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Cell Metab. 2019 Oct 1;30(4):768-783.e7. doi: 10.1016/j.cmet.2019.07.001. Epub 2019 Jul 25.

12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.

Author information

1
Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA.
2
BERG, Framingham, MA, USA.
3
Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative, and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
4
Department of Biochemistry and Tissue Biology, Institute of Biology, State University of Campinas, Campinas, Brazil.
5
Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA; Department of Adipocyte Development and Nutrition, German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany.
6
Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA; Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University, Munich 80336, Germany; German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany.
7
Department of Genetics and Complex Diseases & Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
8
Massachusetts General Hospital, Harvard Medical School, Neuroprotection Research Laboratory, Department of Radiology, Charlestown, MA, USA.
9
Department of Medicine, University of Leipzig, Leipzig, Germany.
10
National Institutes of Health, Bethesda, MD, USA.
11
Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address: yu-hua.tseng@joslin.harvard.edu.

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

PMID:
31353262
PMCID:
PMC6774888
[Available on 2020-10-01]
DOI:
10.1016/j.cmet.2019.07.001

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