Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

Boucher, Jérémie; Quilliot, Didier; Pradère, Jean-Philippe; Simon, Marie‐Pierre; Grès, Sandra; Guigné, Charlotte; Prévot, Danielle; Ferry, Gilles; Boutin, Jean A.; Carpéné, Christian; Valet, Philippe; Saulnier-Blache, Jean Sébastien

doi:10.1007/s00125-004-1660-8

Cited by 101 publications

(98 citation statements)

References 12 publications

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“…After separating the adipocyte and SV fractions, we found that levels of Enpp2 expression were higher in adipocytes than in the SV fraction, as was reported previously (Fig. 1B) (17). Among the cell types present in the SV fraction, Pref1 + CD34 + preadipocytes expressed higher levels of ENPP2 than CD11b + F4/80 + macrophages or CD8 + T cells (Fig.…”

Section: Enpp2 Is Produced By Preadipocytes and Adipocytessupporting

confidence: 87%

“…4). 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).…”

Section: Discussionmentioning

confidence: 99%

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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: Enpp2 Is Produced By Preadipocytes and Adipocytessupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…6B ), as expected from previous work ( 9 ). Adipose tissue is a major source of ATX in the circulation (37)(38)(39)(40), and therefore, we measured the expression of ATX mRNA in the mammary fat pads of the female mice. ATX mRNA was increased by about 5.5-fold in the ONO-8430506-treated mice and this was accompanied by 3-fold increase in the concentration of ATX protein in the plasma ( Fig.…”

Section: Inhibition Of Atx In Vivo Increases Adipose Tissue Atx Expresupporting

confidence: 58%

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

Benesch

Zhao

Curtis

et al. 2015

Journal of Lipid Research

105

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This article is available online at http://www.jlr.org Autotaxin (ATX) is a secreted enzyme, which converts extracellular lysophosphatidylcholine (LPC) into lysophosphatidate (LPA). This is an important reaction in cell signaling because LPA activates at least six G proteincoupled receptors to increase cell division, survival, and migration ( 1, 2 ). ATX serves an essential function in embryonic development because ATX knockout mice die in utero at day 9.5 with defects in vasculogenesis and the development of the neural crest ( 3-6 ). In the postnatal organism, the major function of ATX appears to be in wound healing. ATX is produced in response to infl ammation to mediate wound repair. If the infl ammation is not resolved, then high ATX concentrations persist in association with infl ammatory diseases such as arthritis and infl ammatory bowel disease ( 1,7,8 ). In addition, infl ammatory bowel disease and hepatitis can progress to carcinogenesis in these organs ( 1 ). Signifi cantly, increased ATX activity is associated with the growth of breast tumors ( 9, 10 ) and the ATX gene is among the top 40 most upregulated in metastatic cancer ( 11 ). Blocking LPA production by inhibiting ATX activity with ONO-8430506 decreases the fi rst phase of breast tumor growth and subsequent metastasis by about 60 % in mice ( 9, 12 ). Conversely, increasing the low lipid phosphate phosphatase (LPP)1 activity in cancer cells so as to increase LPA turnover in the tumor and attenuate LPA signaling decreased breast tumor growth and metastasis in mice by about 80% ( 13 ). These studies emphasize the importance of ATX in controlling cell signaling in several physiological and pathological conditions. Consequently, it is important to understand how ATX activity and signaling by LPA are regulated. The present work focuses on the role of ATX and how its expression is controlled.Abstract Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and infl ammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. Howeve...

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“…In contrast to the decreased plasma lysoPLD activity of ATX in fasted rats, progressively increased LPA production from LPC by lysoPLD activity was reported in 24-h incubated serum of rabbits fed with a high cholesterol-diet for different numbers of weeks up to 12, mainly due to an increased total LPC level. 26) Increased expression of ATX by the adipose tissue of patients exhibiting both insulin resistance and impaired glucose tolerance or type 2 diabetes associated with massive obesity was reported, 27) suggesting an increased release of ATX into the blood circulation, about half of which was estimated to be derived from adipose tissue. 28) Further, LPA 1 was reported to be involved positively in high-fat diet-induced obesity in mice.…”

Section: Discussionmentioning

confidence: 99%

Alterations of Plasma Levels of Lysophosphatidic Acid in Response to Fasting of Rats

Ino

Shimizu

Tanaka

et al. 2012

Biological & Pharmaceutical Bulletin

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The aim of this study was to investigate the effect of fasting on in vivo plasma levels of lysophosphatidic acid (LPA), a physiologically important lysophospholipid mediator. We assayed to measure activities of an LPA-producing enzyme (lysophospholipase D) and LPA-degrading enzyme activities (lysophspholipase A, lipid phosphate phosphatase) in rat plasma or blood, by measuring choline, fatty acid and inorganic phosphate, respectively. Both LPA and its precursor lysophosphatidylcholine (LPC) were quantified by liquid chromatography-tandem mass spectrometry. Fasting of rats for 24 h decreased plasma concentrations of oleoyl-, linoleoyl-, arachidonoyl-and docosahexaenoyl-LPAs, but not palmitoyl-and stearoyl-LPAs, possibly due to decreased levels of corresponding LPCs in the plasma and elevated lipid phosphate phosphatase activity for LPAs in the blood. Our results indicate that the in vivo circulating levels of LPAs in rats are affected by fasting.Key words autotaxin; lysophospholipase D; lysophosphatidylcholine; lysophospholipase A; lipid phosphate phosphatase; plasma Lysophosphatidic acid (LPA) is well-known as the first lipidic intermediate of the de novo synthetic pathway for glycero phospholipids. Increasing interest is currently being directed toward its extracellular actions through at least six specific G-protein coupled receptors.1) Both circulating and local levels of LPA are regulated tightly by LPA-producing enzymes, LPA-degrading enzymes and LPA-binding proteins.2,3) Both abnormal production and degradation of LPA are assumed to be relevant to pathophysiological conditions of human such as cancer metastasis, 4) atherosclerosis, 5) organ fibrosis 6) and pain. 7) Although LPA-producing enzymatic activity in human plasma and bovine fetal serum was demonstrated to be largely due to autotaxin (ATX), 8,9) physiological regulation of the circulating LPA level is not yet well understood. 3,10) In this study, we focused our inquiry on whether the stress of nutritional restriction affected the in vivo plasma level and molecular species composition of LPA using quantifying lysophosphatidylcholine (LPC) and LPA by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and its mechanism by comparing LPA-producing and -degrading enzymatic activities during 12 and 24 h fasting. MATERIALS AND METHODSLysophospholipids Fatty acyl moieties of lysophospholipids are designated in terms of the combined number of carbon atoms : the combined number of double bonds. Palmitoyl (16 : 0)-, heptadecanoyl (17 : 0)-and linoleoyl (18 : 2)-LPCs were purchased from Avanti Polar Lipids (Alabaster, AL, U.S.A.). LPA having a heptadecanoyl group was prepared as described previously. 11)Animals Control male Wistar rats (9 wks old) were freely fed a standard chow (Japan SLC, Shizuoka, Japan) until experiments, whereas test rats of the same age were subjected to fasting for 12 h or 24 h. For blood collection, fasted and non-fasted rats were anesthetized with diethyl ether and blood was withdrawn from a catheter inserted into an abdominal a...

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Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/autotaxin expression

Cited by 101 publications

References 12 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

Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

Alterations of Plasma Levels of Lysophosphatidic Acid in Response to Fasting of Rats

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