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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.”

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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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