Using whole‐body knockout mice as well as liver/hepatocyte‐specific gain‐ and loss‐of‐function strategies, we revealed a role for liver GADD45β in the coordination of liver fatty acid uptake, through cytoplasmic retention of FABP1, ultimately impacting obesity‐driven hyperglycaemia. Here, GADD45B is linked to obesity due to melanocortin 4 receptor deficiency.