Pediatric non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in children, and can lead to liver fibrosis, cirrhosis and hepatocellular carcinoma. Nevertheless, no pharmacological treatment is available, except in clinical trials, which are performed almost exclusively in adults. The ‘developmental origins of health and disease’ hypothesis states that the intrauterine and early life environment has a long-term impact on metabolism and risk of metabolic disease. However, the impact of maternal insulin resistance (IR) on offspring NAFLD remains unclear. In this project, I aim to collect clinical and translational data on the complex relationships between maternal IR, offspring IR, NAFLD, and the impact of potential interventions. First, I will characterize hepatic metabolism and mitochondrial function in two novel and complementary murine models characterized by maternal IR. These models, in which I have collected promising preliminary data as proof-of-concept, form the basis for exploring therapeutic strategies. Specifically, I will investigate key NAFLD drug candidates targeting metabolic dysfunction in both offspring as well as maternal mice. Lastly, I will translate these associations to the clinic via unique and large cohorts of children and adolescents with obesity. More than 350 patients have been recruited, in whom the prevalence of NAFLD and significant liver fibrosis was high.