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

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.

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Fig. 1: Inactivation of creatine transport depletes creatine abundance in adipocytes.
Fig. 2: AdCrTKO mice have impaired energy expenditure.
Fig. 3: AdCrTKO mice become obese on a high-fat diet.
Fig. 4: Increased kininogen expression from BAT and SQ of AdCrTKO mice.
Fig. 5: AdCrTKO mice incur adaptive increases in the cold-inducible high-molecular-weight isoform of Kng1.
Fig. 6: CRT expression in human adipocytes is negatively correlated with obesity and insulin resistance.

Data availability

All proteomic data generated or analysed during this study are included in this published article (and its supplementary information files). Additional data that support the findings of this study are available from the corresponding authors on reasonable request.

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research (CIHR; grant PJT-159529), Goodman Cancer Research Centre and McGill University New Investigator Program, and DK114528-01 NIH/NIDDK K99 Pathway to Independence award (to L.K.). We acknowledge funding from a Canderel Fellowship (to J.F.R.). We acknowledge technical assistance from the McGill/GCRC Metabolomics core facility. The GCRC Metabolomics Core Facility is funded by the Dr. John R and Clara M. Fraser Memorial Trust, the Terry Fox Foundation, the Québec Breast Cancer Foundation and McGill University. We acknowledge funding from NIH R01HL 85744 and U24DK100469 Mayo Clinic Metabolomics Resource Core (to P.D.), AHA 13POST14540015 and NIH/NIDDK P30 DK057521 (to L.T.), NIH/NIDDK P30 DK057521, NIH/NIDDK R01 DK102173 and R01 ES017690 (to E.D.R.), and NIH DK31405 and JPB Foundation (to B.M.S.).

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Contributions

L.K. conceptualized the study, designed research, performed biochemical, cellular and in vivo experiments, analysed data and wrote the paper. J.F.R., B.S., G.Z.L. and F.Y.D. performed in vivo experiments. M.P.J. performed proteomics experiments. M.L., L.C.R. and I.R.W. analysed proteomics data. S.Z. performed and analysed NMR experiments. E.T.C., P.D. and E.D.R. provided resources. L.T. recruited human subjects and isolated adipocytes, and D.T. performed RNA-seq experiments. L.K. and B.M.S. co-wrote the paper, with assistance from co-authors.

Corresponding authors

Correspondence to Lawrence Kazak or Bruce M. Spiegelman.

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Supplementary information

Supplementary Information

Supplementary Figures 1–3 and Supplementary Table 1

Reporting Summary

Supplementary Data 1

Proteomics inventory from AdCrTKO and CrTlox/y controls at 30 °C (CrTlox/y, n = 5; AdCrTKO, n = 5).

Supplementary Data 2

Proteomics inventory from AdCrTKO and CrTlox/y controls at 22 °C (CrTlox/y, n = 5; AdCrTKO, n = 5).

Supplementary Data 3

Cross-referenced proteomics inventory from AdCrTKO and CrTlox/y controls at 30 °C and 22 °C (CrTlox/y, n = 10; AdCrTKO, n = 10).

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Kazak, L., Rahbani, J.F., Samborska, B. et al. Ablation of adipocyte creatine transport impairs thermogenesis and causes diet-induced obesity. Nat Metab 1, 360–370 (2019). https://doi.org/10.1038/s42255-019-0035-x

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