Kinase suppressor of Ras2 (KSR2) interacts with the cellular fuel sensor AMP-activated protein kinase (AMPK) and helps maintain energy homeostasis and glucose tolerance; its deficiency causes obesity and insulin resistance in mice. A new study reports numerous KSR2 variants that are associated with obesity in humans and impair glucose and fatty acid oxidation (Cell 155, 765–777, 2013).
I. Sadaf Farooqi and her colleagues sequenced a large number of individuals with severe early-onset obesity and found several KSR2 variants, which were associated with hyperphagia in childhood, reduced basal metabolic rate and insulin resistance. When mutations disrupting or possibly disrupting the highly conserved kinase domain were introduced in different cell lines, this blocked not only the interaction of KSR2 with the fuel sensor AMPK but also its interaction with members of the MAPK cascade, suggesting several pathways are altered by these variants.
Because reduced cellular fuel utilization was associated with KSR2 mutations, the study suggests that KSR2 mutations may promote obesity by increasing energy intake and reducing metabolic rate in humans. Although the antidiabetic drug metformin rescued the reduced fuel oxidation caused by KSR2 mutants in vitro, other drugs may be developed to modulate KSR2 activity and treat obesity and type 2 diabetes.
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Pola, C. Obesity-associated mutations. Nat Med 19, 1582 (2013). https://doi.org/10.1038/nm.3427