Collectively, these findings caution that, while the ob/ob mouse is a valuable model of primary hyperphagia-driven NAFLD, loss of specific actions of leptin on peripheral metabolism, coupled to some degree of immunosuppression, means that it is likely to deviate from pandemic NAFLD in key respects, especially related to the inflammatory and fibrotic end of the disease spectrum. Here, LEP is linked to metabolic dysfunction-associated steatotic liver disease.