@article{9cafd4ae38094f1aa234c8e43831cd11,
title = "12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat",
abstract = "Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.",
keywords = "12-HEPE, adipocytes, brown adipose tissue, diabetes, eicosapentaenoic acid, fat, lipidomic, lipokine, obesity, thermogenesis",
author = "Leiria, {Luiz Os{\'o}rio} and Wang, {Chih Hao} and Lynes, {Matthew D.} and Kunyan Yang and Farnaz Shamsi and Mari Sato and Satoru Sugimoto and Chen, {Emily Y.} and Valerie Bussberg and Narain, {Niven R.} and Sansbury, {Brian E.} and Justin Darcy and Huang, {Tian Lian} and Kodani, {Sean D.} and Masaji Sakaguchi and Rocha, {Andr{\'e}a L.} and Schulz, {Tim J.} and Alexander Bartelt and Hotamisligil, {G{\"o}khan S.} and Hirshman, {Michael F.} and {van Leyen}, Klaus and Goodyear, {Laurie J.} and Matthias Bl{\"u}her and Cypess, {Aaron M.} and Kiebish, {Michael A.} and Matthew Spite and Tseng, {Yu Hua}",
note = "Funding Information: This work was supported in part by US National Institutes of Health (NIH) grants R01DK077097 and R01DK102898 (to Y.-H.T.); R01HL106173 and P01GM095467 (to M.S.); R01DK099511 (to L.J.G.) and P30DK036836 (to Joslin Diabetes Center's Diabetes Research Center) from the National Institute of Diabetes and Digestive and Kidney Diseases ; and by US Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.). L.O.L. was supported by an American Diabetes Association post-doctoral fellowship ( 1-16-PDF-063 ) and by the S{\~a}o Paulo Research Foundation (FAPESP) grant 2017/02684 . M.D.L. was supported by NIH grants T32DK007260 , F32DK102320 , and K01DK111714 . K.v.L. was supported by the grant R21NS087165 . A.B. was supported by a Deutsche Forschungsgemeinschaft research fellowship ( BA 4925/1-1 ) and the Deutsches Zentrum f{\"u}r Herz-Kreislauf-Forschung . B.E.S. is supported by an NRSA from the NIH ( HL136044 ). We thank A. Clermont, A. Dean, and K. Longval of the Joslin Diabetes Center Physiology core. We also would like to thank Dr. Fabio Tucci of Epigen Biosciences, San Diego, who synthesized LOXBlock-1. We apologize to colleagues whose work we could not cite due to space limitations. Funding Information: This work was supported in part by US National Institutes of Health (NIH) grants R01DK077097 and R01DK102898 (to Y.-H.T.); R01HL106173 and P01GM095467 (to M.S.); R01DK099511 (to L.J.G.) and P30DK036836 (to Joslin Diabetes Center's Diabetes Research Center) from the National Institute of Diabetes and Digestive and Kidney Diseases; and by US Army Medical Research grant W81XWH-17-1-0428 (to Y.-H.T.). L.O.L. was supported by an American Diabetes Association post-doctoral fellowship (1-16-PDF-063) and by the S?o Paulo Research Foundation (FAPESP) grant 2017/02684. M.D.L. was supported by NIH grants T32DK007260, F32DK102320, and K01DK111714. K.v.L. was supported by the grant R21NS087165. A.B. was supported by a Deutsche Forschungsgemeinschaft research fellowship (BA 4925/1-1) and the Deutsches Zentrum f?r Herz-Kreislauf-Forschung. B.E.S. is supported by an NRSA from the NIH (HL136044). We thank A. Clermont, A. Dean, and K. Longval of the Joslin Diabetes Center Physiology core. We also would like to thank Dr. Fabio Tucci of Epigen Biosciences, San Diego, who synthesized LOXBlock-1. We apologize to colleagues whose work we could not cite due to space limitations. L.O.L. and Y.-H.T. conceived the study and designed and supervised the experiments. C.H.W. generated Gnas and Alox12 KD cells and performed bioenergetic profile and glucose uptake experiments in these cells. C.H.W. performed immunofluorescence studies. L.O.L. K.Y. and C.H.W. performed the western blottings in tissues and cells. L.O.L. and F.S. generated the AdipoCRE-Alox12 KO mice. L.O.L. C.H.W. M.D.L. F.S. M.S. S.S. T.L.L. J.D. and A.B. planned and performed in vivo glucose uptake. L.O.L. and K.Y. performed in vitro glucose uptake. L.O.L. and F.S. performed the indirect calorimetry in vivo studies. L.O.L. and K.Y. performed the in vivo physiologic studies such as GTT, ITT, and cold tolerance tests. E.Y.C. V.B. N.R.N. and M.A.K. planned and performed the global lipidomics. B.E.S. and M.S. planned and performed the targeted lipidomics. S.D.K. performed the 12-HEPE injections for its quantification in plasma. M.S. performed the flow cytometry experiments. L.O.L. and A.L.R. ran the qPCR experiments in adipose tissues, adipocyte, and SVF fractions. T.J.S. generated Myf5+CRE/Bmpr1aflox. K.v.L. helped design the experiments with 12-LOX-inhibitors. M.B. provided serum samples from obese, overweight, and lean patients. A.M.C. provided plasma samples from mirabegron-treated human volunteers. L.J.G. M.D.L. G.S.H. M.F.H. M.A.K. M.S. A.B. and K.v.L. helped with discussion and interpretation of results. L.O.L and Y.-H.T. wrote the manuscript. E.Y.C. V. B. N.R.N. and M.A.K. are employees of BERG. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = oct,
day = "1",
doi = "10.1016/j.cmet.2019.07.001",
language = "English (US)",
volume = "30",
pages = "768--783.e7",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "4",
}