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 hyperlipidemia1,2. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism3–5. 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’6–8. 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.

Cold-Activated Lipid Dynamics in Adipose Tissue Highlights a Role for Cardiolipin in Thermogenic Metabolism

“…We have previously identified 12,13-diHOME, an oxidized metabolite of linoleic acid, as a lipid biomarker of thermogenic activation (Lynes et al, 2017). In the present study, we focus on non-oxidized structural lipid species dynamics during thermogenic activation and identify phosphatidylglycerol and cardiolipin metabolism as one of the key metabolic pathways regulated in thermogenic fat.…”

“…While these data are informative, a comprehensive database and tools for analyzing specific lipid species are still missing. In addition, although serum lipidomics from mice exposed to cold have recently been reported (Simcox et al, 2017), the circulating lipidome of humans exposed to cold exposure has been, thus far, limited to a small set of fewer than 100 oxidized lipid species (Lynes et al, 2017). …”

Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases

“…The diols formed from sEH action generally lack the activity of the epoxidized precursors however they are dramatically more polar, move rapidly out of cells, and are easily conjugated and excreted (Greene, et al, 2000). Yet, there is some evidence PUFA diols are chemoattractant for monocytes (Kundu, et al, 2013) and that linoleic diols specifically act as lipokines in the regulation of brown adipose tissue and thermogenesis (Lynes, et al, 2017). There is no overt phenotype with the whole body knockout animals not subjected to physiologic stress (Spector & Kim, 2015), however, knockout mice had lower survival following ischemic events (Hutchens, et al, 2008).…”

Nature's fat-burning machine: brown adipose tissue in a hibernating mammal

“…5B). The high levels and strong induction of Ephx2 mRNA in ground squirrel BAT resembles the cold-induction (1 h at 4°C) of Ephx2 in mice leading to 12,13-diHOME production and the resulting increase in BAT fatty acid transport (Lynes et al, 2017). In natural hibernators, seasonal induction of Ephx2 suggests that ground squirrels and possibly other hibernating mammals have the potential to provide additional biochemical clues for increasing BAT size and function.…”

“…Despite the overall improvement in fat catabolism and the potential for weight loss, cold exposure is uncomfortable and not well-tolerated by nonhibernators. In March 2017, Tseng and colleagues (Lynes et al, 2017) showed that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) stimulates BAT activity in mice. Injection of 12,13-diHOME activates the uptake of fuel into mouse BAT, resulting in lowered levels of serum triglycerides and improved tolerance of cold temperatures.…”