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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Townsend, K. & Tseng, Y.H. Brown adipose tissue: Recent insights into development, metabolic function and therapeutic potential. Adipocyte 1, 13–24 (2012).
Lynes, M.D. & Tseng, Y.H. Unwiring the transcriptional heat circuit. Proc. Natl. Acad. Sci. USA 111, 14318–14319 (2014).
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).
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).
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).
Cao, H. et al. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134, 933–944 (2008).
Liu, S. et al. A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use. Nature 502, 550–554 (2013).
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).
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).
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).
Hoene, M. et al. The lipid profile of brown adipose tissue is sex-specific in mice. Biochim. Biophys. Acta 1841, 1563–1570 (2014).
Thompson, D.A. & Hammock, B.D. Dihydroxyoctadecamonoenoate esters inhibit the neutrophil respiratory burst. J. Biosci. 32, 279–291 (2007).
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).
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).
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).
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).
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).
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).
Schulz, T.J. et al. Brown-fat paucity due to impaired BMP signalling induces compensatory browning of white fat. Nature 495, 379–383 (2013).
Sisemore, M.F. et al. Cellular characterization of leukotoxin diol-induced mitochondrial dysfunction. Arch. Biochem. Biophys. 392, 32–37 (2001).
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).
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).
Bartelt, A. et al. Brown adipose tissue activity controls triglyceride clearance. Nat. Med. 17, 200–205 (2011).
Berbée, J.F. et al. Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development. Nat. Commun. 6, 6356 (2015).
Khedoe, P.P. et al. Brown adipose tissue takes up plasma triglycerides mostly after lipolysis. J. Lipid Res. 56, 51–59 (2015).
Schlein, C. et al. FGF21 lowers plasma triglycerides by accelerating lipoprotein catabolism in white and brown adipose tissues. Cell Metab. 23, 441–453 (2016).
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).
Henkin, A.H. et al. Real-time noninvasive imaging of fatty acid uptake in vivo. ACS Chem. Biol. 7, 1884–1891 (2012).
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).
Wu, Q. et al. Fatty acid transport protein 1 is required for nonshivering thermogenesis in brown adipose tissue. Diabetes 55, 3229–3237 (2006).
Putri, M. et al. CD36 is indispensable for thermogenesis under conditions of fasting and cold stress. Biochem. Biophys. Res. Commun. 457, 520–525 (2015).
Richards, M.R. et al. Oligomerization of the murine fatty acid transport protein 1. J. Biol. Chem. 278, 10477–10483 (2003).
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).
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).
Klöting, N. et al. Insulin-sensitive obesity. Am. J. Physiol. Endocrinol. Metab. 299, E506–E515 (2010).
Powell, W.S. Extraction of eicosanoids from biological fluids, cells, and tissues. Methods Mol. Biol. 120, 11–24 (1999).
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).
Best, D.J. & Roberts, D.E. The upper tail probabilities of Spearman's Rho. Appl. Stat. 24, 377–379 (1975).
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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