Enhanced Insulin Sensitivity and Protection Against Diet-induced Obesity in Transgenic Mice Overexpressing NQO1

Authors

• A Di Francesco
• Y Zhang
• K Bullok
• K Kalafut
• C Di Germanio
• J Martindale
• M Gorospe
• D Willmes
• D Siegel
• D Ross
• M Bernier
• R de Cabo

Abstract

NAD(P)H: Quinone oxidoreductase 1 (NQO1) is a multifunctional protein widely known for its role as an antioxidant enzyme and for its ability to catalyze the 2-electron reduction of quinones. Alteration in cellular NAD+/NADH ratio via pharmacological stimulation of NQO1 activity has been associated with protection against metabolic stress and aging in mice, although the underlying mechanisms are largely unknown. More recently, novel functions for NQO1 have been reported, including the ability to regulate mRNA translation in vitro. Here, we show that NQO1 overexpressing mice (NQO1-Tg) on high-fat diet maintain significantly lower plasma levels of glucose and free fatty acids compared with their littermate controls and are protected from diet-induced liver steatosis. A significant increase in glucose infusion rate during hyperinsulinaemic-euglycemic clamps demonstrated that skeletal muscle was the major site of insulin sensitivity in NQO1-Tg mice. In fasting/refeeding experiments, NQO1 overexpression attenuated activation of ribosomal protein S6 kinase 1, an effector of mTOR, preventing insulin receptor desensitization in the muscle. Moreover, NQO1-Tg mice displayed striking differences in S6 ribosomal protein and eukaryotic translation initiation factor 4G, indicating a major role for NQO1 in regulation of mRNA translation initiation. NQO1 co-fractionated with monoribosomes within a sucrose gradient and alterations of NQO1 levels and activity were associated with major differeces in global protein synthesis. These results shed new light on the relationship between translational control and glucose metabolism in vivo. We propose that NQO1 up-regulation may allow animals to remain healthier under metabolic stress conditions, partly through regulation of mRNA translation.

Scientific Focus Area: Molecular Biology and Biochemistry

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