--- - |2+ Key points Maternal high‐fat diet consumption predisposes to metabolic dysfunction in male and female offspring at young adulthood. Maternal obesity programs non‐alcoholic fatty liver disease (NAFLD) in a sex‐dependent manner. We demonstrate sex‐dependent liver transcriptome profiles in rat offspring of obese mothers. In this study, we focused on pathways related to insulin, glucose and lipid signalling. These results improve understanding of the mechanisms by which a maternal high‐fat diet affects the offspring. Abstract Maternal obesity (MO) predisposes offspring (F1) to obesity, insulin resistance (IR) and non‐alcoholic fatty liver disease (NAFLD). MO's effects on the F1 liver transcriptome are poorly understood. We used RNA‐seq to determine the liver transcriptome of male and female F1 of MO and control‐fed mothers. We hypothesized that MO‐F1 are predisposed to sex‐dependent adult liver dysfunction. Female Wistar rat mothers ate a control (C) or obesogenic (MO) diet from the time they were weaned through breeding at postnatal day (PND) 120, delivery and lactation. After weaning, all male and female F1 ate a control diet. At PND 110, F1 serum, liver and fat were collected to analyse metabolites, histology and liver differentially expressed genes. Male and female MO‐F1 showed increased adiposity index, triglycerides, insulin and homeostatic model assessment vs. C‐F1 with similar body weight and glucose serum concentrations. MO‐F1 males presented greater physiological and histological NAFLD characteristics than MO‐F1 females. RNA‐seq revealed 1365 genes significantly changed in male MO‐F1 liver and only 70 genes in female MO‐F1 compared with controls. GO and KEGG analysis identified differentially expressed genes related to metabolic processes. Male MO‐F1 liver showed the following altered pathways: insulin signalling (22 genes), phospholipase D signalling (14 genes), NAFLD (13 genes) and glycolysis/gluconeogenesis (7 genes). In contrast, few genes were altered in these pathways in MO‐F1 females. In summary, MO programs sex‐dependent F1 changes in insulin, glucose and lipid signalling pathways, leading to liver dysfunction and insulin resistance. - The Journal of Physiology, Volume 596, Issue 19, Page 4611-4628, 1 October 2018.