By: Ramzy Burns
Paper: KSR2 Mutations Are Associated with Obesity, Insulin Resistances, and Impaired Cellular Fuel Oxidation
With obesity rates steadily climbing, understanding the underlying chemical and biological changes in obese individuals is essential to fighting the epidemic. The Ras-Raf-MEK-ERK and AMPK signaling pathways are both critical for the regulation of weight and metabolism. AMP-activated protein kinase (AMPK) acts as a fuel sensor and is responsible for inhibiting acetyl-CoA carboxylase. Kinase suppressor of Ras protein 2 (KSR2) binds Raf, MEK, ERK, and AMPK to facilitate their activation thereby stimulating metabolism. The presence and resulting effects of KSR2 mutations in humans were previously undiscovered, but in their recent study, Farooqi et al. provide evidence that KSR2 mutations predispose individuals to obesity by inhibiting the Ras-Raf-MEK-ERK and AMPK pathways.
By sequencing the KSR2 coding region in obese individuals, the authors identify novel rare variants. Transfecting cells with Flag-tagged mutant KSR2 allowed the authors to use coimmunoprecipitation, revealing mutant KSR2’s reduced ability to bind to Raf and MEK, leading to decreased activation of ERK. The disruption of this pathway then contributes to decreased basal metabolic rate. Immunoprecipitation of AMPK in cells containing mutant KSR2 uncovers a decrease in AMPK activation which impairs fatty acid oxidation. When dosed with metformin, a diabetic drug, AMPK is stimulated in cells, reversing the inhibition of fatty acid oxidation.
The identification of KSR2 mutations in obese individuals and understanding of the molecular changes in the Ras-Raf-MEK-ERK and AMPK pathways, provides both an explanation for the early-onset obesity seen in individuals with KSR2 mutations as well as targets to ameliorate the effects. A clinical study of metformin’s ability to reverse AMPK deactivation could lead to an effective drug for obese individuals harboring KSR2 mutations.