Autotaxin and Its Product Lysophosphatidic Acid Suppress Brown Adipose Differentiation and Promote Diet-Induced Obesity in Mice

Federico, Lorenzo; Ren, Hongmei; Müeller, Paul; Wu, Tao; Liu, Shuying; Popović, Jelena; Blalock, Eric M.; Sunkara, Manjula; Ovaa, Huib; Albers, Harald M. H. G.; Mills, Gordon B.; Morris, Andrew J.; Smyth, Susan S.

doi:10.1210/me.2011-1229

Cited by 59 publications

(83 citation statements)

References 47 publications

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“…On the other hand, it has also been reported that ENPP2 expression is elevated in adipose tissue from diabetic db/db mice and that DIO mice show no significant changes in ENPP2 expression (17). What's more, earlier studies produced contradictory results regarding BAT mass, locomotor activity, thermogenic profiles, and systemic metabolism (6,7). The precise mechanisms responsible for these discrepancies between the results of the current study and those earlier ones are not immediately clear, but there were several experimental differences.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Dusaulcy et al (6) reported that adipocytespecific Enpp2 knockout (KO) mice fed a high-fat diet showed greater adiposity and less systemic insulin resistance than control mice, with no difference in food intake. By contrast, Federico et al (7) reported that fat pad weights were higher in mice overexpressing Enpp2, although locomotor activities, thermogenic profiles, and systemic metabolism were unchanged. These apparently contradictory results prompted us to examine the role of Enpp2 in systemic metabolism.…”

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confidence: 89%

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ENPP2 Contributes to Adipose Tissue Expansion and Insulin Resistance in Diet-Induced Obesity

et al. 2014

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Body weight is tightly regulated by food intake and energy dissipation, and obesity is related to decreased energy expenditure (EE). Herein, we show that nucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2, autotaxin) is an adipose-derived, secreted enzyme that controls adipose expansion, brown adipose tissue (BAT) function, and EE. In mice, Enpp2 was highly expressed in visceral white adipose tissue and BAT and is downregulated in hypertrophied adipocytes/adipose tissue. Enpp2 +/2 mice and adipocyte-specific Enpp2 knockout mice fed a highfat diet showed smaller body weight gains and less insulin resistance than control mice fed the same diet. BAT was functionally more active and EE was increased in Enpp2-deficient mice. In humans, ENPP2 expression in subcutaneous fat and ENPP2 levels in serum were reduced in obese subjects. Taken together, our results establish ENPP2 as an adipose-derived, secreted enzyme that regulates adipose obesity and systemic metabolism. They also suggest ENPP2 could be a useful therapeutic target for the treatment of metabolic disease.Until recently, adipose tissue was viewed as a passive energy storage organ, but with the discovery of leptin and the adipose-derived humoral factors now known as "adipokines," it has become apparent that adipose tissue is an active endocrine organ that is essential for energy homeostasis (1). Moreover, obese adipose tissue secretes various inflammatory cytokines, including interleukin-6 (IL-6) and tumor necrosis factor-a (TNF-a), whose activities are known to contribute to the development of metabolic and cardiovascular diseases (2).Enpp2, also designated autotaxin, phosphodiesterase I a/autotaxin, and nucleotide pyrophosphatase/phosphodiesterase 2, was originally discovered as an autocrine motility-stimulating factor released from cancer cells (3). ENPP2 catalyzes the conversion of lysophosphatidylcholine to lysophosphatidic acid (LPA), which exerts a variety of biological effects, in part via G-protein-coupled receptors (3,4). In addition, the COOH-terminal noncatalytic domain of ENPP2 also has biological effects independent of LPA (3). Homozygous Enpp2-deficient mice die in utero due to profound vascular defects, but heterozygous Enpp2-deficient (Enpp2 +/2 ) mice are apparently healthy, with plasma LPA levels about half those in wild-type (WT) mice (5). Enpp2 is reportedly expressed in mouse adipose tissue and 3T3-F442A preadipocytes, and medium conditioned by Enpp2-expressing COS7 cells increased proliferation of 3T3-F442A cells. Recently, Dusaulcy et al. (6) reported that adipocytespecific Enpp2 knockout (KO) mice fed a high-fat diet showed greater adiposity and less systemic insulin resistance

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Section: Discussionmentioning

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ENPP2 Contributes to Adipose Tissue Expansion and Insulin Resistance in Diet-Induced Obesity

et al. 2014

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“…OEA is one of the endocannabinoid-like metabolites, which is modulating satiety and decreases body weight through activation of peroxisome proliferatoractivated receptor-a but do not regulate the endocannabionid system (Capasso and Izzo, 2008). Lysophosphatidic acid is another bioactive lipid that mediates adipocyte proliferation and differentiation through downregulation of peroxisome proliferator-activated receptor-g and is involved in obesity (Nobusue et al, 2010;Federico et al, 2012). Enterolactone and enterodiol are bacterial metabolites, produced by certain bacteria and have been reported to exert beneficial effects in the body (Woting et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Distinct signatures of host–microbial meta-metabolome and gut microbiome in two C57BL/6 strains under high-fat diet

et al. 2014

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A combinatory approach using metabolomics and gut microbiome analysis techniques was performed to unravel the nature and specificity of metabolic profiles related to gut ecology in obesity. This study focused on gut and liver metabolomics of two different mouse strains, the C57BL/6J (C57J) and the C57BL/6N (C57N) fed with high-fat diet (HFD) for 3 weeks, causing dietinduced obesity in C57N, but not in C57J mice. Furthermore, a 16S-ribosomal RNA comparative sequence analysis using 454 pyrosequencing detected significant differences between the microbiome of the two strains on phylum level for Firmicutes, Deferribacteres and Proteobacteria that propose an essential role of the microbiome in obesity susceptibility. Gut microbial and liver metabolomics were followed by a combinatory approach using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS) and ultra performance liquid chromatography time of tlight MS/MS with subsequent multivariate statistical analysis, revealing distinctive host and microbial metabolome patterns between the C57J and the C57N strain. Many taurine-conjugated bile acids (TBAs) were significantly elevated in the cecum and decreased in liver samples from the C57J phenotype likely displaying different energy utilization behavior by the bacterial community and the host. Furthermore, several metabolite groups could specifically be associated with the C57N phenotype involving fatty acids, eicosanoids and urobilinoids. The mass differences based metabolite network approach enabled to extend the range of known metabolites to important bile acids (BAs) and novel taurine conjugates specific for both strains. In summary, our study showed clear alterations of the metabolome in the gastrointestinal tract and liver within a HFD-induced obesity mouse model in relation to the host-microbial nutritional adaptation.

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“…Over the course of two decades of research, a large number of studies have established that in addition to cellautonomous cancer hallmarks such as differentiation ( 58,(103)(104)(105)(106), survival (107)(108)(109)(110)(111)(112), proliferation ( 58,(113)(114)(115)(116), and migration/metastatic behavior ( 50, 74,92,[117][118][119][120][121][122], the aberrant expression/amplifi cation of ATX activity can also dysregulate multiple cancer pathobiology systemic hallmarks including angiogenesis ( 119,123 ), metabolic homeostasis ( 56-59, 104, 124, 125 ), and immune system function ( 126 ).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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Autotaxin and Its Product Lysophosphatidic Acid Suppress Brown Adipose Differentiation and Promote Diet-Induced Obesity in Mice

Cited by 59 publications

References 47 publications

ENPP2 Contributes to Adipose Tissue Expansion and Insulin Resistance in Diet-Induced Obesity

ENPP2 Contributes to Adipose Tissue Expansion and Insulin Resistance in Diet-Induced Obesity

Distinct signatures of host–microbial meta-metabolome and gut microbiome in two C57BL/6 strains under high-fat diet

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

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