The current study demonstrates that hepatocyte‐specific loss of the IL‐1R1 does not affect the development of obesity or NAFLD from a high‐fat, high‐carbohydrate diet (HFD) but led to a significant reduction of hepatocyte injury and improved both hepatic and whole‐body insulin sensitivity. This evidence concerns the gene IL1R1 and obesity due to melanocortin 4 receptor deficiency.