Regarding Fgf21, this hepatokine was found to be almost always overexpressed in mice and humans with metabolic diseases (Figure 4, Figure S4 and Table S7), but such upregulation was previously demonstrated to result from the development of a resistant state to endogenous FGF21 action with obesity [43]. Here, FGF21 is linked to obesity due to melanocortin 4 receptor deficiency.