All these data point to the idea that FGF21 activation under glucolipotoxicity may induce autophagic flux via inhibition of AMPK-mTOR signaling in islets, and that FGF21 may be an important mediator of islet β-cell functions and pathophysiology related to obesity and T2DM. Here, MTOR is linked to obesity due to melanocortin 4 receptor deficiency.