifically the LepRb-mediated regulation of STAT3 activation and Socs3 gene expression in the hypothalamus were inversely modulated by the CAF diet in LEW (upregulated) and WKY rats (downregulated). In the present study, we show evidence of gene-environment interactions in obesity exerted by differential phenotypic responses to CAF diet between LEW and WKY rats. Specifically, we found the leptin-signalling pathway as a divergent point between the strain-specific adaptations to diet.

Identification of a nutrient sensing transcriptional network in monocytes by using inbred rat models of cafeteria diet

“…1. Experimental design used to study the role of inbred rat models in nutritional genomics. The phenotypic response (described previously in Martínez-Micaelo et al, 2016) shows a differential susceptibility of LEW and WKY rats to the CAF diet. Here, we studied the differential modulation of the peripheral monocyte transcriptome of LEW and WKY rats by the CAF diet, as consequence of the prone and resistant responses of LEW and WKY rats, respectively, to the diet-induced obesity.…”

“…Based on our previous results (Martínez-Micaelo et al, 2016), although both strains showed increased weight gain and adiposity in response to the CAF diet, plasma metabolic profiling evidenced contrasting phenotypic responses. Indeed, CAF diet challenge induced hyperglycaemia, hypertriglyceridaemia and higher levels of NEFAs in LEW rats, which was not the case for WKY rats.…”

“…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). Strain-specific differences were also observed in the modulation of the circulating levels of inflammatory biomarkers.…”

“…See Fig. 1 and Martínez-Micaelo et al (2016) for more detailed experimental design. Heparinised plasma was obtained by centrifugation from blood samples and stored at −80°C until analysis.…”

“…Hence, by comparing the responses of Lewis (LEW) and Wistar Kyoto (WKY) rats to an obesogenic diet, we recently showed significant differences in metabolic and morphometric parameters (Martínez-Micaelo et al, 2016). Specifically, our results suggested the leptin signalling pathway as a divergent point between the strain-specific adaptations to CAF diet.…”