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

Lawrence Kazak, Edward T. Chouchani, Mark P. Jedrychowski, Brian K. Erickson, Kosaku Shinoda, Paul Cohen, Ramalingam Vetrivelan, Gina Z. Lu, Dina Laznik-Bogoslavski, Sebastian C. Hasenfuss, Shingo Kajimura, Steve P. Gygi, Bruce M. Spiegelman

Research output: Contribution to journalArticle

259 Scopus citations

Abstract

Summary 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. PaperClip.

Original languageEnglish (US)
Pages (from-to)643-655
Number of pages13
JournalCell
Volume163
Issue number3
DOIs
StatePublished - Oct 22 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Kazak, L., Chouchani, E. T., Jedrychowski, M. P., Erickson, B. K., Shinoda, K., Cohen, P., Vetrivelan, R., Lu, G. Z., Laznik-Bogoslavski, D., Hasenfuss, S. C., Kajimura, S., Gygi, S. P., & Spiegelman, B. M. (2015). A Creatine-Driven Substrate Cycle Enhances Energy Expenditure and Thermogenesis in Beige Fat. Cell, 163(3), 643-655. https://doi.org/10.1016/j.cell.2015.09.035