Defining “FGF21 Resistance” during obesity: Controversy, criteria and unresolved questions [version 1; referees: 1 approved, 2 approved with reservations]

The term “FGF21 resistance” was first used to describe increased circulating FGF21 levels concomitant to decreased FGF21 receptor complex expression in white adipose tissue of obese mice. Since this initial report, the term has been associated with a wide range of pathological states, including human obesity, in which circulating FGF21 levels are elevated. 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 sensitivity in vivo and finally, crucial unresolved questions regarding the function of FGF21 during obesity.