Journal
NATURE METABOLISM
Volume 1, Issue 3, Pages 360-370Publisher
NATURE RESEARCH
DOI: 10.1038/s42255-019-0035-x
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Funding
- Canadian Institutes of Health Research (CIHR) [PJT-159529]
- Goodman Cancer Research Centre
- McGill University New Investigator Program
- NIH/NIDDK [DK114528-01, P30 DK057521, R01 DK102173, R01 ES017690]
- Canderel Fellowship
- Dr. John R and Clara M. Fraser Memorial Trust
- Terry Fox Foundation
- Quebec Breast Cancer Foundation
- McGill University
- NIH [R01HL 85744, U24DK100469, DK31405]
- AHA [13POST14540015]
- JPB Foundation
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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 dietand beta 3-adrenergic-induced thermogenesis, whereas creatine supplementation during high-fat feeding increases whole-body energy expenditure in response to beta 3-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.
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