As obesity represents a complex scenario of dysregulated glucose, insulin, lipid, and hormone homeostasis that all affect liver energy metabolism1, we investigated which obesity-related nutrients, hormonal factors, and nutrient-sensitive TFs, in addition to MAFG, regulated LincIRS2. For this, we expressed constitutively active (ca) versions of metaboregulatory TFs in primary hepatocytes, including glucose-sensing MLX-interacting protein like/carbohydrate response element-binding protein (caMLXIPL/ChREBP52), FOXO1 (caFOXO1153), or lipogenic caSREBP1C54. Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.