FGF21 and obesity due to melanocortin 4 receptor deficiency: However, the notion of “FGF21 resistance” has been controversial partly due to difficulty in delineating the mechanisms underlying the physiological versus pharmacological effects of FGF21.  Here, key aspects of the term “FGF21 resistance” are discussed including; the origin and experimental context surrounding the term “FGF21 resistance”, new criteria for evaluating FGF21 sensitivityin vivo and finally, crucial unresolved questions regarding the function of FGF21 during obesity.