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

Leiria, Luiz O.; Wang, Chih-Hao; Lynes, Matthew D.; Yang, Kunyan; Shamsi, Farnaz; Sato, Mari; Sugimoto, Seiji; Chen, Emily Y.; Bussberg, Valerie; Narain, Niven R.; Sansbury, Brian E.; Darcy, Justin; Huang, Tian Lian; Kodani, Sean D.; Sakaguchi, Masaji; Rocha, Andréa L.; Schulz, Tim J.; Bartelt, Alexander; Hotamışlıgil, Gökhan S.; Hirshman, Michael F.; Leyen, Klaus van; Goodyear, Laurie J.; Blüher, Matthias; Cypess, Aaron M.; Kiebish, Michael A.; Spite, Matthew; Tseng, Yu–Hua

doi:10.1016/j.cmet.2019.07.001

Cited by 136 publications

(90 citation statements)

References 71 publications

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“…Consequently, the relevance of 9-and 13-HODE in a physiological context needs further experimental validation. Interestingly, 12-HETE and 14-HDoHE, two LOX products reported to be upregulated in murine interscapular BAT and inguinal WAT upon cold simulation (17), were also high contributors explaining variability between murine BAT and WAT in our study. In contrast to previously published observations, 14-HDoHE was not only lower at 5 • C compared to 30 • C in BAT but also lacked regulation in WAT (Supplementary Figure 4).…”

Section: Discussionmentioning

confidence: 51%

“…Within this scope, metabolites of PUFA (especially oxylipins) are discussed as potential effectors. Several studies have associated selected oxylipins with improved BAT functionality (17,18) or the recruitment of brite adipocytes (13)(14)(15) in mice. However, evidence in the human context is scarce.…”

Section: Discussionmentioning

confidence: 99%

“…The COX derived ARA metabolites prostaglandin E2 (PGE2) and prostacyclin (PGI2) facilitate the formation of brite adipocytes in vitro (13)(14)(15)(16). The oxylipin 12-hydroxyeicosapentaenoic acid (12-HEPE), identified in a PUFA metabolite screen in murine serum samples, facilitates glucose uptake into brown adipocytes (17). In a similar approach, increased levels of 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) were identified in oxylipin profiles of human serum after cold acclimatization (18).…”

Section: Introductionmentioning

confidence: 99%

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Fatty Acid Metabolite Profiling Reveals Oxylipins as Markers of Brown but Not Brite Adipose Tissue

et al. 2020

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Metabolites of omega-6 and omega-3 polyunsaturated fatty acids are important signaling molecules implicated in the control of adipogenesis and energy balance regulation. Some of these metabolites belonging to the group of oxylipins have been associated with non-shivering thermogenesis in mice mediated by brown or brite adipose tissue. We aimed to identify novel molecules with thermogenic potential and to clarify the relevance of these findings in a translational context. Therefore, we characterized and compared the oxylipin profiles of murine and human adipose tissues with different abundance of brown or brite adipocytes. A broad panel of 36 fatty acid metabolites was quantified in brown and white adipose tissues of C57BL/6J mice acclimatized to different ambient temperatures and in biopsies of human supraclavicular brown and white adipose tissue. The oxylipin profile of murine brite adipose tissue was not distinguishable from white adipose tissue, suggesting that adipose tissue browning in vivo is not associated with major changes in the oxylipin metabolism. Human brown and white adipose tissue also exhibited similar metabolite profiles. This is in line with previous studies proposing human brown adipose tissue to resemble the nature of murine brite adipose tissue representing a heterogeneous mixture of brite and white adipocytes. Although the global oxylipin profile served as a marker for the abundance of thermogenic adipocytes in bona fide brown but not white adipose tissue, we identified 5-HETE and 5,6-EET as individual compounds consistently associated with the abundance of brown or brite adipocytes in human BAT and murine brite fat. Further studies need to establish whether these candidates are mere markers or functional effectors of thermogenic capacity.

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Section: Discussionmentioning

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Fatty Acid Metabolite Profiling Reveals Oxylipins as Markers of Brown but Not Brite Adipose Tissue

et al. 2020

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“…Despite the abundance of evidence in rodents, however, the thermogenic effect of EPA and DHA and its relation to BAT in humans remain to be investigated. In this context, one interesting development is a recent report by Leiria et al (98), who observed that administration of a β3AR agonist induces a rapid increase in the plasma levels of 12-hydroxyeicosapentaenoic acid (12-HEPE) and 14-hydroxydocosahesanoic acids (14-HDHA), lipoxygenase products of EPA and DHA, in parallel with the BAT activity assessed by FDG-PET/CT, in humans. They also demonstrated in mice that activated brown adipocytes released 12-HEPE to promote glucose uptake into skeletal muscle and adipose tissues.…”

Section: Bat Thermogenesis and Dietary Fatmentioning

confidence: 99%

Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men

et al. 2020

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Since the recent rediscovery of brown adipose tissue (BAT) in adult humans, this thermogenic tissue has been attracting increasing interest. The inverse relationship between BAT activity and body fatness suggests that BAT, because of its energy dissipating activity, is protective against body fat accumulation. Cold exposure activates and recruits BAT, resulting in increased energy expenditure and decreased body fatness. The stimulatory effects of cold exposure are mediated through transient receptor potential (TRP) channels and the sympathetic nervous system (SNS). Most TRP members also function as chemesthetic receptors for various food ingredients, and indeed, agonists of TRP vanilloid 1 such as capsaicin and its analog capsinoids mimic the effects of cold exposure to decrease body fatness through the activation and recruitment of BAT. The antiobesity effect of other food ingredients including tea catechins may be attributable, at least in part, to the activation of the TRP-SNS-BAT axis. BAT is also involved in the facultative thermogenesis induced by meal intake, referred to as diet-induced thermogenesis (DIT), which is a significant component of the total energy expenditure in our daily lives. Emerging evidence suggests a crucial role for the SNS in BAT-associated DIT, particularly during the early phase, but several gut-derived humoral factors may also participate in meal-induced BAT activation. One intriguing factor is bile acids, which activate BAT directly through Takeda G-protein receptor 5 (TGR5) in brown adipocytes. Given the apparent beneficial effects of some TRP agonists and bile acids on whole-body substrate and energy metabolism, the TRP/TGR5-BAT axis represents a promising target for combating obesity and related metabolic disorders in humans.

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“…Of note, these oxylipins of AA change with the progression of ICH and the destructive oxylipins appear to peak 3 days after ICH when the protective oxylipins of AA have descended suggesting that AA-derived oxylipins tend to cause damage with the development of ICH. Studies show that HEPE tends to present anti-inflammatory effects and 12-HEPE can improve glucose metabolism by promoting glucose uptake through the insulin-like intracellular signaling pathway (Leiria et al, 2019). 18-HEPE, the precursor of the E-series specialized pro-resolving mediators, is another inhibitor of inflammation, and can halt the development of maladaptive cardiac remodeling and atherosclerosis (Endo et al, 2014;Liu et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Quantitative Profiling of Oxylipins in Acute Experimental Intracerebral Hemorrhage

et al. 2020

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Oxylipins are a series of bioactive lipid metabolites derived from polyunsaturated fatty acids that are involved in cerebral homeostasis and the development of intracerebral hemorrhage (ICH). However, comprehensive quantification of the oxylipin profile in ICH remains unknown. Therefore, an ICH mouse model was constructed and liquid chromatography tandem mass spectrometry was then performed to quantify the change in oxylipins in ICH. The expression of the oxylipin relative enzymes was also reanalyzed based on RNA-seq data from our constructed ICH dataset. A total of 58 oxylipins were quantifiable and the levels of 17 oxylipins increased while none decreased significantly in the first 3 days following ICH. The most commonly increased oxylipins in ICH were derived from AA (10/17) and EPA (4/17) followed by LA (2/17) and DHA (1/17). 18-HEPE from EPA was the only oxylipin that remained significantly increased from 0.5 to 3 days following ICH. Furthermore, 14 of the increased oxylipins reached a peak level on the first day of ICH, and soon decreased while five oxylipins (PGJ2, 15-oxo-ETE, 12-HEPE, 18-HEPE, and 5-oxo-ETE) had increased 3 days after ICH suggesting that the profile shifted with the progression of ICH. In our constructed RNA-seq dataset based on ICH rats, 90 oxylipin relative molecules were detected except for COX. Among these, Cyp4f18, Cyp1b1, Cyp2d3, Cyp2e1, Cyp1a1, ALOX5AP, and PLA2g4a were found up-regulated and Cyp26b1 was found to decrease in ICH. In addition, there was no significant change in sEH in ICH. This study provides fundamental data on the profile of oxylipins and their enzymes in ICH. We found that the profile shifted as the progression of ICH and the metabolism of arachidonic acid and eicosapentaenoic acid was highly affected in ICH, which will help further studies explore the functions of oxylipins in ICH.

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

Abstract: Highlights d Cold exposure increases 12-LOX activity in brown adipose tissue d 12-LOX activity in BAT contributes to cold adaptation d 12-HEPE is a cold-induced and BAT-secreted oxylipin d 12-HEPE promotes glucose uptake in vivo and in vitro

Cited by 136 publications

References 71 publications

Fatty Acid Metabolite Profiling Reveals Oxylipins as Markers of Brown but Not Brite Adipose Tissue

Fatty Acid Metabolite Profiling Reveals Oxylipins as Markers of Brown but Not Brite Adipose Tissue

Brown Adipose Tissue, Diet-Induced Thermogenesis, and Thermogenic Food Ingredients: From Mice to Men

Quantitative Profiling of Oxylipins in Acute Experimental Intracerebral Hemorrhage

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