Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity

Lawrence Kazak, Janane F. Rahbani, Bozena Samborska, Gina Z. Lu, Mark P. Jedrychowski, Mathieu Lajoie, Song Zhang, Lee Ann Ramsay, Florence Y. Dou, Danielle Tenen, Edward T. Chouchani, Petras Dzeja, Ian R. Watson, Linus Tsai, Evan D. Rosen, Bruce M. Spiegelman

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Depleting creatine levels in thermogenic adipocytes by inhibiting creatine biosynthesis reduces thermogenesis and causes obesity. However, whether creatine import from the circulation affects adipocyte thermogenesis is unknown. Here we show that deletion of the cell-surface creatine transporter (CrT) selectively in fat (AdCrTKO) substantially reduces adipocyte creatine and phosphocreatine levels, and reduces whole-body energy expenditure in mice. AdCrTKO mice are cold intolerant and become more obese than wild-type animals when fed a high-fat diet. Loss of adipocyte creatine transport blunts diet- and β3-adrenergic-induced thermogenesis, whereas creatine supplementation during high-fat feeding increases whole-body energy expenditure in response to β3-adrenergic agonism. In humans, CRT expression in purified subcutaneous adipocytes correlates with lower body mass index and increased insulin sensitivity. Our data indicate that adipocyte creatine abundance depends on creatine sequestration from the circulation. Given that it affects whole-body energy expenditure, enhancing creatine uptake into adipocytes may offer an opportunity to combat obesity and obesity-associated metabolic dysfunction.

Original languageEnglish (US)
Pages (from-to)360-370
Number of pages11
JournalNature Metabolism
Volume1
Issue number3
DOIs
StatePublished - Mar 1 2019

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Internal Medicine
  • Cell Biology

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    Kazak, L., Rahbani, J. F., Samborska, B., Lu, G. Z., Jedrychowski, M. P., Lajoie, M., Zhang, S., Ramsay, L. A., Dou, F. Y., Tenen, D., Chouchani, E. T., Dzeja, P., Watson, I. R., Tsai, L., Rosen, E. D., & Spiegelman, B. M. (2019). Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity. Nature Metabolism, 1(3), 360-370. https://doi.org/10.1038/s42255-019-0035-x