Locus-specific epigenetic changes associated with peripheral leptin resistance in increased resistance to a high-fat diet in mice born to obese mothers fed a control diet during gestation
2013
Attig, Linda | Jais, J.P. | Vigé, A. | Beauger, Aurore | Gross, M.S. | Gallou-Kabani, C. | Gothié, J.D. | Gabory, Anne | Jouneau, Luc | Junien, Claudine
Epigenetic mechanisms are evoked to explain interindividual and across-generation variations in the proneness or resistance to develop diet-induced obesity (DIO) of inbred C57BL/6J mice even under the same high-fat diet.1,2 Feeding obese and diabetic mothers a control diet during the periconceptional/gestation/ lactation period led to a pronounced sex-specific shift from proneness to resistance to DIO in the offspring.3 In this study, Affymetrix microarrays highlighted the prominent role of leptin–leptin receptor cytokine pathways and a cross-talk between muscle and liver. The top-ranking genes were the leptin (Lep) gene upregulated in muscle, and the leptin receptor (Lepr) and suppressor of cytokine signaling 2 (Socs2) genes drastically downregulated in liver only. Weight-gain proneness as opposed to resistance was associated in muscle with an inflammatory process related to altered levels of adipokines, and in liver with an altered lipid processing and increased lipid droplets formation, suggesting a strong connection of Lepr and Socs2 to fat metabolism. Locus-specific epigenetic analyses by bisulfite-pyrosequencing and ChIP PCR of Lep, Lepr and Socs2 revealed a role for specific CpG methylation and histone acetylation and methylation marks in the tissue-specific regulation of these genes with specific profiles associated with the obesity-prone phenotype, whereas resistant mice epigenetic landscapes evoked a strong tendency toward ‘normality’. Emphasizing the hitherto unsuspected role of Lepr gene expression in peripheral leptin resistance4 and its liver specificity, this work is the first to describe epigenetic changes in Lepr associated with its downregulation as potentially useful markers in the follow-up of leptin resistance treatment in obese patients.
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