Maternal postpartum sedentary life exacerbates the metabolic impact of moderately fat-rich diet in male mice.

Profound social and economic changes in recent generations have led to reduced physical activity and increased calorie intake, leading to a higher incidence of metabolic disease. These effects may propagate across generations, amplifying the impact on descendants. Here we found that limited physical activity of dams brought about increased liver weight and lipid accumulation in the male offspring on a moderate fat calorie western-like diet from weaning to adulthood, while maternal voluntary exercise on running wheels during the postpartum period was sufficient to prevent the development of the phenotype in the otherwise sedentary offspring. Elevated fatty acid (FA) and reduced acylcarnitine levels in the liver of offspring of exercising mothers suggested increased FA flux for oxidation that, with elevated mitochondrial β-oxidation, indicated a maternally programmed mechanism to cope with increased fat calories. Finally, single-nucleus transcriptional profiling indicated dysregulated lipid metabolism in hepatocytes and upregulation of phagocytosis-related genes in Kupffer cells/macrophages and minimal response in stellate cells, indicating a moderate liver damage in the offspring of sedentary but not exercising mothers. A similar combination of maternal sedentary lifestyle and increased fat calorie intake from childhood could contribute to the increased incidence of obesity and NAFLD in recent generations.