An Evolutionarily Conserved uORF Regulates PGC1α and Oxidative Metabolism in Mice, Flies, and Bluefin Tuna.

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Authors: 
Dumesic PA1, Egan DF1, Gut P1, Tran MT2, Parisi A1, Chatterjee N3, Jedrychowski M1, Paschini M4, Kazak L5, Wilensky SE6, Dou F6, Bogoslavski D6, Cartier JA7, Perrimon N3, Kajimura S8, Parikh SM2, Spiegelman BM9.
Journal: 
Cell Metab.
Publication Date: 
Tue, 2019-07-02
Institutions: 
1Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA. 2Division of Nephrology and Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA; Center for Vascular Biology Research, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA. 3Department of Genetics, Harvard University Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA. 4Boston Children's Hospital, Boston, MA 02115, USA. 5Goodman Cancer Research Centre, Department of Biochemistry, McGill University, Montreal, Canada. 6Dana-Farber Cancer Institute, Boston, MA 02115, USA. 7Cartier and Company, LLC, Harwich, MA 02645, USA. 8Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, CA 94143, USA. 9Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA.
Abstract: 
Diet-induced thermogenesis is an important homeo-static mechanism that limits weight gain in responseto caloric excess and contributes to the relativestability of body weight in most individuals. We previ-ously demonstrated that creatine enhances energyexpenditure through stimulation of mitochondrialATP turnover, but the physiological role and impor-tance of creatine energetics in adipose tissue havenot been explored. Here, we have inactivated the firstand rate-limiting enzyme of creatine biosynthesis,glycine amidinotransferase (GATM), selectively infat (Adipo-Gatm KO). Adipo-Gatm KO mice are proneto diet-induced obesity due to the suppression ofelevated energy expenditure that occurs in responseto high-calorie feeding. This is paralleled by a bluntedcapacity forb3-adrenergic activation of metabolicrate, which is rescued by dietary creatine supplemen-tation. These results provide strong in vivo geneticsupport for a role of GATM and creatine metabolismin energy expenditure, diet-induced thermogenesis,and defense against diet-induced obesity.