Several mutations at the KSR2 loci in humans have been associated with severe early-onset obesity (Pearce et al., 2013), and studies in Ksr2 KO mice have revealed a centrally regulated mechanism by Ksr2 expression and function in the hypothalamus that results in hyperphagia, changes in metabolic rate, and consequently, obesity and T2D (Costanzo-Garvey et al., 2009; Guo et al., 2017; Henry et al., 2014; Pearce et al., 2013; Revelli et al., 2011). Here, KSR2 is linked to type 2 diabetes mellitus.