Maternal Alcohol Dehydrogenase 1 Heterozygosity Drives Resistance of Offspring to Weight Gain

OBJECTIVES: Prior research has shown that Alcohol Dehydrogenase 1 (ADH1) polymorphisms affect body weight and adiposity. We observed that wild-type mice offspring from heterozygous Adh1 (Adh1(+/−)) intercrosses were resistant to weight gain. The objective of this study was to determine the mechanisms that underlie this observation. METHODS: We monitored the body composition of wild-type mice consuming a high-fat diet (60% calories from fat) from three specific parental crosses Adh1(+/−)dam x Adh1(+/−)sire (n = 8), Adh1(+/−)dam crossed with wild type C57Bl/6J (B6) sire (n = 10), and B6 dam x Adh1(+/−)sire (n = 5). Tissues were collected at the end of the 8-week period and RNA sequencing was performed on liver tissue of wild-type offspring. Gene Set Enrichment Analysis (GSEA) was conducted using the Hallmark & Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. Expression changes in a subset of genes were validated using quantitative reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: Maternal Adh1(+/)(−) genotype, but not paternal Adh1(+/)(−) genotype, leads to weight-gain resistant wild-type offspring. Additionally, wild-type offspring from Adh1(+/)(−) dams exhibited decreased epididymal adipose tissue mass (p = 0.03) and lower plasma total cholesterol (p = 0.03). Sequencing of liver RNA demonstrated that wild-type offspring from Adh1(+/)(−) dams exhibited negative enrichment in gene pathways associated with oxidative phosphorylation and fatty acid metabolism, and positive enrichment in pathways associated with cholesterol homeostasis. Genes of interest that were downregulated include JUN, ANGPTL4, IGFBP1, CD36, and upregulated include FZDZ and RARA. CONCLUSIONS: Adh1 heterozygosity is associated with resistance to adiposity gain in wild-type offspring exposed to a high-fat diet. Differences in gene expression in the liver suggest that changes in oxidative phosphorylation and fatty acid metabolism in these offspring could be moderating the decreased adiposity. FUNDING SOURCES: None.