Intriguingly, while fasting is known to potently enhance FGF21 levels, as major mechanisms to coordinate adaptive responses to starvation50, obesity has been shown to cause also an enhancement of FGF21 levels in rodents and humans34,35, suggesting a state of “FGF21 resistance”, defined by elevated FGF21 levels and impaired FGF21 receptor function51, which might contribute to the aggravation of metabolic state in conditions of obesity. This evidence concerns the gene FGF21 and obesity due to melanocortin 4 receptor deficiency.