Sesn2 ablation exacerbates obesity-induced mTORC1-S6K activation, and moreover, the concomitant ablation of Sesn2 and Sesn3 provokes hepatic mTORC1-S6K activation and insulin resistance even in the absence of nutritional overload and obesity (Lee et al., 2012). Here, SESN3 is linked to obesity due to melanocortin 4 receptor deficiency.