Spectral tracing of deuterium for imaging glucose metabolism

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Abstract

Cells and tissues often display pronounced spatial and dynamical metabolic heterogeneity. Common glucose-imaging techniques report glucose uptake or catabolism activity, yet do not trace the functional utilization of glucose-derived anabolic products. Here we report a microscopy technique for the optical imaging, via the spectral tracing of deuterium (STRIDE), of diverse macromolecules derived from glucose. Based on stimulated Raman-scattering imaging, STRIDE visualizes the metabolic dynamics of newly synthesized macromolecules, such as DNA, protein, lipids and glycogen, via the enrichment and distinct spectra of carbon–deuterium bonds transferred from the deuterated glucose precursor. STRIDE can also use spectral differences derived from different glucose isotopologues to visualize temporally separated glucose populations using a pulse–chase protocol. We also show that STRIDE can be used to image glucose metabolism in many mouse tissues, including tumours, brain, intestine and liver, at a detection limit of 10 mM of carbon–deuterium bonds. STRIDE provides a high-resolution and chemically informative assessment of glucose anabolic utilization.

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Fig. 1: SRS imaging of overall metabolic activity by [D7]-glucose labelling.
Fig. 2: Principle of STRIDE.
Fig. 3: Multiplexed imaging of macromolecule biosynthesis activity using STRIDE of [D7]-glucose.
Fig. 4: STRIDE imaging in mouse tissue.
Fig. 5: STRIDE imaging of protein and lipid biosynthesis in mouse brain.
Fig. 6: STRIDE imaging reveals fast and unidirectional lipid absorption in newborn mouse intestine.
Fig. 7: Pulse–chase STRIDE imaging of metabolic dynamics through sequentially labelled [D7]- and [D2]- glucose.

Data availability

The authors declare that all data supporting the results of this study are available within the paper and its Supplementary Information. All raw and processed images generated in this work are available from the corresponding author on reasonable request.

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Acknowledgements

We thank F. Hu and C. Zheng for suggestions on this manuscript. W.M. acknowledges support from a National Institutes of Health Director’s New Innovator Award (1DP2EB016573), NIH R01 (grant EB020892), the Alfred P. Sloan Foundation, the Camille and Henry Dreyfus Foundation and a Pilot and Feasibility grant from the New York Obesity Nutrition Research Center.

Author information

L.Z., L.S., Y.S. and W.M. designed the experiment. L.Z. and L.S. performed mouse labelling and imaging. L.Z., M.W., Y.L. and L.S. performed macromolecule isolation and analysis. Y.M. and N.Q. performed NMR measurement and analysis. L.Z., L.S., Y.S. and Y.M. analysed the data. Y. S., L.Z. and W.M. wrote the manuscript with contributions from all authors.

Correspondence to Wei Min.

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Supplementary Information

Supplementary Information

Supplementary figures, tables, discussion, references and video caption.

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Supplementary Video 1

SRS imaging of glucose metabolism in the skin of the ears of a living mouse.

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Zhang, L., Shi, L., Shen, Y. et al. Spectral tracing of deuterium for imaging glucose metabolism. Nat Biomed Eng 3, 402–413 (2019) doi:10.1038/s41551-019-0393-4

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