A Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat.

Authors: 
Kazak L1, Chouchani ET1, Jedrychowski MP2, Erickson BK2, Shinoda K3, Cohen P1, Vetrivelan R4, Lu GZ5, Laznik-Bogoslavski D5, Hasenfuss SC1, Kajimura S3, Gygi SP2, Spiegelman BM6.
Journal: 
Cell
Publication Date: 
Thu, 2015-10-22
Institutions: 
1Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA. 2Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA. 3Diabetes Center, University of California, San Francisco (UCSF), San Francisco, CA 94143, USA. 4Department of Neurology, Harvard Medical School and Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. 5Dana-Farber Cancer Institute, Boston, MA 02115, USA. 6Dana-Farber Cancer Institute, Boston, MA 02115, USA; Department of Cell Biology, Harvard University Medical School, Boston, MA 02115, USA.
Abstract: 
Thermogenic brown and beige adipose tissues dissipate chemical energy as heat, and their thermogenic activities can combat obesity and diabetes. Herein the functional adaptations to cold of brown and beige adipose depots are examined using quantitative mitochondrial proteomics. We identify arginine/creatine metabolism as a beige adipose signature and demonstrate that creatine enhances respiration in beige-fat mitochondria when ADP is limiting. In murine beige fat, cold exposure stimulates mitochondrial creatine kinase activity and induces coordinated expression of genes associated with creatine metabolism. Pharmacological reduction of creatine levels decreases whole-body energy expenditure after administration of a β3-agonist and reduces beige and brown adipose metabolic rate. Genes of creatine metabolism are compensatorily induced when UCP1-dependent thermogenesis is ablated, and creatine reduction in Ucp1-deficient mice reduces core body temperature. These findings link a futile cycle of creatine metabolism to adipose tissue energy expenditure and thermal homeostasis.