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.

Noninvasive identification and assessment of functional brown adipose tissue in rodents using hyperpolarized 13C imaging

Abstract

Objective:

The recent identification of functional depots of brown adipose tissue (BAT) in adult humans has potential implications for the treatment of obesity. In order to evaluate new therapies aimed at inducing the production of more BAT or activating BAT in humans, it will be important to develop noninvasive methods to assess the functional state of the tissue in vivo. In this study, we investigate the feasibility of using hyperpolarized 13C imaging to noninvasively identify functional, activated BAT in an in vivo rodent model, in less than 1 min, following an infusion of pre-polarized [1-13C] pyruvate.

Design:

Hyperpolarized 13C imaging was used to monitor BAT metabolic conversion of pre-polarized [1-13C] pyruvate in rats during baseline and norepinephrine (NE)-stimulated conditions.

Results:

Activated BAT, stimulated by NE injection, can be detected in rats by increased conversion of pre-polarized [1-13C] pyruvate into its downstream products 13C bicarbonate and [1-13C] lactate. The colocalization of the 13C signal to interscapular BAT was validated using hematoxylin–eosin histological staining.

Conclusion:

The radiation-free nature and recent translation into the clinic of the hyperpolarized 13C-imaging test may potentially facilitate trials of therapeutics targeting BAT activation in humans.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. Celi FS . Brown adipose tissue--when it pays to be inefficient. N Engl J Med 2009; 360: 1553–1556.

    CAS  Article  Google Scholar 

  2. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T et al. Functional brown adipose tissue in healthy adults. N Engl J Med 2009; 360: 1518–1525.

    CAS  Article  Google Scholar 

  3. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med 2009; 360: 1500–1508.

    CAS  Article  Google Scholar 

  4. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB et al. Identification and importance of brown adipose tissue in adult humans. N Engl J Med 2009; 360: 1509–1517.

    CAS  Article  Google Scholar 

  5. Hu HH, Smith DL Jr, Nayak KS, Goran MI, Nagy TR . Identification of brown adipose tissue in mice with fat-water IDEAL-MRI. J Magn Reson Imaging 2010; 31: 1195–1202.

    Article  Google Scholar 

  6. Hu HH, Tovar JP, Pavlova Z, Smith ML, Gilsanz V . Unequivocal identification of brown adipose tissue in a human infant. J Magn Reson Imaging 2012; 35: 938–942.

    Article  Google Scholar 

  7. Baron DM, Clerte M, Brouckaert P, Raher MJ, Flynn AW, Zhang H et al. In vivo noninvasive characterization of brown adipose tissue blood flow by contrast ultrasound in mice. Circ Cardiovasc Imaging 2012; 5: 652–659.

    Article  Google Scholar 

  8. Khanna A, Branca RT . Detecting brown adipose tissue activity with BOLD MRI in mice. J Magn Reson Imaging 2012; 68: 1285–1290.

    Google Scholar 

  9. Lubura M, Hesse D, Neumann N, Scherneck S, Wiedmer P, Schurmann A . Non-invasive quantification of white and brown adipose tissues and liver fat content by computed tomography in mice. PLOS One 2012; 7: e37026.

    CAS  Article  Google Scholar 

  10. Symonds ME, Henderson K, Elvidge L, Bosman C, Sharkey D, Perkins AC et al. Thermal imaging to assess age-related changes of skin temperature within the supraclavicular region co-locating with brown adipose tissue in healthy children. J Pediatr 2012; 161: 892–898.

    Article  Google Scholar 

  11. Ardenkjaer-Larsen JH, Fridlund B, Gram A, Hansson G, Hansson L, Lerche MH et al. Increase in signal-to-noise ratio of>10,000 times in liquid-state NMR. Proc Natl Acad Sci USA 2003; 100: 10158–10163.

    CAS  Article  Google Scholar 

  12. Golman K, RIt Zandt, Lerche M, Pehrson R, Ardenkjaer-Larsen JH . Metabolic imaging by hyperpolarized 13C magnetic resonance imaging for in vivo tumor diagnosis. Cancer Res 2006; 66: 10855–10860.

    CAS  Article  Google Scholar 

  13. Day SE, Kettunen MI, Gallagher FA, Hu D-E, Lerche M, Wolber J et al. Detecting tumor response to treatment using hyperpolarized 13C magnetic resonance imaging and spectroscopy. Nat Med 2007; 13: 1382–1387.

    CAS  Article  Google Scholar 

  14. Schroeder MA, Cochlin LE, Heather LC, Clarke K, Radda GK, Tyler DJ . In vivo assessment of pyruvate dehydrogenase flux in the heart using hyperpolarized carbon-13 magnetic resonance. Proc Natl Acad Sci USA 2008; 105: 12051–12056.

    CAS  Article  Google Scholar 

  15. Schroeder MA, Atherton HJ, Ball DR, Cole MA, Heather LC, Griffin JL et al. Real-time assessment of Krebs cycle metabolism using hyperpolarized 13C magnetic resonance spectroscopy. FASEB J 2009; 23: 2529–2538.

    CAS  Article  Google Scholar 

  16. Golman K, Petersson JS, Magnusson P, Johansson E, Akeson P, Chai C-M et al. Cardiac metabolism measured noninvasively by hyperpolarized 13C MRI. Magn Reson Med 2008; 59: 1005–1013.

    CAS  Article  Google Scholar 

  17. Merritt ME, Harrison C, Storey C, Jeffrey FM, Sherry AD, Malloy CR . Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR. Proc Natl Acad Sci USA 2007; 104: 19773–19777.

    CAS  Article  Google Scholar 

  18. Merritt ME, Harrison C, Storey C, Sherry AD, Malloy CR . Inhibition of carbohydrate oxidation during the first minute of reperfusion after brief ischemia: NMR detection of hyperpolarized 13CO2 and H13CO3. Magn Reson Med 2008; 60: 1029–1036.

    CAS  Article  Google Scholar 

  19. Lau AZ, Chen AP, Ghugre NR, Ramanan V, Lam WW, Connelly KA et al. Rapid multislice imaging of hyperpolarized (13)C pyruvate and bicarbonate in the heart. Magn Reson Med 2010; 64: 1323–1331.

    CAS  Article  Google Scholar 

  20. Lau AZ, Chen AP, Barry J, Graham JJ, Dominguez-Viqueira W, Ghugre NR et al. Reproducibility study for free-breathing measurements of pyruvate metabolism using hyperpolarized (13) C in the heart. Magn Reson Med 2013; 69: 1063–1071.

    CAS  Article  Google Scholar 

  21. Merritt ME, Harrison C, Sherry AD, Malloy CR, Burgess SC . Flux through hepatic pyruvate carboxylase and phosphoenolpyruvate carboxykinase detected by hyperpolarized 13C magnetic resonance. Proc Natl Acad Sci USA 2011; 108: 19084–19089.

    CAS  Article  Google Scholar 

  22. Lee P, Leong W, Tan T, Lim M, Han W, Radda GK . In vivo hyperpolarized carbon-13 magnetic resonance spectroscopy reveals increased pyruvate carboxylase flux in an insulin resistant mouse model. Hepatology 2012; 57: 515–524.

    Article  Google Scholar 

  23. Nelson SJ, Kurhanewicz J, Vigneron DB, Larson PEZ, Harzstark A, Ferrone M et al Proof of Concept Clinical Trial of Hyperpolarized C-13 Pyruvate in Patients with Prostate Cancer International Society for Magnetic Resonance in Medicine (ISMRM): Melbourne, Australia 2012. (abstract 274).

  24. Ardenkjaer-Larsen JH, Leach AM, Clarke N, Urbahn J, Anderson D, Skloss TW . Dynamic nuclear polarization polarizer for sterile use intent. NMR Biomed 2011; 24: 927–932.

    CAS  Article  Google Scholar 

  25. Lau AZ, Chen AP, Cunningham CH . Integrated Bloch-Siegert B(1) mapping and multislice imaging of hyperpolarized (13) C pyruvate and bicarbonate in the heart. Magn Reson Med 2011; 67: 62–71.

    Article  Google Scholar 

  26. Lau AZ, Chen AP, Hurd RE, Cunningham CH . Spectral-spatial excitation for rapid imaging of DNP compounds. NMR Biomed 2011; 24: 988–996.

    CAS  Article  Google Scholar 

  27. Ma SW, Foster DO . Uptake of glucose and release of fatty acids and glycerol by rat brown adipose tissue in vivo. Can J Physiol Pharmacol 1986; 64: 609–614.

    CAS  Article  Google Scholar 

  28. Menichetti L, Frijia F, Flori A, Wiesinger F, Lionetti V, Giovannetti G et al. Assessment of real-time myocardial uptake and enzymatic conversion of hyperpolarized [1-(13) C]pyruvate in pigs using slice selective magnetic resonance spectroscopy. Contrast Media Mol Imaging 2012; 7: 85–94.

    CAS  Article  Google Scholar 

  29. Lopez-Soriano FJ, Alemany M . In vitro alanine utilization by rat interscapular brown adipose tissue. Biochim Biophys Acta 1990; 1036: 6–10.

    CAS  Article  Google Scholar 

  30. Cannon B, Nedergaard J . The physiological role of pyruvate carboxylation in hamster brown adipose tissue. Eur J Biochem 1979; 94: 419–426.

    CAS  Article  Google Scholar 

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

    CAS  Article  Google Scholar 

  32. Whittle AJ, Lopez M, Vidal-Puig A . Using brown adipose tissue to treat obesity—the central issue. Trends Mol Med 2011; 17: 405–411.

    Article  Google Scholar 

  33. Carter EA, Bonab AA, Hamrahi V, Pitman J, Winter D, Macintosh LJ et al. Effects of burn injury, cold stress and cutaneous wound injury on the morphology and energy metabolism of murine brown adipose tissue (BAT) in vivo. Life Sci 2011; 89: 78–85.

    CAS  Article  Google Scholar 

  34. Ouellet V, Labbé SM, Blondin DP, Phoenix S, Guérin B, Haman F et al. Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest 2012; 122: 545–552.

    Article  Google Scholar 

  35. Rothwell NJ, Stock MJ . A role for brown adipose tissue in diet-induced thermogenesis. Nature 1979; 281: 31–35.

    CAS  Article  Google Scholar 

  36. Rothwell NJ, Stock MJ . Effect of chronic food restriction on energy balance, thermogenic capacity, and brown-adipose-tissue activity in the rat. Bioscience Rep 1982; 2: 543–549.

    CAS  Article  Google Scholar 

  37. Williams G, Kolodny GM . Method for decreasing uptake of 18F-FDG by hypermetabolic brown adipose tissue on PET. AJR Am J Roentgenol 2008; 190: 1406–1409.

    Article  Google Scholar 

  38. Zierhut ML, Yen Y-F, Chen AP, Bok R, Albers MJ, Zhang V et al. Kinetic modeling of hyperpolarized (13)C(1)-pyruvate metabolism in normal rats and TRAMP mice. J Magn Reson 2009; 202: 85–92.

    Article  Google Scholar 

  39. Bartelt A, Bruns OT, Reimer R, Hohenberg H, Ittrich H, Peldschus K et al. Brown adipose tissue activity controls triglyceride clearance. Nat Med 2011; 17: 200–205.

    CAS  Article  Google Scholar 

  40. Ball DR, Dodd MS, Atherton HJ, Schroeder MA, Carr C, Radda GK et al. Hyperpolarized butyrate: a novel substrate for the assessment of cardiac fatty acid metabolism. 19th Proceedings of the ISMRM International Society for Magnetic Resonance in Medicine (ISMRM): Montreal, Canada 2011. (abstract 658).

  41. Colombo Serra S, Karlsson M, Giovenzana GB, Cavallotti C, Tedoldi F, Aime S . Hyperpolarized (13) C-labelled anhydrides as DNP precursors of metabolic MRI agents. Contrast Media Mol Imaging 2012; 7: 469–477.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We gratefully acknowledge support from the Ontario Institute for Cancer Research (OICR) Smarter Imaging Program.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A Z Lau.

Ethics declarations

Competing interests

APC is an employee of GE Healthcare. CHC received research support from GE Healthcare in regard to the subject matter of this report.

Additional information

Supplementary Information accompanies this paper on International Journal of Obesity website

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lau, A., Chen, A., Gu, Y. et al. Noninvasive identification and assessment of functional brown adipose tissue in rodents using hyperpolarized 13C imaging. Int J Obes 38, 126–131 (2014). https://doi.org/10.1038/ijo.2013.58

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2013.58

Keywords

  • brown adipose tissue
  • hyperpolarized 13C imaging
  • magnetic resonance
  • metabolism
  • pyruvate

This article is cited by

Search

Quick links