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The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue

Nature Medicine volume 23, pages 631–637 (2017)Cite this article

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A Corrigendum to this article was published on 01 November 2017

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Abstract

Brown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia1,2. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism3,4,5. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as 'lipokines'6,7,8. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin resistance. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.

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Figure 1: Discovery of 12,13-diHOME, a cold-induced lipokine linked to BAT activation.
Figure 2: The biosynthetic pathway of 12,13-diHOME is selectively increased in mouse BAT by cold exposure.
Figure 3: 12,13-diHOME enhances cold tolerance and facilitates fatty acid uptake by BAT.
Figure 4: 12,13-diHOME promotes fatty acid uptake in vitro by activating the translocation and oligomerization of FA transporters.

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  • 23 August 2017

    In the phrase, “Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity,” located in the abstract, the word “resistance” should take the place of the word “sensitivity”. Also, the authors have clarified in more detail how the FATP1 oligomer density was quantitated in Figure 4f. This information can be found in the “Membrane Fractionation” section of the Online Methods: “To quantify FATP1 in scanned immunoblots, regions of interest of identical size were drawn in each lane at the same molecular weight, and integrated pixel density was measured using ImageJ software. For each independent experimental replicate, the integrated pixel density for each lane was expressed normalized to the control lane, or in the case of the experimental replicate with two control lanes, the integrated pixel density for each lane was expressed normalized to the average of both control lanes. The data are expressed as the average normalized value for each lane, with the error bars representing s.e.m.”

References

  1. Townsend, K. & Tseng, Y.H. Brown adipose tissue: Recent insights into development, metabolic function and therapeutic potential. Adipocyte 1, 13–24 (2012).

    Article  CAS  Google Scholar 

  2. Lynes, M.D. & Tseng, Y.H. Unwiring the transcriptional heat circuit. Proc. Natl. Acad. Sci. USA 111, 14318–14319 (2014).

    Article  CAS  Google Scholar 

  3. Romu, T. et al. A randomized trial of cold-exposure on energy expenditure and supraclavicular brown adipose tissue volume in humans. Metabolism 65, 926–934 (2016).

    Article  CAS  Google Scholar 

  4. Schellen, L., Loomans, M.G., de Wit, M.H., Olesen, B.W. & van Marken Lichtenbelt, W.D. The influence of local effects on thermal sensation under non-uniform environmental conditions—gender differences in thermophysiology, thermal comfort and productivity during convective and radiant cooling. Physiol. Behav. 107, 252–261 (2012).

    Article  CAS  Google Scholar 

  5. Hanssen, M.J. et al. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus. Nat. Med. 21, 863–865 (2015).

    Article  CAS  Google Scholar 

  6. Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).

    Article  CAS  Google Scholar 

  7. Liu, S. et al. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550–554 (2013).

    Article  CAS  Google Scholar 

  8. Yore, M.M. et al. Discovery of a class of endogenous mammalian lipids with anti-diabetic and anti-inflammatory effects. Cell 159, 318–332 (2014).

    Article  CAS  Google Scholar 

  9. Cypess, A.M. et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc. Natl. Acad. Sci. USA 109, 10001–10005 (2012).

    Article  CAS  Google Scholar 

  10. Oh, D.Y. et al. GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects. Cell 142, 687–698 (2010).

    Article  CAS  Google Scholar 

  11. Hoene, M. et al. The lipid profile of brown adipose tissue is sex-specific in mice. Biochim. Biophys. Acta 1841, 1563–1570 (2014).

    Article  CAS  Google Scholar 

  12. Thompson, D.A. & Hammock, B.D. Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst. J. Biosci. 32, 279–291 (2007).

    Article  CAS  Google Scholar 

  13. Su, A.I. et al. A gene atlas of the mouse and human protein-encoding transcriptomes. Proc. Natl. Acad. Sci. USA 101, 6062–6067 (2004).

    Article  CAS  Google Scholar 

  14. Sinal, C.J. et al. Targeted disruption of soluble epoxide hydrolase reveals a role in blood pressure regulation. J. Biol. Chem. 275, 40504–40510 (2000).

    Article  CAS  Google Scholar 

  15. Miyata, M. et al. Targeted disruption of the microsomal epoxide hydrolase gene. Microsomal epoxide hydrolase is required for the carcinogenic activity of 7,12-dimethylbenz[a]anthracene. J. Biol. Chem. 274, 23963–23968 (1999).

    Article  CAS  Google Scholar 

  16. Marcher, A.B. et al. RNA-seq and mass-spectrometry-based lipidomics reveal extensive changes of glycerolipid pathways in brown adipose tissue in response to cold. Cell Rep. 13, 2000–2013 (2015).

    Article  CAS  Google Scholar 

  17. Hao, Q. et al. Transcriptome profiling of brown adipose tissue during cold exposure reveals extensive regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 308, E380–E392 (2015).

    Article  CAS  Google Scholar 

  18. Rosell, M. et al. Brown and white adipose tissues: intrinsic differences in gene expression and response to cold exposure in mice. Am. J. Physiol. Endocrinol. Metab. 306, E945–E964 (2014).

    Article  CAS  Google Scholar 

  19. Schulz, T.J. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013).

    Article  CAS  Google Scholar 

  20. Sisemore, M.F. et al. Cellular characterization of leukotoxin diol-induced mitochondrial dysfunction. Arch. Biochem. Biophys. 392, 32–37 (2001).

    Article  CAS  Google Scholar 

  21. Redman, L.M. et al. Lack of an effect of a novel β3-adrenoceptor agonist, TAK-677, on energy metabolism in obese individuals: a double-blind, placebo-controlled randomized study. J. Clin. Endocrinol. Metab. 92, 527–531 (2007).

    Article  CAS  Google Scholar 

  22. Klingenspor, M. et al. Multiple regulatory steps are involved in the control of lipoprotein lipase activity in brown adipose tissue. J. Lipid Res. 37, 1685–1695 (1996).

    CAS  PubMed  Google Scholar 

  23. Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).

    Article  CAS  Google Scholar 

  24. Berbée, J.F. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6, 6356 (2015).

    Article  Google Scholar 

  25. Khedoe, P.P. et al. Brown adipose tissue takes up plasma triglycerides mostly after lipolysis. J. Lipid Res. 56, 51–59 (2015).

    Article  CAS  Google Scholar 

  26. Schlein, C. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 23, 441–453 (2016).

    Article  CAS  Google Scholar 

  27. Warner, A. et al. Activation of β3-adrenoceptors increases in vivo free fatty acid uptake and utilization in brown but not white fat depots in high-fat fed rats. Am. J. Physiol. Endocrinol. Metab. 311, E901–E910 (2016).

    Article  Google Scholar 

  28. Henkin, A.H. et al. Real-time noninvasive imaging of fatty acid uptake in vivo. ACS Chem. Biol. 7, 1884–1891 (2012).

    Article  CAS  Google Scholar 

  29. Stahl, A., Evans, J.G., Pattel, S., Hirsch, D. & Lodish, H.F. Insulin causes fatty acid transport protein translocation and enhanced fatty acid uptake in adipocytes. Dev. Cell 2, 477–488 (2002).

    Article  CAS  Google Scholar 

  30. Wu, Q. et al. Fatty acid transport protein 1 is required for nonshivering thermogenesis in brown adipose tissue. Diabetes 55, 3229–3237 (2006).

    Article  CAS  Google Scholar 

  31. Putri, M. et al. CD36 is indispensable for thermogenesis under conditions of fasting and cold stress. Biochem. Biophys. Res. Commun. 457, 520–525 (2015).

    Article  CAS  Google Scholar 

  32. Richards, M.R. et al. Oligomerization of the murine fatty acid transport protein 1. J. Biol. Chem. 278, 10477–10483 (2003).

    Article  CAS  Google Scholar 

  33. Shabalina, I.G., Kalinovich, A.V., Cannon, B. & Nedergaard, J. Metabolically inert perfluorinated fatty acids directly activate uncoupling protein 1 in brown-fat mitochondria. Arch. Toxicol. 90, 1117–1128 (2016).

    Article  CAS  Google Scholar 

  34. Tseng, Y.H., Kriauciunas, K.M., Kokkotou, E. & Kahn, C.R. Differential roles of insulin receptor substrates in brown adipocyte differentiation. Mol. Cell. Biol. 24, 1918–1929 (2004).

    Article  CAS  Google Scholar 

  35. Klöting, N. et al. Insulin-sensitive obesity. Am. J. Physiol. Endocrinol. Metab. 299, E506–E515 (2010).

    Article  Google Scholar 

  36. Powell, W.S. Extraction of eicosanoids from biological fluids, cells, and tissues. Methods Mol. Biol. 120, 11–24 (1999).

    CAS  PubMed  Google Scholar 

  37. Nishiumi, S. & Ashida, H. Rapid preparation of a plasma membrane fraction from adipocytes and muscle cells: application to detection of translocated glucose transporter 4 on the plasma membrane. Biosci. Biotechnol. Biochem. 71, 2343–2346 (2007).

    Article  CAS  Google Scholar 

  38. Best, D.J. & Roberts, D.E. The upper tail probabilities of Spearman's Rho. Appl. Stat. 24, 377–379 (1975).

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported in part by US National Institutes of Health (NIH) grants R01DK077097 and R01DK102898 (to Y.-H.T.), R01DK099511 (to L.J.G.), K01DK105109 (to K.I.S.), institutional research training grant T32DK007260 and individual research fellowship F32DK102320 (to M.D.L.); P30DK036836 (to Joslin Diabetes Center's Diabetes Research Center); a research grant from the American Diabetes Foundation (ADA 7-12-BS-191 to Y.-H.T.); a Deutsche Forschungsgemeinschaft Research Fellowship (BA 4925/1-1 to A.B.); and a grant from the Danish Council for Independent Research (to M.L.). This research was supported in part by the Intramural Research Program of the NIH, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We thank K. Longval and A. Clermont of the Joslin Diabetes Center Animal Physiology core, H. Rockwell, K. Schlosser and J. McDaniel at BERG for expert technical assistance. We thank K. Inouye and P. Lizotte for critical discussion.

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Authors and Affiliations

  1. Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

    Matthew D Lynes, Luiz O Leiria, Morten Lundh, Farnaz Shamsi, Tian Lian Huang, Hirokazu Takahashi, Michael F Hirshman, Laurie J Goodyear & Yu-Hua Tseng

  2. The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark

    Morten Lundh

  3. Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA

    Alexander Bartelt, Christian Schlein, Alexandra Lee & Gökhan S Hotamisligil

  4. Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA

    Lisa A Baer, Francis J May & Kristin I Stanford

  5. BERG, Framingham, Massachusetts, USA

    Fei Gao, Niven R Narain, Emily Y Chen & Michael A Kiebish

  6. National Institutes of Health, Bethesda, Maryland, USA

    Aaron M Cypess

  7. Department of Medicine, University of Leipzig, Leipzig, Germany

    Matthias Blüher

  8. Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA

    Yu-Hua Tseng

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Contributions

M.D.L. designed research, carried out experiments, analyzed data and wrote the paper. L.O.L. carried out fatty acid uptake in vitro and Seahorse assays. M.L. carried out translocation assays. A.B., A.L. and C.S. carried out fatty acid–, triglyceride- and glucose-uptake assays in vivo. F.S. and T.L.H. performed gene-expression analysis and immunoblotting. H.T. carried out fatty acid–uptake assays in vitro. M.F.H., L.A.B. and F.J.M. carried out in vivo experiments. F.G., N.R.N. and M.A.K. oversaw lipidomics experiments. E.Y.C. performed lipidomic experiments and analyzed data. A.M.C. designed research and carried out human cold-exposure experiments. M.B. provided human plasma from well-phenotyped human individuals for 12,13-diHOME measurements. L.J.G. oversaw FA-uptake experiments. G.S.H. oversaw tracer-uptake experiments in vivo. K.I.S. oversaw in vivo experiments and analyzed data. M.D.L. and Y.-H.T. directed the research and co-wrote the paper.

Corresponding author

Correspondence to Yu-Hua Tseng.

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Competing interests

M.A.K., E.Y.C., N.R.N. and F.G. are employees of BERG.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Tables 1–4 (PDF 2138 kb)

Supplementary Video 1

Representative imaging of FFA-SS-Luc uptake in UCP1cre+/−Rosa(stop)Luc+/− injected intravenously with luciferin-conjugated fatty acid and 12,13-diHOME or vehicle. Data from individual images using sequential, one-minute exposures over approximately 50 minutes was stacked into a movie. The animal on the left is the vehicle treated and the mouse on the right is treated with 12,13-diHOME. (MOV 198 kb)

Supplementary Video 2

Representative imaging of FFA-SS-Luc uptake in CAG-Luc+/+ brown adipocyte cells treated with 12,13-diHOME or vehicle and then incubate with luciferin-conjugated fatty acid. Data from individual images using sequential, 30 second exposures over approximately 50 minutes was stacked into a movie. The well on the left is vehicle treated and the well on the right is treated with 12,13-diHOME. (AVI 154 kb)

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Lynes, M., Leiria, L., Lundh, M. et al. The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue. Nat Med 23, 631–637 (2017). https://doi.org/10.1038/nm.4297

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