The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue

Nat Med. 2017 May;23(5):631-637. doi: 10.1038/nm.4297. Epub 2017 Mar 27.


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.

Publication types

  • Video-Audio Media

MeSH terms

  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Biological Transport / drug effects
  • CD36 Antigens / drug effects
  • CD36 Antigens / metabolism
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cold Temperature*
  • Energy Metabolism / drug effects
  • Fatty Acid Transport Proteins / drug effects
  • Fatty Acid Transport Proteins / metabolism
  • Fatty Acids / metabolism*
  • Female
  • Fluorodeoxyglucose F18
  • Humans
  • Insulin Resistance*
  • Male
  • Mice
  • Obesity / metabolism*
  • Oleic Acids / biosynthesis
  • Oleic Acids / metabolism*
  • Oleic Acids / pharmacology
  • Overweight / metabolism
  • Positron Emission Tomography Computed Tomography
  • RNA, Messenger / metabolism
  • Radiopharmaceuticals
  • Thermogenesis*
  • Triglycerides / metabolism


  • 12,13-dihydroxyoctadecenoic acid
  • CD36 Antigens
  • Fatty Acid Transport Proteins
  • Fatty Acids
  • Oleic Acids
  • RNA, Messenger
  • Radiopharmaceuticals
  • Slc27a1 protein, mouse
  • Triglycerides
  • Fluorodeoxyglucose F18