Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Adipocyte and Cell Biology

Toward noninvasive quantification of adipose tissue oxygenation with MRI

International Journal of Obesity volume 44, pages 1776–1783 (2020)Cite this article

Subjects

Abstract

Background

Molecular oxygen (O2) plays a key role in normal and pathological adipose tissue function, yet technologies to measure its role in adipose tissue function are limited. O2 is paramagnetic and, in principle, directly influences the magnetic resonance (MR) 1H longitudinal relaxation rate constant of lipids, R1; thus, we hypothesize that MR imaging (MRI) can directly measure adipose O2 via a simple measure of R1.

Methods

R1 was measured in a 4.7T preclinical MRI system at discrete oxygen partial pressure (pO2) levels. These measures were made in vitro in an idealized system and in vivo in subcutaneous and visceral white adipose of rodents. pO2 was determined using an invasive fiber-optic oxygen monitor. From the MRI and fiber optic data we determined the “relaxivity” of O2 in lipid, a critical parameter in converting the MRI-based R1 measurement into pO2. We used breathing gas challenge to estimate the changes in lipid pO2 (ΔpO2).

Results

The relaxivity of O2 in lipid was determined to be 1.7·10−3 ± 4·10−4 mmHg−1s−1 at 4.7T and 37 °C, and was consistent between in vitro and in vivo adipose tissue. There was a strong, significant correlation between MRI- and gold standard OxyLite-based measurements of lipid ΔpO2 for in vivo visceral and subcutaneous fat depots in rodents.

Conclusion

This study lays the foundation for a direct, noninvasive measure of adipose pO2 using MRI and will allow for noninvasive measurement of O2 flux in adipose tissue. The proposed approach would be of particular importance in the interrogation of the pathogenesis of type 2 diabetes, where it has been suggested that adipose tissue hypoxia is an independent driver of insulin resistance pathway.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: The system used for lard phantom preparation.
Fig. 2: MR spectra of fat specimens at 4.7T.
Fig. 3: \({r}_{1,{\mathrm{pO}}_2}\) determination and the utility of the \({r}_{1,{\mathrm{pO}}_2}\) in measuring short-time oxygen flux in adipose tissue.
Fig. 4: Comparison between \({r}_{1,{\mathrm{pO}}_2}\) and R1,0 of lard and adipose depots.

References

  1. Rasouli N. Adipose tissue hypoxia and insulin resistance. J Investig Med. 2016;64:830–2.

    Article  PubMed  Google Scholar 

  2. Trayhurn P. Hypoxia and adipose tissue function and dysfunction in obesity. Physio Rev. 2013;93:1–21.

    Article  CAS  Google Scholar 

  3. Sun K, Kusminski CM, Scherer PE. Adipose tissue remodeling and obesity. J Clin Invest. 2011;121:2094–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ye J. Emerging role of adipose tissue hypoxia in obesity and insulin resistance. Int J Obes. 2009;33:54–66.

    Article  CAS  Google Scholar 

  5. Goossens GH. The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol Behav. 2008;94:206–18.

    Article  CAS  PubMed  Google Scholar 

  6. Chondronikola M, Volpi E, Børsheim E, Porter C, Annamalai P, Enerbäck S, et al. Brown adipose tissue improves whole-body glucose homeostasis and insulin sensitivity in humans. Diabetes. 2014;63:4089–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cannon B, Nedergaard J. Brown adipose tissue: function and physiological significance. Physiol Rev. 2004;84:277–359.

    Article  CAS  PubMed  Google Scholar 

  8. Chondronikola M, Beeman SC, Wahl RL. Non-invasive methods for the assessment of brown adipose tissue in humans. J Physiol. 2018;596:363–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Dmitriev RI, Papkovsky DB. Optical probes and techniques for O2 measurement in live cells and tissue. Cell Mol Life Sci. 2012;69:2025–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wang X-D, Wolfbeis OS. Optical methods for sensing and imaging oxygen: materials, spectroscopies and applications. Chem Soc Rev. 2014;43:3666–761.

    Article  CAS  PubMed  Google Scholar 

  11. Mills A. Optical oxygen sensors: utilising the luminescence of platinum metals complexes. Platin Met Rev. 1997;41:115–27.

    CAS  Google Scholar 

  12. Lapi SE, Voller TF, Welch MJ. Positron emission tomography imaging of hypoxia. PET Clin. 2009;4:39–47.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Lapi SE, Lewis JS, Dehdashti F. Evaluation of hypoxia with copper-labeled diacetyl-bis(N-methylthiosemicarbazone). Semin Nucl Med. 2015;45:177–85.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Tong X, Srivatsan A, Jacobson O, Wang Y, Wang Z, Yang X, et al. Monitoring tumor hypoxia using (18)F-FMISO PET and pharmacokinetics modeling after photodynamic therapy. Sci Rep. 2016;6:31551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. He X, Yablonskiy DA. Quantitative BOLD: mapping of human cerebral deoxygenated blood volume and oxygen extraction fraction: default state. Magn Reson Med. 2007;57:115–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. He X, Zhu M, Yablonskiy DA. Validation of oxygen extraction fraction measurement by qBOLD technique. Magn Reson Med. 2008;60:882–8.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Xia M, Kodibagkar V, Liu H, Mason RP. Tumour oxygen dynamics measured simultaneously by near-infrared spectroscopy and 19F magnetic resonance imaging in rats. Phys Med Biol. 2005;51:45–60.

    Article  PubMed  CAS  Google Scholar 

  18. Mason RP, Rodbumrung W, Antich PP. Hexafluorobenzene: a sensitive 19F NMR indicator of tumor oxygenation. NMR Biomed. 1996;9:125–34.

    Article  CAS  PubMed  Google Scholar 

  19. Kodibagkar VD, Wang X, Pacheco-Torres J, Gulaka P, Mason RP. Proton imaging of siloxanes to map tissue oxygenation levels (PISTOL): a tool for quantitative tissue oximetry. NMR Biomed. 2008;21:899–907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Agarwal S, Shankar RV, Inge LJ, Kodibagkar V. MRI assessment of changes in tumor oxygenation post hypoxia-targeted therapy. Proc. SPIE 2015;9417:941714.

    Article  Google Scholar 

  21. O’Connor JPB, Boult JKR, Jamin Y, Babur M, Finegan KG, Williams KJ, et al. Oxygen-enhanced MRI accurately identifies, quantifies, and maps tumor hypoxia in preclinical cancer models. Cancer Res. 2016;76:787–95.

    Article  PubMed  CAS  Google Scholar 

  22. Chiarotti G, Cristiani G, Giulotto L. Proton relaxation in pure liquids and in liquids containing paramagnetic gases in solution. Il Nuovo Cimento. 1955;1:863–73.

    Article  Google Scholar 

  23. Zaharchuk G, Martin AJ, Rosenthal G, Manley GT, Dillon WP. Measurement of cerebrospinal fluid oxygen partial pressure in humans using MRI. Magn Reson Med. 2005;54:113–21.

    Article  PubMed  Google Scholar 

  24. Nestle N, Baumann T, Niessner R. Oxygen determination in oxygen-supersaturated drinking waters by NMR relaxometry. Water Res. 2003;37:3361–6.

    Article  CAS  PubMed  Google Scholar 

  25. Beeman SC, Shui Y-B, Perez-Torres CJ, Engelbach JA, Ackerman JJH, Garbow JR. O2-sensitive MRI distinguishes brain tumor versus radiation necrosis in murine models. Magn Reson Med. 2016;75:2442–7.

    Article  CAS  PubMed  Google Scholar 

  26. Berkowitz BA, McDonald C, Ito Y, Tofts PS, Latif Z, Gross J. Measuring the human retinal oxygenation response to a hyperoxic challenge using MRI: eliminating blinking artifacts and demonstrating proof of concept. Magn Reson Med. 2001;46:412–6.

    Article  CAS  PubMed  Google Scholar 

  27. Hallac RR, Zhou H, Pidikiti R, Song K, Stojadinovic S, Zhao D, et al. Correlations of noninvasive BOLD and TOLD MRI with pO2 and relevance to tumor radiation response. Magn Reson Med. 2014;71:1863–73.

    Article  CAS  PubMed  Google Scholar 

  28. Jordan BF, Magat J, Colliez F, Ozel E, Fruytier A-C, Marchand V, et al. Mapping of oxygen by imaging lipids relaxation enhancement: a potential sensitive endogenous MRI contrast to map variations in tissue oxygenation. Magn Reson Med. 2013;70:732–44.

    Article  CAS  PubMed  Google Scholar 

  29. Quirk JD, Bretthorst GL, Garbow JR, Ackerman JJH. Magnetic resonance data modeling: the Bayesian analysis toolbox. Concept in Magn Reson A. 2018;47A:e21467.

    Article  CAS  Google Scholar 

  30. Kotyk JJ, Hoffman NG, Hutton WC, Larry Bretthorst G, Ackerman JJH. Comparison of Fourier and Bayesian analysis of nmr signals. I. Well-separated resonances (the single-frequency case). J Magn Reson. 1992;98:483–500.

    CAS  Google Scholar 

  31. Bretthorst GL. Bayesian analysis. II. Signal detection and model selection. J Magn Reson. 1990;88:552–70.

    CAS  Google Scholar 

  32. Bretthorst GL. Bayesian analysis. III. Applications to NMR signal detection, model selection, and parameter estimation. J Magn Reson. 1990;88:571–95.

    CAS  Google Scholar 

  33. Bretthorst GL, Hutton WC, Garbow JR, Ackerman JJH. Exponential model selection (in NMR) using Bayesian probability theory. Concept Magn Reson A. 2005;27A:64–72.

    Article  CAS  Google Scholar 

  34. Beeman SC, Osei-Owusu P, Duan C, Engelbach J, Bretthorst GL, Ackerman JJH, et al. Renal DCE-MRI model selection using Bayesian probability theory. Tomography. 2015;1:61–8.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Meinerz K, Beeman SC, Duan C, Bretthorst GL, Garbow JR, Ackerman JJH. Bayesian modeling of nmr data: quantifying longitudinal relaxation in vivo, and in vitro with a tissue-water-relaxation mimic (crosslinked bovine serum albumin). Appl Magn Reson. 2018;49:3–24.

    Article  CAS  PubMed  Google Scholar 

  36. Duan C, Kallehauge JF, Bretthorst GL, Tanderup K, Ackerman JJH, Garbow JR. Are complex DCE-MRI models supported by clinical data? Magn Reson Med. 2017;77:1329–39.

    Article  PubMed  Google Scholar 

  37. Bretthorst GL. On the difference in means. In: Grandy WT, Milonni PW, editors. Physics & probability essays in honor of Edwin T Jaynes. England: Cambrige University Press; 1993: p. 177–94.

  38. Cohen J. Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, NJ: Erlbaum; 1988.

    Google Scholar 

  39. Kruschke JK. Bayesian estimation supersedes the t test. J Exp Psychol Gen. 2013;142:573–603.

    Article  PubMed  Google Scholar 

  40. Cypess AM, Kahn CR. Brown fat as a therapy for obesity and diabetes. Curr Opin Endocrinol Diabetes Obes. 2010;17:143–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Franz D, Weidlich D, Freitag F, Holzapfel C, Drabsch T, Baum T, et al. Association of proton density fat fraction in adipose tissue with imaging-based and anthropometric obesity markers in adults. Int J Obes. 2018;42:175–82.

    Article  CAS  Google Scholar 

  42. Gifford A, Towse TF, Walker RC, Avison MJ, Welch EB. Characterizing active and inactive brown adipose tissue in adult humans using PET-CT and MR imaging. Am J Physiol Endocrinol Metab. 2016;311:E95–104.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Matsumoto K-i, Bernardo M, Subramanian S, Choyke P, Mitchell JB, Krishna MC, et al. MR assessment of changes of tumor in response to hyperbaric oxygen treatment. Magn Reson Med. 2006;56:240–6.

    Article  PubMed  Google Scholar 

  44. Silvennoinen MJ, Kettunen MI, Kauppinen RA. Effects of hematocrit and oxygen saturation level on blood spin-lattice relaxation. Magn Reson Med. 2003;49:568–71.

    Article  PubMed  Google Scholar 

  45. Janne d'Othee B, Rachmuth G, Munasinghe J, Lang EV. The effect of hyperoxygenation on T1 relaxation time in vitro. Acad Radiol. 2003;10:854–60.

    Article  PubMed  Google Scholar 

  46. Bennett HF, Swartz HM, Koenig S. Modification of relaxation of lipid protons by molecular oxygen and nitroxides. Invest Radiol. 1987;22:502–7.

    Article  CAS  PubMed  Google Scholar 

  47. Riess JG. Understanding the fundamentals of perfluorocarbons and perfluorocarbon emulsions relevant to in vivo oxygen delivery. Artif Cells Blood Substit Biotechnol. 2005;33:47–63.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to thank their colleagues Drs Joseph J.H. Ackerman and Joel R. Garbow for their invaluable input. These MR experiments were conducted in the Small Animal Magnetic Resonance Facility in the Washington University School of Medicine.

Funding

This work was supported by NIH grants K01 DK109119 and P30 DK020579.

Author information

Authors and Affiliations

  1. Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO, USA

    Darya Morozov & James D. Quirk

  2. School of Biological and Health Systems Engineering, Arizona State University, Tempe, AZ, USA

    Scott C. Beeman

Authors
  1. Darya Morozov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. James D. Quirk
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Scott C. Beeman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott C. Beeman.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Morozov, D., Quirk, J.D. & Beeman, S.C. Toward noninvasive quantification of adipose tissue oxygenation with MRI. Int J Obes 44, 1776–1783 (2020). https://doi.org/10.1038/s41366-020-0567-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-020-0567-x

Search

Advanced search

Quick links