Dysfunction of hepatic lipid metabolism in mice haploinsufficient for the histone methyltransferase Kmt2c

Metabolic dysfunction is influenced by various factors including environmental effects and genetic variants, and recent evidence reveals close associations between metabolic dysfunction and neurodevelopmental or neuropsychiatric disorders. However, the mechanistic link between them remains unclear. To clarify these relationships, we utilized mice with haploinsufficiency in the autism spectrum disorder-related gene lysine methyltransferase 2c (Kmt2c) (Kmt2c+/fs mice), in which we previously confirmed significantly less body weight. We characterized body composition, small intestinal transcriptome, fecal metagenome, plasma metabolome, and hepatic mitochondrial morphology and biochemical activity in male Kmt2c+/fs mice and wild-type controls. Hepatic transcriptomic changes and lipid accumulation were also assessed. Group comparisons were performed using two-sided Mann-Whitney U-tests, two-way repeated measures ANOVA, and enrichment analyses with appropriate multiple-testing correction. Here we show that Kmt2c+/fs mice have decreased body mass index and body fat mass. The small intestine and fecal metagenome show minimal alterations, while plasma metabolomic analysis reveals an increase of metabolites related to glucose and amino acid metabolism. Hepatic mitochondria display altered morphology and biochemical activity. The liver of Kmt2c+/fs mice exhibits decreased lipid accumulation and the downregulation of genes related to lipid metabolism, particularly fatty acid synthesis. These findings indicate that KMT2C deficiency triggers functional defects in lipid metabolism in the liver, accompanied by upregulation of glucose and amino acid metabolism and consequently less body weight. The mechanism of metabolic dysfunction observed in neurodevelopmental and neuropsychiatric disorders largely remains unclear. Lysine methyltransferase 2c (Kmt2c) is one of autism spectrum disorder (ASD)-related genes, and Kmt2c mutant mice exhibit ASD-like phenotypes and less body weight. We precisely analyzed metabolic profiles of Kmt2c+/fs mice, and discovered lower body mass index and decreased fat mass. While these phenotypes were unlikely to be explained by changes in the intestine or gut bacteria, we found changes in morphology and biochemical activity of hepatic mitochondria. The liver of Kmt2c+/fs mice showed decreased lipid accumulation and downregulation of lipid metabolism-related genes. These results provide insight into the onset mechanism of metabolic dysfunction in neurodevelopmental and neuropsychiatric disorders, especially associated with epigenetic regulations.