Akt-mTORC1 signaling potently contributes to diet-induced obesity with diabetes and liver steatosis (Khamzina et al, 2005; Dann et al, 2007; Zhang et al, 2009), and we find these effects are unaltered in homozygous TSC2 knock-in mice expressing S1364A or S1364E. Here, TSC2 is linked to obesity due to melanocortin 4 receptor deficiency.