Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity

Lawrence Kazak, Edward T. Chouchani, Gina Z. Lu, Mark P. Jedrychowski, Curtis J. Bare, Amir I. Mina, Manju Kumari, Song Zhang, Ivan Vuckovic, Dina Laznik-Bogoslavski, Petras P Dzeja, Alexander S. Banks, Evan D. Rosen, Bruce M. Spiegelman

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

Diet-induced thermogenesis is an important homeostatic mechanism that limits weight gain in response to caloric excess and contributes to the relative stability of body weight in most individuals. We previously demonstrated that creatine enhances energy expenditure through stimulation of mitochondrial ATP turnover, but the physiological role and importance of creatine energetics in adipose tissue have not been explored. Here, we have inactivated the first and rate-limiting enzyme of creatine biosynthesis, glycine amidinotransferase (GATM), selectively in fat (Adipo-Gatm KO). Adipo-Gatm KO mice are prone to diet-induced obesity due to the suppression of elevated energy expenditure that occurs in response to high-calorie feeding. This is paralleled by a blunted capacity for β3-adrenergic activation of metabolic rate, which is rescued by dietary creatine supplementation. These results provide strong in vivo genetic support for a role of GATM and creatine metabolism in energy expenditure, diet-induced thermogenesis, and defense against diet-induced obesity. Kazak et al. investigate the physiological effects of creatine energetics through loss of function of the rate-limiting enzyme glycine amidinotransferase (GATM) in adipose tissue. Adipo-Gatm KO mice cannot counteract increased calories with energy expenditure and gain weight. Their lower metabolic rate can be rescued by dietary creatine supplementation.

Original languageEnglish (US)
JournalCell Metabolism
DOIs
StateAccepted/In press - 2017

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Keywords

  • Brown adipose tissue
  • CL 316,243
  • Creatine
  • Diet-induced thermogenesis
  • Energy balance
  • Energy expenditure
  • Glycine amidinotransferase
  • Obesity
  • Thermoneutrality

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

Cite this

Kazak, L., Chouchani, E. T., Lu, G. Z., Jedrychowski, M. P., Bare, C. J., Mina, A. I., Kumari, M., Zhang, S., Vuckovic, I., Laznik-Bogoslavski, D., Dzeja, P. P., Banks, A. S., Rosen, E. D., & Spiegelman, B. M. (Accepted/In press). Genetic Depletion of Adipocyte Creatine Metabolism Inhibits Diet-Induced Thermogenesis and Drives Obesity. Cell Metabolism. https://doi.org/10.1016/j.cmet.2017.08.009