European Journal of Nutrition

, Volume 53, Issue 8, pp 1625–1635

Combination of low dose of the anti-adipogenic agents resveratrol and phenelzine in drinking water is not sufficient to prevent obesity in very-high-fat diet-fed mice

  • C. Carpéné
  • S. Gomez-Zorita
  • R. Gupta
  • S. Grès
  • C. Rancoule
  • T. Cadoudal
  • J. Mercader
  • A. Gomez
  • C. Bertrand
  • Z. Iffiu-Soltész
Original Contribution



Resveratrol inhibits lipid accumulation but suffers from limited bioavailability. The anti-depressive agent phenelzine limits adipogenesis in various models of cultured preadipocytes, and this hydrazine derivative also inhibits de novo lipogenesis in mature adipocytes. It was therefore tested whether resveratrol effects on adiposity reduction and glucose tolerance improvement could be reinforced by co-administration with phenelzine.


Mice fed a very-high-fat diet (VHFD, 60 % calories as fat) were subjected to drinking solution containing low dose of resveratrol (0.003 %) and/or 0.02 % phenelzine for 12 weeks. Body fat content, glucose tolerance, food and water consumption were checked during treatment while fat depot mass was determined at the end of supplementation. Direct influence of the agents on lipogenesis and glucose uptake was tested in adipocytes.


Epididymal fat depots were reduced in mice drinking phenelzine alone or with resveratrol. No limitation of body weight gain or body fat content was observed in the groups drinking resveratrol or phenelzine, separately or in combination. The altered glucose tolerance and the increased fat body composition of VHFD-fed mice were not reversed by resveratrol and/or phenelzine. Such lack of potentiation between resveratrol and phenelzine prompted us to verify in vitro their direct effects on mouse adipocytes. Both molecules inhibited de novo lipogenesis, but did not potentiate each other at 10 or 100 μM. Only resveratrol inhibited hexose uptake in a manner that was not improved by phenelzine.


Phenelzine has no interest to be combined with low doses of resveratrol for treating/preventing obesity, when considering the VHFD mouse model.


Adipocyte lipogenesis Resveratrol Phenelzine Glucose tolerance Adiposity Combination 


  1. 1.
    Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, Prabhu VV, Allard JS, Lopez-Lluch G, Lewis K, Pistell PJ, Poosala S, Becker KG, Boss O, Gwinn D, Wang M, Ramaswamy S, Fishbein KW, Spencer RG, Lakatta EG, Le Couteur D, Shaw RJ, Navas P, Puigserver P, Ingram DK, de Cabo R, Sinclair DA (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342CrossRefGoogle Scholar
  2. 2.
    Lagouge M, Argmann C, Gerhart-Hines Z, Meziane H, Lerin C, Daussin F, Messadeq N, Milne J, Lambert P, Elliott P, Geny B, Laakso M, Puigserver P, Auwerx J (2006) Resveratrol improves mitochondrial function and protects against metabolic disease by activating SIRT1 and PGC-1alpha. Cell 127:1109–1122CrossRefGoogle Scholar
  3. 3.
    Baile CA, Yang JY, Rayalam S, Hartzell DL, Lai CY, Andersen C, Della-Fera MA (2011) Effect of resveratrol on fat mobilization. Ann N Y Acad Sci 1215:40–47CrossRefGoogle Scholar
  4. 4.
    Floyd ZE, Wang ZQ, Kilroy G, Cefalu WT (2008) Modulation of peroxisome proliferator-activated receptor gamma stability and transcriptional activity in adipocytes by resveratrol. Metabolism 57:S32–S38CrossRefGoogle Scholar
  5. 5.
    Costa CS, Rohden F, Hammes TO, Margis R, Bortolotto JW, Padoin AV, Mottin CC, Guaragna RM (2011) Resveratrol upregulated SIRT1, FOXO1, and adiponectin and downregulated PPARγ1-3 mRNA expression in human visceral adipocytes. Obes Surg 21:356–361CrossRefGoogle Scholar
  6. 6.
    Chen S, Li Z, Li W, Shan Z, Zhu W (2011) Resveratrol inhibits cell differentiation in 3T3-L1 adipocytes via activation of AMPK. Can J Physiol Pharmacol 89:793–799Google Scholar
  7. 7.
    Lasa A, Churruca I, Eseberri I, Andrés-Lacueva C, Portillo MP (2012) Delipidating effect of resveratrol metabolites in 3T3-L adipocytes. Mol Nutr Food Res 56:1559–1568CrossRefGoogle Scholar
  8. 8.
    Rayalam S, Yang J-Y, Ambati S, Della-Fera MA, Baile CA (2008) Resveratrol induces apoptosis and inhibits adipogenesis in 3T3-L1 adipocytes. Phytother Res 22:1367–1371CrossRefGoogle Scholar
  9. 9.
    Mercader J, Palou A, Bonet ML (2011) Resveratrol enhances fatty acid oxidation capacity and reduces resistin and Retinol-Binding Protein 4 expression in white adipocytes. J Nutr Biochem 22:828–834CrossRefGoogle Scholar
  10. 10.
    Lasa A, Schweiger M, Kotzbeck P, Churruca I, Simón E, Zechner R, Del Puy Portillo M (2012) Resveratrol regulates lipolysis via adipose triglyceride lipase. J Nutr Biochem 23:379–384CrossRefGoogle Scholar
  11. 11.
    Gomez-Zorita S, Tréguer K, Mercader J, Carpéné C (2013) Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells. J Physiol Biochem 69:585–593CrossRefGoogle Scholar
  12. 12.
    Maraculla MT, Alberdi G, Gomez S, Tueros I, Bald C, Rodriguez VM, Martinez JA, Portillo MP (2009) Effects of different doses of resveratrol on body fat and serum parameters in rats fed a hypercaloric diet. J Physiol Biochem 65:369–376CrossRefGoogle Scholar
  13. 13.
    Cho SJ, Jung UJ, Choi MS (2012) Differential effects of low-dose resveratrol on adiposity and hepatic steatosis in diet-induced obese mice. Br J Nutr 108:2166–2175CrossRefGoogle Scholar
  14. 14.
    Chen S, Li J, Zhang Z, Li W, Sun Y, Zhang Q, Feng X, Zhu W (2012) Effects of resveratrol on the amelioration of insulin resistance in KKAy mice. Can J Physiol Pharmacol 90:237–242CrossRefGoogle Scholar
  15. 15.
    Do GM, Jung UJ, Park HJ, Kwon EY, Jeon SM, McGregor RA, Choi MS (2012) Resveratrol ameliorates diabetes-related metabolic changes via activation of AMP-activated protein kinase and its downstream targets in db/db mice. Mol Nutr Food Res 56:1282–1291CrossRefGoogle Scholar
  16. 16.
    Louis XL, Thandapilly SJ, MohanKumar SK, Yu L, Taylor CG, Zahradka P, Netticadan T (2012) Treatment with low-dose resveratrol reverses cardiac impairment in obese prone but not in obese resistant rats. J Nutr Biochem 23:1163–1169CrossRefGoogle Scholar
  17. 17.
    Rivera L, Moron R, Zarzuelo A, Galisteo M (2009) Long-term resveratrol administration reduces metabolic disturbances and lowers blood pressure in obese Zucker rats. Biochem Pharmacol 77:1053–1063CrossRefGoogle Scholar
  18. 18.
    Larrosa M, Azorín-Ortuño M, Yañez-Gascón MJ, García-Conesa MT, Tomás-Barberán F, Espín JC (2011) Lack of effect of oral administration of resveratrol in LPS-induced systemic inflammation. Eur J Nutr 50:673–680CrossRefGoogle Scholar
  19. 19.
    Gómez-Zorita S, Fernández-Quintela A, Macarulla MT, Aguirre L, Hijona E, Bujanda L, Milagro F, Martínez JA, Portillo MP (2012) Resveratrol attenuates steatosis in obese Zucker rats by decreasing fatty acid availability and reducing oxidative stress. Br J Nutr 107:202–210CrossRefGoogle Scholar
  20. 20.
    Arias N, Miranda J, Macarulla MT, Aguirre L, Fernandez-Quintela A, Andres-Lacueva C, Urpi-Sarda M, Portillo MP (2013) The combination of resveratrol and conjugated linoleic acid attenuates the individual effects of these molecules on triacylglycerol metabolism in adipose tissue. Eur J Nutr. doi:10.1007/s00394-013-0566-y Google Scholar
  21. 21.
    Crandall JP, Oram V, Trandafirescu G, Reid M, Kishore P, Hawkins M, Cohen HW, Barzilai N (2012) Pilot study of resveratrol in older adults with impaired glucose tolerance. J Gerontol A Biol Sci Med Sci 67:1307–1312CrossRefGoogle Scholar
  22. 22.
    Timmers S, Konings E, Bilet L, Houtkooper RH, van de Weijer T, Goossens G, Hoeks J, van der Krieken S, Ryu D, Kersten S, Moonen-Kornips E, Hesselink M, Kunz I, Schrauwen-Hinderling V, Blaak E, Auwerx J, Schrauwen P (2011) Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. Cell Metab 14:612–622CrossRefGoogle Scholar
  23. 23.
    Konings E, Timmers S, Boekschoten MV, Goossens GH, Jocken JW, Afman LA, Müller M, Schrauwen P, Mariman EC, Blaak EE (2013) The effects of 30 days resveratrol supplementation on adipose tissue morphology and gene expression patterns in obese men. Int J Obes (Lond). doi:10.1038/ijo.2013.1155
  24. 24.
    Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J (2008) Specific SIRT1 activation mimics low energy levels and protects against diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab 8:347–358CrossRefGoogle Scholar
  25. 25.
    Yang JY, Della-Fera MA, Rayalam S, Ambati S, Hartzell DL, Park HJ, Baile CA (2008) Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin. Life Sci 82:1032–1039CrossRefGoogle Scholar
  26. 26.
    Park HJ, Yang JY, Ambati S, Della-Fera MA, Hausman DB, Rayalam S, Baile CA (2008) Combined effects of genistein, quercetin, and resveratrol in human and 3T3-L1 adipocytes. J Med Food 11:773–783CrossRefGoogle Scholar
  27. 27.
    Bruckbauer A, Zemel MB, Thorpe T, Akula MR, Stuckey AC, Osborne D, Martin EB, Kennel S, Wall JS (2012) Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice. Nutr Metab (Lond) 9:77CrossRefGoogle Scholar
  28. 28.
    Arias N, Macarulla MT, Aguirre L, Martínez-Castaño MG, Gómez-Zorita S, Miranda J, Martínez JA, Portillo MP (2011) The combination of resveratrol and conjugated linoleic acid is not useful in preventing obesity. J Physiol Biochem 67:471–477CrossRefGoogle Scholar
  29. 29.
    Al-Nuaimi SK, Mackenzie EM, Baker GB (2012) Monoamine oxidase inhibitors and neuroprotection: a review. Am J Ther 19:436–448CrossRefGoogle Scholar
  30. 30.
    Chiche F, Le Guillou M, Chetrite G, Lasnier F, Dugail I, Carpéné C, Moldes M, Fève B (2009) The antidepressant phenelzine alters differentiation of cultured human and mouse preadipocytes. Mol Pharmacol 75:1052–1061CrossRefGoogle Scholar
  31. 31.
    Carpéné C, Abello V, Iffiú-Soltész Z, Mercier N, Fève B, Valet P (2008) Limitation of adipose tissue enlargement in rats chronically treated with semicarbazide-sensitive amine oxidase and monoamine oxidase inhibitors. Pharmacol Res 57:426–434CrossRefGoogle Scholar
  32. 32.
    Carpéné C, Grès S, Rascalou S (2013) The amine oxidase inhibitor phenelzine limits lipogenesis in adipocytes without inhibiting insulin action on glucose uptake. J Neural Transm 120:997–1004CrossRefGoogle Scholar
  33. 33.
    Bhatt JK, Thomas S, Nanjan MJ (2012) Resveratrol supplementation improves glycemic control in type 2 diabetes mellitus. Nutr Res 32:537–541CrossRefGoogle Scholar
  34. 34.
    Szkudelski T, Szkudelska K (2011) Anti-diabetic effects of resveratrol. Ann N Y Acad Sci 1215:34–39CrossRefGoogle Scholar
  35. 35.
    Wong YT, Gruber J, Jenner AM, Ng MP, Ruan R, Tay FE (2009) Elevation of oxidative-damage biomarkers during aging in F2 hybrid mice: protection by chronic oral intake of resveratrol. Free Radic Biol Med 46:799–809CrossRefGoogle Scholar
  36. 36.
    Attané C, Foussal C, Le Gonidec S, Benani A, Daviaud D, Wanecq E, Guzmán-Ruiz R, Dray C, Bezaire V, Rancoule C, Kuba K, Ruiz-Gayo M, Levade T, Penninger J, Burcelin R, Pénicaud L, Valet P, Castan-Laurell I (2012) Apelin treatment increases complete fatty acid oxidation, mitochondrial oxidative capacity, and biogenesis in muscle of insulin-resistant mice. Diabetes 61:310–320CrossRefGoogle Scholar
  37. 37.
    Morin N, Visentin V, Calise D, Marti L, Zorzano A, Testar X, Valet P, Fischer Y, Carpéné C (2002) Tyramine stimulates glucose uptake in insulin-sensitive tissues in vitro and in vivo via its oxidation by amine oxidases. J Pharmacol Exp Ther 303:1238–1247CrossRefGoogle Scholar
  38. 38.
    Bour S, Prévot D, Guigne C, Stolen C, Jalkanen S, Valet P, Carpéné C (2007) Semicarbazide-sensitive amine oxidase substrates fail to induce insulin-like effects in fat cells from AOC3 knockout mice. J Neural Transm 114:829–833CrossRefGoogle Scholar
  39. 39.
    Iglesias-Osma MC, Bour S, Garcia-Barrado MJ, Visentin V, Pastor MF, Testar X, Marti L, Enrique-Tarancon G, Valet P, Moratinos J, Carpéné C (2005) Methylamine but not mafenide mimics insulin-like actvity of the semicarbazide-sensitive amine oxidase-substrate benzylamine on glucose tolerance and on human adipocyte metabolism. Pharmacol Res 52:475–484CrossRefGoogle Scholar
  40. 40.
    Moody AJ, Stan MA, Stan M, Gliemann J (1974) A simple free fat cell bioassay for insulin. Horm Metab Res 6:12–16CrossRefGoogle Scholar
  41. 41.
    Lasa A, Miranda J, Churruca I, Simón E, Arias N, Milagro F, Martínez JA, Portillo MP (2011) The combination of resveratrol and CLA does not increase the delipidating effect of each molecule in 3T3-L1 adipocytes. Nutr Hosp 26:997–1003Google Scholar
  42. 42.
    Alberdi G, Rodríguez VM, Miranda J, Macarulla MT, Arias N, Andrés-Lacueva C, Portillo MP (2011) Changes in white adipose tissue metabolism induced by resveratrol in rats. Nutr Metab (Lond) 8:29CrossRefGoogle Scholar
  43. 43.
    Szkudelska K, Nogowski L, Szkudelski T (2009) Resveratrol, a naturally occurring diphenolic compound, affects lipogenesis, lipolysis and antilipolytic action of insulin in isolated rat adipocytes. J Steroid Biochem Mol Biol 113:17–24CrossRefGoogle Scholar
  44. 44.
    Breen DM, Sanli T, Giacca A, Tsiani E (2008) Stimulation of muscle cell glucose uptake by resveratrol through sirtuins and AMPK. Biochem Biophys Res Commun 374:117–122CrossRefGoogle Scholar
  45. 45.
    Salas M, Obando P, Ojeda L, Ojeda PG, Perez AA, Vargas-Uribe M, Rivas CI, Vera JC, Reyes AM (2013) Resolution of the direct interaction and inhibition of the human GLUT1 hexose transporter by resveratrol from its effect on glucose accumulation. Am J Physiol Cell Physiol 305:C90–C99 Google Scholar
  46. 46.
    Pandey PR, Okuda H, Watabe M, Pai SK, Liu W, Kobayashi A, Xing F, Fukuda K, Hirota S, Sugai T, Wakabayashi G, Koeda K, Kashiwaba M, Suzuki K, Chiba T, Endo M, Fujioka T, Tanji S, Mo YY, Cao D, Wilber AC, Watabe K (2011) Resveratrol suppresses growth of cancer stem-like cells by inhibiting fatty acid synthase. Breast Cancer Res Treat 130:387–398CrossRefGoogle Scholar
  47. 47.
    Kang W, Hong HJ, Guan J, Kim DG, Yang EJ, Koh G, Park D, Han CH, Lee YJ, Lee DH (2012) Resveratrol improves insulin signaling in a tissue-specific manner under insulin-resistant conditions only: in vitro and in vivo experiments in rodents. Metabolism 61:424–433CrossRefGoogle Scholar
  48. 48.
    Andres-Lacueva C, Macarulla MT, Rotches-Ribalta M, Boto-Ordóñez M, Urpi-Sarda M, Rodríguez VM, Portillo MP (2012) Distribution of resveratrol metabolites in liver, adipose tissue, and skeletal muscle in rats fed different doses of this polyphenol. J Agric Food Chem 60:4833–4840CrossRefGoogle Scholar
  49. 49.
    Mercader J, Iffiú-Soltész Z, Bour S, Carpéné C (2011) Oral administration of semicarbazide limits weight gain together with inhibition of fat deposition and of primary amine oxidase activity in adipose tissue. J Obes 2011:475786CrossRefGoogle Scholar
  50. 50.
    MacKenzie EM, Grant SL, Baker GB, Wood PL (2008) Phenelzine causes an increase in brain ornithine that is prevented by prior monoamine oxidase inhibition. Neurochem Res 33:430–436CrossRefGoogle Scholar
  51. 51.
    Matveychuk D, Nunes E, Ullah N, Velázquez-Martinez CA, Mackenzie EM, Baker GB (2013) Comparison of phenelzine and geometric isomers of its active metabolite, β-phenylethylidenehydrazine, on rat brain levels of amino acids, biogenic amine neurotransmitters and methylamine. J Neural Transm 120:987–996CrossRefGoogle Scholar
  52. 52.
    McIntyre RS, Soczynska JK, Konarski JZ, Kennedy SH (2006) The effect of antidepressants on glucose homeostasis and insulin sensitivity: synthesis and mechanisms. Expert Opin Drug Saf 5:157–168CrossRefGoogle Scholar
  53. 53.
    Haeckel R, Oellerich M (1977) The influence of hydrazine, phenelzine and nialamide on gluconeogenesis and cell respiration in the perfused guinea-pig liver. Eur J Clin Invest 7:393–400CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • C. Carpéné
    • 1
  • S. Gomez-Zorita
    • 1
  • R. Gupta
    • 2
  • S. Grès
    • 1
  • C. Rancoule
    • 1
  • T. Cadoudal
    • 1
  • J. Mercader
    • 1
  • A. Gomez
    • 1
  • C. Bertrand
    • 1
  • Z. Iffiu-Soltész
    • 1
  1. 1.Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Institut National de la Santé et de la Recherche Médicale, U 1048, Team 3, CHU RangueilUniversité de Toulouse, UPSToulouse Cedex 4France
  2. 2.Seminal Applied Sciences Pvt. Ltd.JaipurIndia

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