Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern? Florence Massiera, Perla Saint-Marc, Josiane Seydoux, Takahiko Murata, Takuya Kobayashi, Shuh Narumiya, Philippe Guesnet, Ez-Zoubir Amri, Raymond Negrel, Gérard Ailhaud To cite this version: Florence Massiera, Perla Saint-Marc, Josiane Seydoux, Takahiko Murata, Takuya Kobayashi, et al.. Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern?. Journal of Lipid Research, American Society for Biochemistry and Molecular Biology, 2003, 44 (2), pp.271-9. 10.1194/jlr.M200346-JLR200. hal-00326113 HAL Id: hal-00326113 https://hal.archives-ouvertes.fr/hal-00326113 Submitted on 1 Jun 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Copyright Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern? Florence Massiera,* Perla Saint-Marc,* Josiane Seydoux,† Takahiko Murata,§ Takuya Kobayashi,§ Shuh Narumiya,§ Philippe Guesnet,** Ez-Zoubir Amri,* Raymond Negrel,* and Gérard Ailhaud1,* Institut de Recherche Signalisation,* Biologie du Développement et Cancer, Centre de Biochimie (UMR6543CNRS), UNSA, Faculté des Sciences, Parc Valrose, 06108 Nice cedex 2, France; Centre Médical Downloaded from Universitaire,† Département de Physiologie, 1 rue Michel Servet, 1211 Genève 4, Switzerland; Department of Pharmacology,§ Kyoto University, Faculty of Medicine, Yoshida, Sakyo-ku, Kyoto 606-8315, Japan; and Laboratoire de Nutrition et Sécurité Alimentaire,** INRA, 78352 Jouy-en-Josas, France Abstract High fat intake is associated with fat mass gain cess in severe obesities is typically due to an increase in www.jlr.org through fatty acid activation of peroxisome proliferator-acti- adipocyte size and number. The formation of adipocytes ␦ ␥ vated receptors and , which promote adipogenesis. We is a critical event, as mature adipocytes do not divide in show herein that, compared to a combination of specific ag- vivo and do not undergo significant turnover under phys- onists to both receptors or to saturated, monounsaturated, at INRA Institut National de la Recherche Agronomique, on May 6, 2019 iological conditions. The capacity for proliferation of pre- and ␻-3 polyunsaturated fatty acids, arachidonic acid (C20:4, ␻-6) promoted substantially the differentiation of clonal cursor cells and their differentiation into adipocytes is preadipocytes. This effect was blocked by cyclooxygenase highest at early age and decrease thereafter in humans inhibitors and mimicked by carbacyclin, suggesting a role for and rodents. A limited number of hormones can affect the prostacyclin receptor and activation of the cyclic AMP- the adipose tissue mass and possibly its distribution (1). dependent pathways that regulate the expression of the High dietary fat intake is now recognized to be associated CCAAT enhancer binding proteins ␤ and ␦ implicated in ad- with a gain of fat mass in animals and humans at all ages ipogenesis. During the pregnancy-lactation period, mother (2–5). However, the lack of evidence of a general increase mice were fed either a high-fat diet rich in linoleic acid, a in energy intake as fat among youths, despite a striking precursor of arachidonic acid (LO diet), or the same isoca- loric diet enriched in linoleic acid and ␣-linolenic acid (LO/ increase in the prevalence of obesity in industrial and de- LL diet). Body weight from weaning onwards, fat mass, epi- veloping countries, may be due in part to decreased phys- didymal fat pad weight, and adipocyte size at 8 weeks of age ical activity and nonexercise activity thermogenesis (6), were higher with LO diet than with LO/LL diet. In contrast, but also to the composition of food intake in early life. prostacyclin receptor-deficient mice fed either diet were The long-term relationship between the fatty acid compo- similar in this respect, indicating that the prostacyclin sig- sition of dietary fats and the development of adipose tis- naling contributes to adipose tissue development. These sue in humans is difficult to assess in contrast to animals. results raise the issue of the high content of linoleic acid of When mother rats were fed a high-fat diet rich in linoleic i) ingested lipids during pregnancy and lactation, and ii) acid (C18:2, ␻-6) or saturated fatty acids, suckling pups at formula milk and infant foods in relation to the epidemic of childhood obesity.—Massiera, F., P. Saint-Marc, J. Sey- 17 days of age exhibited hyperplasia or hypertrophy of doux, T. Murata, T. Kobayashi, S. Narumiya, P. Guesnet, E-Z. white adipose tissue, respectively (7). Moreover, fish oil Amri, R. Negrel, and G, Ailhaud. Arachidonic acid and rich in eicosapentaenoic acid (C20:5, ␻-3, EPA) and prostacyclin signaling promote adipose tissue development: docosahexaenoic acid (C22:6, ␻-3, DHA) prevents obe- a human health concern? J. Lipid Res. 2003. 44: 271–279. sity in rats (8, 9), as well as feeding rats after weaning with dietary fats rich in ␣-linolenic acid (C18:3, ␻-3), the pre- Supplementary key words prostacyclin receptor-deficient mice • adi- cursor of EPA and DHA, prevents excessive growth of adi- pogenesis • pregnancy-lactation • childhood obesity pose tissue (10). The mechanisms underlying the differential adipo- genic effect of ␻-6 versus ␻-3 polyunsaturated fatty acids Obesity is associated with metabolic disorders such as dyslipidemia, diabetes, and hypertension, and fat mass ex- Abbreviations: ALBP (aP2), adipocyte lipid binding protein; PKA, Manuscript received 29 August 2002 and in revised form 28 October 2002. protein kinase A. Published, JLR Papers in Press, November 4, 2002. 1 To whom correspondence should be addressed. DOI 10.1194/jlr.M200346-JLR200 e-mail: [email protected] Copyright © 2003 by Lipid Research, Inc. This article is available online at http://www.jlr.org Journal of Lipid Research Volume 44, 2003 271 suggest differences between fatty acids and/or fatty acid MATERIALS AND METHODS metabolites in promoting differentiation of adipose pre- cursor cells into adipocytes. In vitro, at the preadipocyte Mice stage, a member of the peroxisome proliferator-activated The ip-r-null mice were established by gene targeting and receptor (PPAR) family, i.e., PPAR␦, and two members of backcrossed with C57/BL6J mice for at least 10 generations (28), Ϫ/Ϫ Ϫ/Ϫ the CCAAT-enhancer binding protein family, i.e., C/EBP␤ then ip-r males and ip-r females were bred to generate fur- ther generations. Both ip-rϪ/Ϫ and C57/BL6J control mice were and C/EBP␦, act concomitantly to upregulate the sub- ␥ maintained on a light/dark cycle with light from 6 AM to 6 PM at sequent and critical expression of PPAR leading to ad- 25ЊC. The female mice designated to be mothers were fed either ipogenesis (11–15). Natural long-chain fatty acids act a standard diet which consisted (by energy) of 7% fat, 66% car- in preadipocytes as adipogenic hormones, participate as bohydrates, and 27% proteins, or a high-fat diet containing 15% transcriptional regulators of the expression of various corn oil (LO diet) or a mixture of 10% corn oil and 5% perilla lipid-related genes, and promote adipogenesis (16). oil (LO/LL diet). Both high-fat diets consisted (by energy) of These effects implicate PPARs that bind long-chain fatty 40% fat, 35% carbohydrates, and 25% proteins, and were supple- acids and fatty acid metabolites (17). Among fatty acids, mented with 0.04% vitamin C and 0.02% vitamin E (UAR, Car- ␻ bon Blanc, France). Corn oil contained, expressed in g/100 g of arachidonic acid (C20:4, -6, ARA), a precursor of pros- ␻ total fatty acids, 13% saturated, 27% monounsaturated, 59% -6 Downloaded from taglandin I2 (prostacyclin), synthesized and released polyunsaturated, and 1% ␻-3 polyunsaturated fatty acids. The from preadipocytes, has been identified as one of the mixture of corn oil and perilla oil contained 10.9% saturated, main adipogenic components of serum. Arachidonic acid 22.9% monounsaturated, 44.3% ␻-6 polyunsaturated, and 21.9% induces a rapid cAMP production. Both this effect and its ␻-3 polyunsaturated fatty acids. At 8 weeks of age, female mice long-term adipogenic effect are impaired by cyclooxygen- fed the same diet since weaning were bred to male mice and maintained throughout mating, pregnancy, and lactation on the ase inhibitors such as aspirin and indomethacin (18). www.jlr.org Consistent with an autocrine-paracrine mechanism via re- same diet. At 18 days of age, male pups were weaned onto the leased prostacyclin, antibodies directed against this pros- same diets that their mothers had consumed and maintained thereafter. Food intake, body weight, body composition, and cel- tanoid and added externally decrease by half the adipo- lularity measurements of epididymal fat pad were performed as at INRA Institut National de la Recherche Agronomique, on May 6, 2019 genic effect of arachidonic acid (19). Also consistent with described previously (29). All experimental animal protocols a role of prostacyclin acting as a ligand at the cell surface, were performed in accordance with the recommendations of the it has been shown that i) prostacyclin and its stable ana- French Accreditation of Laboratory Animal Care. log carbacyclin mimic the effects of arachidonic acid (20) and also promote adipogenesis of clonal mouse preadi- Fibroblast culture Ϫ Ϫ pocytes and primary preadipocytes from rat and human Embryos from C57 BL/6J wild-type and ip-r / mice at 14.5 (21), and ii) prostacyclin binding to its cell surface recep- day postcoitus were used to prepare fibroblasts after removing head, heart, and legs.