Stable Isotope Tracing and Metabolomics to Study In Vivo Brown Adipose Tissue Metabolic Fluxes

Overview

Journal Methods Mol Biol

Specialty Molecular Biology

Date 2022 Feb 15

PMID 35167094

Authors

Su Myung Jung

Johnny Le

Will G Doxsey

John A Haley

Grace Park

David A Guertin

Cholsoon Jang

Affiliations

Soon will be listed here.

Abstract

Brown adipose tissue (BAT) demonstrates extraordinary metabolic capacity. Previous research using conventional radio tracers reveals that BAT can act as a sink for a diverse menu of nutrients; still, the question of how BAT utilizes these nutrients remains unclear. Recent advances in mass spectrometry (MS) coupled to stable isotope tracing methods have greatly improved our understanding of metabolism in biology. Here, we have developed a BAT-tailored metabolomics and stable isotope tracing protocol using, as an example, the universally labeled C-glucose, a key nutrient heavily utilized by BAT. This method enables metabolic roadmaps to be drawn and pathway fluxes to be inferred for each nutrient tracer within BAT and its application could uncover new metabolic pathways not previously appreciated for BAT physiology.

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References

Cannon B, Nedergaard J . Brown adipose tissue: function and physiological significance. Physiol Rev. 2004; 84(1):277-359. DOI: 10.1152/physrev.00015.2003. View

Nedergaard J, Bengtsson T, Cannon B . Unexpected evidence for active brown adipose tissue in adult humans. Am J Physiol Endocrinol Metab. 2007; 293(2):E444-52. DOI: 10.1152/ajpendo.00691.2006. View

Cypess A, Lehman S, Williams G, Tal I, Rodman D, Goldfine A . Identification and importance of brown adipose tissue in adult humans. N Engl J Med. 2009; 360(15):1509-17. PMC: 2859951. DOI: 10.1056/NEJMoa0810780. View

Virtanen K, Lidell M, Orava J, Heglind M, Westergren R, Niemi T . Functional brown adipose tissue in healthy adults. N Engl J Med. 2009; 360(15):1518-25. DOI: 10.1056/NEJMoa0808949. View

van Marken Lichtenbelt W, Vanhommerig J, Smulders N, Drossaerts J, Kemerink G, Bouvy N . Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009; 360(15):1500-8. DOI: 10.1056/NEJMoa0808718. View

Saito M, Okamatsu-Ogura Y, Matsushita M, Watanabe K, Yoneshiro T, Nio-Kobayashi J . High incidence of metabolically active brown adipose tissue in healthy adult humans: effects of cold exposure and adiposity. Diabetes. 2009; 58(7):1526-31. PMC: 2699872. DOI: 10.2337/db09-0530. View

Labbe S, Caron A, Bakan I, Laplante M, Carpentier A, Lecomte R . In vivo measurement of energy substrate contribution to cold-induced brown adipose tissue thermogenesis. FASEB J. 2015; 29(5):2046-58. DOI: 10.1096/fj.14-266247. View

Yoneshiro T, Wang Q, Tajima K, Matsushita M, Maki H, Igarashi K . BCAA catabolism in brown fat controls energy homeostasis through SLC25A44. Nature. 2019; 572(7771):614-619. PMC: 6715529. DOI: 10.1038/s41586-019-1503-x. View

Ouellet V, Labbe S, Blondin D, Phoenix S, Guerin B, Haman F . Brown adipose tissue oxidative metabolism contributes to energy expenditure during acute cold exposure in humans. J Clin Invest. 2012; 122(2):545-52. PMC: 3266793. DOI: 10.1172/JCI60433. View

10.

Zhang F, Hao G, Shao M, Nham K, An Y, Wang Q . An Adipose Tissue Atlas: An Image-Guided Identification of Human-like BAT and Beige Depots in Rodents. Cell Metab. 2018; 27(1):252-262.e3. PMC: 5764189. DOI: 10.1016/j.cmet.2017.12.004. View

11.

Lai Z, Fiehn O . Mass spectral fragmentation of trimethylsilylated small molecules. Mass Spectrom Rev. 2016; 37(3):245-257. DOI: 10.1002/mas.21518. View

12.

Jang C, Chen L, Rabinowitz J . Metabolomics and Isotope Tracing. Cell. 2018; 173(4):822-837. PMC: 6034115. DOI: 10.1016/j.cell.2018.03.055. View

13.

Kaushik A, DeBerardinis R . Applications of metabolomics to study cancer metabolism. Biochim Biophys Acta Rev Cancer. 2018; 1870(1):2-14. PMC: 6193562. DOI: 10.1016/j.bbcan.2018.04.009. View

14.

Held N, Kuipers E, van Weeghel M, van Klinken J, Denis S, Lombes M . Pyruvate dehydrogenase complex plays a central role in brown adipocyte energy expenditure and fuel utilization during short-term beta-adrenergic activation. Sci Rep. 2018; 8(1):9562. PMC: 6015083. DOI: 10.1038/s41598-018-27875-3. View

15.

Panic V, Pearson S, Banks J, Tippetts T, Velasco-Silva J, Lee S . Mitochondrial pyruvate carrier is required for optimal brown fat thermogenesis. Elife. 2020; 9. PMC: 7476754. DOI: 10.7554/eLife.52558. View

16.

Winther S, Isidor M, Basse A, Skjoldborg N, Cheung A, Quistorff B . Restricting glycolysis impairs brown adipocyte glucose and oxygen consumption. Am J Physiol Endocrinol Metab. 2017; 314(3):E214-E223. DOI: 10.1152/ajpendo.00218.2017. View

17.

Jang C, Hui S, Lu W, Cowan A, Morscher R, Lee G . The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids. Cell Metab. 2018; 27(2):351-361.e3. PMC: 6032988. DOI: 10.1016/j.cmet.2017.12.016. View

18.

Neinast M, Jang C, Hui S, Murashige D, Chu Q, Morscher R . Quantitative Analysis of the Whole-Body Metabolic Fate of Branched-Chain Amino Acids. Cell Metab. 2018; 29(2):417-429.e4. PMC: 6365191. DOI: 10.1016/j.cmet.2018.10.013. View

19.

Lau K, Fatania H, Randle P . Regulation of the branched chain 2-oxoacid dehydrogenase kinase reaction. FEBS Lett. 1982; 144(1):57-62. DOI: 10.1016/0014-5793(82)80568-1. View

20.

Taguchi R, Minami A, Matsuda Y, Takahashi T, Otsubo T, Ikeda K . Preferential Accumulation of 14C-N-Glycolylneuraminic Acid over 14C-N-Acetylneuraminic Acid in the Rat Brain after Tail Vein Injection. PLoS One. 2015; 10(6):e0131061. PMC: 4476740. DOI: 10.1371/journal.pone.0131061. View