title: The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue.
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 hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. 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'. 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 sensitivity. 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.
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lynes
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Luiz O
authors.initials: LO
authors.lastname: Leiria
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.|The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Morten
authors.initials: M
authors.lastname: Lundh
authors.affiliation: Department of Genetics and Complex Diseases &Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Bartelt
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Farnaz
authors.initials: F
authors.lastname: Shamsi
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Tian Lian
authors.initials: TL
authors.lastname: Huang
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hirshman
authors.affiliation: Department of Genetics and Complex Diseases &Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Schlein
authors.affiliation: Department of Genetics and Complex Diseases &Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Baer
authors.affiliation: Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: May
authors.affiliation: BERG, Framingham, Massachusetts, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Gao
authors.affiliation: BERG, Framingham, Massachusetts, USA.
authors.forename: Niven R
authors.initials: NR
authors.lastname: Narain
authors.affiliation: BERG, Framingham, Massachusetts, USA.
authors.forename: Emily Y
authors.initials: EY
authors.lastname: Chen
authors.affiliation: BERG, Framingham, Massachusetts, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kiebish
authors.affiliation: National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Cypess
authors.affiliation: Department of Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Blüher
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Goodyear
authors.affiliation: Department of Genetics and Complex Diseases &Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.affiliation: Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio, USA.
authors.forename: Kristin I
authors.initials: KI
authors.lastname: Stanford
authors.affiliation: Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.|Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Tseng
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D018955:CD36 Antigens / Q000187:drug effects / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D003080:Cold Temperature; D004734:Energy Metabolism / Q000187:drug effects; D050612:Fatty Acid Transport Proteins / Q000187:drug effects / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009765:Obesity / Q000378:metabolism*; D009829:Oleic Acids / Q000096:biosynthesis / Q000378:metabolism* / Q000494:pharmacology; D050177:Overweight / Q000378:metabolism; D000072078:Positron Emission Tomography Computed Tomography; D012333:RNA, Messenger / Q000378:metabolism; D019275:Radiopharmaceuticals; D022722:Thermogenesis; D014280:Triglycerides / Q000378:metabolism
chemical_list: C425204:12,13-dihydroxyoctadecenoic acid; D018955:CD36 Antigens; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D009829:Oleic Acids; D012333:RNA, Messenger; D019275:Radiopharmaceuticals; C493569:Slc27a1 protein, mouse; D014280:Triglycerides; D019788:Fluorodeoxyglucose F18