Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
FASEB J. 2019 May;33(5):6269-6280. doi: 10.1096/fj.201801879RR. Epub 2019 Feb 15.
Paternal preconceptional high-fat diet (HFD) alters whole-body glucose and energy homeostasis over several generations, which may be mediated by altered transcriptomic profiles of metabolic organs. We investigated the effect of paternal HFD on the hepatic transcriptomic and metabolic signatures of female grand-offspring. Paternal HFD strongly impacted the liver transcriptome of the second-generation offspring. Gene set enrichment analysis (GSEA) revealed grandpaternal-HFD altered the TNF-α signaling NFκB pathway, independent of the grand-offspring's diet. Reduction in the hepatic cytokine levels, including the TNF-α, as well as NFκB content and activity, suggest that the basal inflammatory response in F2 rats is disturbed. GSEA also show altered expression of various genes annotated to the fatty acid metabolism. Grandpaternal-HFD reduced G/G switch gene 2 () expression, concomitant with reduced hepatic triglyceride content in F2 rats. In conclusion, the hepatic transcriptome is altered in grand-offspring from HFD-fed grandfathers. Altered TNF-α/NFκB signaling and levels of inflammatory cytokines indicate grandpaternal HFD impacts hepatic immunometabolism. Overall, our findings indicate that paternal exposure to environmental factors transgenerationally reprograms metabolism in a tissue-specific manner, affecting the development and health of future generations.-De Castro Barbosa, T., Alm, P. S., Krook, A., Barrès, R., Zierath, J. R. Paternal high-fat diet transgenerationally impacts hepatic immunometabolism.
父系孕前高脂饮食（HFD）会在几代人中改变全身葡萄糖和能量稳态，这可能是通过改变代谢器官的转录组谱来介导的。我们研究了父系 HFD 对雌性隔代表代肝脏转录组和代谢特征的影响。父系 HFD 强烈影响了第二代后代的肝脏转录组。基因集富集分析（GSEA）显示，HFD 改变了 TNF-α 信号转导 NFκB 途径，与隔代表代的饮食无关。肝细胞因子水平（包括 TNF-α）、NFκB 含量和活性的降低表明 F2 大鼠的基础炎症反应受到干扰。GSEA 还显示出各种与脂肪酸代谢相关的基因表达发生改变。HFD 改变了 G/G 开关基因 2 ()的表达，同时降低了 F2 大鼠的肝甘油三酯含量。总之，来自 HFD 喂养祖父的隔代表代的肝脏转录组发生了改变。TNF-α/NFκB 信号和炎症细胞因子水平的改变表明，HFD 改变了隔代的肝脏免疫代谢。总的来说，我们的研究结果表明，父系暴露于环境因素会以组织特异性的方式在代际间重新编程代谢，影响后代的发育和健康。
