We confirmed that multiple hepatokines, including Enho, Igfbp2, Fgl1, and Fst, are regulated through the p110α-dependent axis, and this effect is further accentuated upon HFD feeding, suggesting that p110α interferes with alterations in the communication between the liver and periphery that occurs during HFD-induced obesity (S9 Fig). Here, FST is linked to obesity due to melanocortin 4 receptor deficiency.