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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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.
M.A.K., E.Y.C., N.R.N. and F.G. are employees of BERG.
Supplementary Figures 1–7 and Supplementary Tables 1–4 (PDF 2138 kb)
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)
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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