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Journal ArticleDOI

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

TL;DR: It is shown 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, and this data suggest that 12,13 -diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.
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.

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Corrigendum: Host DNA released by NETosis promotes rhinovirus-induced
type-2 allergic asthma exacerbation
Marie Toussaint, David J Jackson, Dawid Swieboda, Anabel Guedán, Theodora-Dorita Tsourouktsoglou, Yee Man Ching,
Coraline Radermecker, Heidi Makrinioti, Julia Aniscenko, Michael R Edwards, Roberto Solari, Frédéric Farnir,
Venizelos Papayannopoulos, Fabrice Bureau, Thomas Marichal & Sebastian L Johnston
Nat. Med. 23, 681–691 (2017); published online 1 May 2017; corrected after print 12 July 2017
In the version of this article initially published, Dr. Nathan W Bartlett was inadvertently omitted from the author list and the Contributions section.
The errors have been corrected in the HTML and PDF versions of the article.
Corrigendum: The cold-induced lipokine 12,13-diHOME promotes fatty acid
transport into brown adipose tissue
Matthew D Lynes, Luiz O Leiria, Morten Lundh, Alexander Bartelt, Farnaz Shamsi, Tian Lian Huang, Hirokazu Takahashi,
Michael F Hirshman, Christian Schlein, Alexandra Lee, Lisa A Baer, Francis J May, Fei Gao, Niven R Narain, Emily Y Chen,
Michael A Kiebish, Aaron M Cypess, Matthias Blüher, Laurie J Goodyear, Gökhan S Hotamisligil, Kristin I Stanford & Yu-Hua Tseng
Nat. Med. 23, 631–637 (2017); published online 27 March 2017; corrected after print 23 August 2017
In the phrase, “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,” located in the abstract, the word “resistance” should take the place
of the wordsensitivity.
Also, the authors have clarified in more detail how the FATP1 oligomer density was quantitated in Figure 4f. This information can be found in
the “Membrane Fractionation” section of the Online Methods: “To quantify FATP1 in scanned immunoblots, regions of interest of identical size
were drawn in each lane at the same molecular weight, and integrated pixel density was measured using ImageJ software. For each independent
experimental replicate, the integrated pixel density for each lane was expressed normalized to the control lane, or in the case of the experimental
replicate with two control lanes, the integrated pixel density for each lane was expressed normalized to the average of both control lanes. The data
are expressed as the average normalized value for each lane, with the error bars representing s.e.m.
Corrigendum: Targeting cellular senescence prevents age-related bone loss in
mice
Joshua N Farr, Ming Xu, Megan M Weivoda, David G Monroe, Daniel G Fraser, Jennifer L Onken, Brittany A Negley, Jad G Sfeir,
Mikolaj B Ogrodnik, Christine M Hachfeld, Nathan K LeBrasseur, Matthew T Drake, Robert J Pignolo, Tamar Pirtskhalava,
Tamara Tchkonia, Merry Jo Oursler, James L Kirkland & Sundeep Khosla
Nat. Med. 23, 1072–1079 (2017); published online 21 August 2017; corrected after print 11 October 2017
In the version of this article initially published, the representative images in Fig. 2n were inadvertently duplicated in Fig. 4h. A correct version of
the images for Fig. 4h has been supplied. The authors wish to point out that this error did not affect the other data reported in the paper or the
conclusions drawn. The error has been corrected in the HTML and PDF versions of the article.
Corrigendum: Genome-wide CRISPR screens reveal a Wnt–FZD5 signaling
circuit as a druggable vulnerability of RNF43-mutant pancreatic tumors
Zachary Steinhart, Zvezdan Pavlovic, Megha Chandrashekhar, Traver Hart, Xiaowei Wang, Xiaoyu Zhang, Mélanie Robitaille,
Kevin R Brown, Sridevi Jaksani, René Overmeer, Sylvia F Boj, Jarrett Adams, James Pan, Hans Clevers, Sachdev Sidhu, Jason Moffat &
Stéphane Angers
Nat. Med. 23, 60–68 (2017); published online 21 November 2016; corrected after print 20 September 2017
In the version of this article initially published, duplicate panels in Figure 5e were incorrectly used in the assembly of the figure, for which all original
panels are presented in Supplementary Figure 10. The errors in Figure 5e have been corrected in the HTML and PDF versions of the article.
1384 VOLUME 23
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NUMBER 11
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NOVEMBER 2017 NATURE MEDICINE
CORRIGENDA
© 2017 Nature America, Inc., part of Springer Nature. All rights reserved.
Citations
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Journal ArticleDOI
TL;DR: The findings that led to these conclusions are reviewed and how this sets the stage for new lines of investigation in which extracellular miRNAs are recognized as important mediators of intercellular communication and potential candidates for therapy of disease.

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TL;DR: The rapidly expanding field of adipose tissue as an endocrine organ is explored, and how adipOSE tissue communicates with other tissues to regulate systemic metabolism both centrally and peripherally through secretion of adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, and miRNAs packaged in exosomes is explored.
Abstract: Over the past decade, great progress has been made in understanding the complexity of adipose tissue biology and its role in metabolism. This includes new insights into the multiple layers of adipose tissue heterogeneity, not only differences between white and brown adipocytes, but also differences in white adipose tissue at the depot level and even heterogeneity of white adipocytes within a single depot. These inter- and intra-depot differences in adipocytes are developmentally programmed and contribute to the wide range of effects observed in disorders with fat excess (overweight/obesity) or fat loss (lipodystrophy). Recent studies also highlight the underappreciated dynamic nature of adipose tissue, including potential to undergo rapid turnover and dedifferentiation and as a source of stem cells. Finally, we explore the rapidly expanding field of adipose tissue as an endocrine organ, and how adipose tissue communicates with other tissues to regulate systemic metabolism both centrally and peripherally through secretion of adipocyte-derived peptide hormones, inflammatory mediators, signaling lipids, and miRNAs packaged in exosomes. Together these attributes and complexities create a robust, multidimensional signaling network that is central to metabolic homeostasis.

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Cites background from "The cold-induced lipokine 12,13-diH..."

  • ...have shown that 12,13-diHOME is elevated in BAT versus WAT, and its levels in BAT and serum increase upon cold exposure in humans and rodents (172)....

    [...]

  • ...12,13-diHOME then acts back on BAT to increase fatty acid uptake, resulting in enhanced cold tolerance (172)....

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Journal ArticleDOI
TL;DR: The functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and how these factors contribute to the development of cardiometabolic diseases are discussed.
Abstract: In addition to their role in glucose and lipid metabolism, adipocytes respond differentially to physiological cues or metabolic stress by releasing endocrine factors that regulate diverse processes, such as energy expenditure, appetite control, glucose homeostasis, insulin sensitivity, inflammation and tissue repair. Both energy-storing white adipocytes and thermogenic brown and beige adipocytes secrete hormones, which can be peptides (adipokines), lipids (lipokines) and exosomal microRNAs. Some of these factors have defined targets; for example, adiponectin and leptin signal through their respective receptors that are expressed in multiple organs. For other adipocyte hormones, receptors are more promiscuous or remain to be identified. Furthermore, many of these hormones are also produced by other organs and tissues, which makes defining the endocrine contribution of adipose tissues a challenge. In this Review, we discuss the functional role of adipose tissue-derived endocrine hormones for metabolic adaptations to the environment and we highlight how these factors contribute to the development of cardiometabolic diseases. We also cover how this knowledge can be translated into human therapies. In addition, we discuss recent findings that emphasize the endocrine role of white versus thermogenic adipocytes in conditions of health and disease. Adipocytes respond to environmental cues, such as metabolic stress, by releasing endocrine factors that modulate diverse physiological processes. This Review discusses the metabolic functions of adipose tissue-derived endocrine hormones and highlights how these factors might contribute to cardiometabolic diseases.

311 citations

Journal ArticleDOI
TL;DR: This review will update the current knowledge of DNL in white and brown adipose tissues with the focus on transcriptional, post-translational, and central regulation of D NL.
Abstract: De novo lipogenesis (DNL) is a complex and highly regulated process in which carbohydrates from circulation are converted into fatty acids that are then used for synthesizing either triglycerides or other lipid molecules. Dysregulation of DNL contributes to human diseases such as obesity, type 2 diabetes, and cardiovascular diseases. Thus, the lipogenic pathway may provide a new therapeutic opportunity for combating various pathological conditions that are associated with dysregulated lipid metabolism. Hepatic DNL has been well documented, but lipogenesis in adipocytes and its contribution to energy homeostasis and insulin sensitivity are less studied. Recent reports have gained significant insights into the signaling pathways that regulate lipogenic transcription factors and the role of DNL in adipose tissues. In this review, we will update the current knowledge of DNL in white and brown adipose tissues with the focus on transcriptional, post-translational, and central regulation of DNL. We will also summarize the recent findings of adipocyte DNL as a source of some signaling molecules that critically regulate energy metabolism.

216 citations

Journal ArticleDOI
TL;DR: Analysis of lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12, 13-diHOME) in male, female, young, old, sedentary, and active human subjects.

199 citations


Cites background or methods or result from "The cold-induced lipokine 12,13-diH..."

  • ...Our recent study determined that BAT is the source of the increase in circulating 12,13diHOME in cold exposed mice (Lynes et al., 2017)....

    [...]

  • ...Lipokines can be released from adipose tissue (Cao et al., 2008; Lynes et al., 2017; Yore et al., 2014) and liver (Burhans et al., 2015; Liu et al., 2013) and have been reported to both improve skeletal muscle insulin sensitivity (Cao et al., 2008; Liu et al., 2013; Yore et al., 2014) or impair…...

    [...]

  • ...5μM 12,13-diHOME or methyl acetate vehicle for 15 min, similar to previous studies (Lynes et al., 2017)....

    [...]

  • ...Our recent study investigated the effects of cold exposure on BAT and identified 12,13- diHOME as a metabolite elevated in response to both short term (1 h) and chronic (7–11 days) cold exposure in rodents and humans (Lynes et al., 2017)....

    [...]

  • ...Lipokines can be released from adipose tissue (Cao et al., 2008; Lynes et al., 2017; Yore et al., 2014) and liver (Burhans et al....

    [...]

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Q1. What are the contributions in "Corrigendum: the cold-induced lipokine 12,13-dihome promotes fatty acid transport into brown adipose tissue" ?

Lynes, Luiz O Leiria, Morten Lundh, Alexander Bartelt, Farnaz Shamsi, Tian Lian Huang, Hirokazu Takahashi, Michael F Hirshman, Christian Schlein, Alexandra Lee, Lisa A Baer, Francis J May, Fei Gao, Niven R Narain, Emily Y Chen, Michael A Kiebish, Aaron M Cypess, Matthias Blüher, Laurie J Goodyear, Gökhan S Hotamisligil, Kristin I Stanford & Yu-Hua Ts