Early complete weaning in mice induces hepatic steatosis, which is associated with changes in phospholipids, metabolites, gene expression, and epigenome.

Early complete weaning may increase the risk of developing metabolic diseases. This study investigated whether early complete weaning in mice leads to the development of steatosis. Institute of Cancer Research (ICR) mouse male pups were weaned at 17 days [early complete weaning (EW)] or 21 days [normal complete weaning (NW)] and subsequently fed the AIN93G diet until 32 weeks of age. We measured the diameter of lipid droplets, primary metabolites, protein expression related to phospholipid synthesis, and histone modifications of the Pemt in the liver. The lipid droplet diameter was larger in EW mice than in NW mice. A set of phosphatidylcholine (PC) species, particularly PC(38:6), demonstrated lower mRNA and protein expression of Pemt and methylenetetrahydrofolate reductase, as well as decreased primary metabolites related to S-adenosylmethionine/choline, and a reduction in an antioxidative marker in EW mice. Moreover, histone methylation (H3K4 tri-methyl and H3K36 di-/tri-methyl) and acetylation around Pemt were also lower in these mice. The steatosis development due to early complete weaning in mice is closely and positively associated with a reduced amount of PC.NEW & NOTEWORTHY The development of steatosis due to early complete weaning in mice is closely positively associated with a reduced amount of PC and related metabolites, transcriptome changes including Pemt, and alterations in histone modifications around Pemt.