Given the increasing body of data demonstrating a role for retinoids in the pathophysiology and treatment of obesity-related disorders, the divergent metabolic effects of the RARα and RARβ2 specific agonists AM80 and AC261066 presented in this work reinforce the therapeutic potential of retinoids, but, equally important, also underscore the need for further preclinical studies to determine the therapeutic relevance and potential limitations of isotype-specific RAR agonists in the treatment of NAFLD and other obesity related disorders. Here, RARA is linked to metabolic dysfunction-associated steatotic liver disease.