Though the IR/Akt/mTORC1 axis seemed to be further altered in the absence of p110α upon HFD feeding, the RAS/MAPK pathway remained intact in the presence or absence of p110α during HFD feeding, meaning that this pathway is largely mediated by IR-dependent but p110α-independent signaling, even during obesity. Here, INSR is linked to obesity due to melanocortin 4 receptor deficiency.