The effect of fasting and ketogenic diets to increase FGF21 is not nearly as robust in humans as initially observed in mice (131–133), FGF21 is also increased in settings of obesity (132, 134, 135), and more recent work has led to the suggestion that FGF21 is more appropriately a signal of metabolic or cellular stress (136). This evidence concerns the gene FGF21 and obesity due to melanocortin 4 receptor deficiency.