Skip to main content

Advertisement

SpringerLink
Log in

The anxiolytic drug opipramol inhibits insulin-induced lipogenesis in fat cells and insulin secretion in pancreatic islets

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

The antidepressant drug opipramol has been reported to exert antilipolytic effect in human adipocytes, suggesting that alongside its neuropharmacological properties, this agent might modulate lipid utilization by peripheral tissues. However, patients treated for depression or anxiety disorders by this tricyclic compound do not exhibit the body weight gain or the glucose tolerance alterations observed with various other antidepressant or antipsychotic agents such as amitriptyline and olanzapine, respectively. To examine whether opipramol reproduces or impairs other actions of insulin, its direct effects on glucose transport, lipogenesis and lipolysis were investigated in adipocytes while its influence on insulin secretion was studied in pancreatic islets. In mouse and rat adipocytes, opipramol did not activate triglyceride breakdown, but partially inhibited the lipolytic action of isoprenaline or forskolin, especially in the 10–100 μM range. At 100 μM, opipramol also inhibited the glucose incorporation into lipids without limiting the glucose transport in mouse adipocytes. In pancreatic islets, opipramol acutely impaired the stimulation of insulin secretion by various activators (high glucose, high potassium, forskolin...). Similar inhibitory effects were observed in mouse and rat pancreatic islets and were reproduced with 100 μM haloperidol, in a manner that was independent from alpha2-adrenoceptor activation but sensitive to Ca2+ release. All these results indicated that the anxiolytic drug opipramol is not only active in central nervous system but also in multiple peripheral tissues and endocrine organs. Due to its capacity to modulate the lipid and carbohydrate metabolisms, opipramol deserves further studies in order to explore its therapeutic potential for the treatment of obese and diabetic states.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Albaugh VL, Vary TC, Ilkayeva O, Wenner BR, Maresca KP, Joyal JL, Breazeale S, Elich TD, Lang CH, Lynch CJ (2012) Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents. Schizophr Bull 38:153–166. https://doi.org/10.1093/schbul/sbq053

    Article  PubMed  Google Scholar 

  2. Bernstein JG (1987) Induction of obesity by psychotropic drugs. Ann N Y Acad Sci 499:203–215

    Article  CAS  PubMed  Google Scholar 

  3. Bowen WD, Moses EL, Tolentino PJ, Walker JM (1990) Metabolites of haloperidol display preferential activity at sigma receptors compared to dopamine D-2 receptors. Eur J Pharmacol 177:111–118. https://doi.org/10.1016/0014-2999(90)90260-d

    Article  CAS  PubMed  Google Scholar 

  4. 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 (Vienna) 120:997–1003. https://doi.org/10.1007/s00702-012-0951-3

    Article  CAS  PubMed  Google Scholar 

  5. Carpéné C, Galitzky J, Belles C, Zakaroff-Girard A (2018) Mechanisms of the antilipolytic response of human adipocytes to tyramine, a trace amine present in food. J Physiol Biochem 74:623–633. https://doi.org/10.1007/s13105-018-0643-z

    Article  CAS  PubMed  Google Scholar 

  6. Carpéné C, Les F, Casedas G, Peiro C, Fontaine J, Chaplin A, Mercader J, Lopez V (2019) Resveratrol anti-obesity effects: rapid inhibition of adipocyte glucose utilization. Antioxidants (Basel) 8:74. https://doi.org/10.3390/antiox8030074

    Article  CAS  PubMed  Google Scholar 

  7. Carpéné C, Les F, Mercader J, Gomez-Zorita S, Grolleau JL, Boulet N, Fontaine J, Iglesias-Osma MC, Garcia-Barrado MJ (2020) Opipramol inhibits lipolysis in human adipocytes without altering glucose uptake and differently from antipsychotic and antidepressant drugs with adverse effects on body weight control. Pharmaceuticals (Basel) 13(3):41. https://doi.org/10.3390/ph13030041

    Article  CAS  PubMed  Google Scholar 

  8. Doggrell SA, Woodruff GN (1977) Effects of antidepressant drugs on noradrenaline accumulation and contractile responses in the rat anococcygeus muscle. Br J Pharmacol 59:403–409. https://doi.org/10.1111/j.1476-5381.1977.tb08393.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Duckworth WC, Solomon SS, Liepnieks J, Hamel FG, Hand S, Peavy DE (1988) Insulin-like effects of vanadate in isolated rat adipocytes. Endocrinology 122:2285–2289. https://doi.org/10.1210/endo-122-5-2285

    Article  CAS  PubMed  Google Scholar 

  10. Feldman JM, Chapman B (1975) Monoamine oxidase inhibitors: nature of their interaction with rabbit pancreatic islets to alter insulin secretion. Diabetologia 11:487–494. https://doi.org/10.1007/bf01222097

    Article  CAS  PubMed  Google Scholar 

  11. Furukawa S, Fujita T, Shimabukuro M, Iwaki M, Yamada Y, Nakajima Y, Nakayama O, Makishima M, Matsuda M, Shimomura I (2004) Increased oxidative stress in obesity and its impact on metabolic syndrome. J Clin Invest 114:1752–1761. https://doi.org/10.1172/jci21625

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gahr M, Hiemke C, Connemann BJ (2017) Update Opipramol. Fortschr Neurol Psychiatr 85:139–145. https://doi.org/10.1055/s-0043-100762

    Article  PubMed  Google Scholar 

  13. Garcia Barrado MJ, Pastor MF, Iglesias-Osma MC, Carpéné C, J. M (2010) Comparative effects of idazoxan, efaroxan, and BU 224 on insulin secretion in the rabbit: not only interaction with pancreatic imidazoline I2 binding sites. Health 2:112-123.

  14. Garcia-Rizo C (2020) Antipsychotic-induced weight gain and clinical improvement: A psychiatric paradox. Front Psychiatry 11:560006. https://doi.org/10.3389/fpsyt.2020.560006

    Article  PubMed  PubMed Central  Google Scholar 

  15. García-Tornadú I, Ornstein AM, Chamson-Reig A, Wheeler MB, Hill DJ, Arany E, Rubinstein M, Becu-Villalobos D (2010) Disruption of the dopamine D2 receptor impairs insulin secretion and causes glucose intolerance. Endocrinology 151:1441–1450. https://doi.org/10.1210/en.2009-0996

    Article  CAS  PubMed  Google Scholar 

  16. Girousse A, Tavernier G, Valle C, Moro C, Mejhert N, Dinel AL, Houssier M, Roussel B, Besse-Patin A, Combes M, Mir L, Monbrun L, Bezaire V, Prunet-Marcassus B, Waget A, Vila I, Caspar-Bauguil S, Louche K, Marques MA et al (2013) Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS Biol 11:e1001485. https://doi.org/10.1371/journal.pbio.1001485

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Gomez-Zorita S, Treguer K, Mercader J, Carpéné C (2013) Resveratrol directly affects in vitro lipolysis and glucose transport in human fat cells. J Physiol Biochem 69:585–593. https://doi.org/10.1007/s13105-012-0229-0

    Article  CAS  PubMed  Google Scholar 

  18. Haj Ahmed W, Boulet N, Briot A, Ryan BJ, Kinsella GK, O’Sullivan J, Les F, Mercader-Barceló J, Henehan GTM, Carpéné C (2021) Novel facet of an old dietary molecule? Direct influence of caffeine on glucose and biogenic amine handling by human adipocytes. Molecules 26(13):3831. https://doi.org/10.3390/molecules26133831

    Article  CAS  Google Scholar 

  19. Harant-Farrugia I, Garcia J, Iglesias-Osma MC, Garcia-Barrado MJ, Carpene C (2014) Is there an optimal dose for dietary linoleic acid? Lessons from essential fatty acid deficiency supplementation and adipocyte functions in rats. J Physiol Biochem 70:615–627. https://doi.org/10.1007/s13105-014-0315-6

    Article  CAS  PubMed  Google Scholar 

  20. Henquin JC (1981) Effects of trifluoperazine and pimozide on stimulus-secretion coupling in pancreatic B-cells. Suggestion for a role of calmodulin? Biochem J 196:771–780. https://doi.org/10.1042/bj1960771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Holoubek G, Müller WE (2003) Specific modulation of sigma binding sites by the anxiolytic drug opipramol. J Neural Transm 110:1169–1179

    Article  CAS  PubMed  Google Scholar 

  22. Iglesias-Osma MC, Garcia-Barrado MJ, Visentin V, Pastor-Mansilla MF, Bour S, Prevot D, Valet P, Moratinos J, Carpéné C (2004) Benzylamine exhibits insulin-like effects on glucose disposal, glucose transport, and fat cell lipolysis in rabbits and diabetic mice. J Pharmacol Exp Ther 309:1020–1028. https://doi.org/10.1124/jpet.103.063636

    Article  CAS  PubMed  Google Scholar 

  23. Kraus T, Haack M, Schuld A, Hinze-Selch D, Kühn M, Uhr M, Pollmächer T (1999) Body weight and leptin plasma levels during treatment with antipsychotic drugs. Am J Psychiatry 156:312–314. https://doi.org/10.1176/ajp.156.2.312

    Article  CAS  PubMed  Google Scholar 

  24. Krausz Y, Eylon L, Cerasi E (1987) Calcium-binding proteins and insulin release. Differential effects of phenothiazines on first- and second-phase secretion and on islet cAMP response to glucose. Acta Endocrinol (Copenh) 116:241–246

    CAS  PubMed  Google Scholar 

  25. Krieger-Brauer HI, Medda PK, Kather H (1997) Insulin-induced activation of NADPH-dependent H2O2 generation in human adipocyte plasma membranes is mediated by Galphai2. J Biol Chem 272:10135–10143

    Article  CAS  PubMed  Google Scholar 

  26. Krysta K, Murawiec S, Warchala A, Zawada K, Cubała WJ, Wiglusz MS, Jakuszkowiak-Wojten K, Krzystanek M, Krupka-Matuszczyk I (2015) Modern indications for the use of opipramol. Psychiatr Danub 27(Suppl 1):S435–S437

    PubMed  Google Scholar 

  27. 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 5:157–168. https://doi.org/10.1517/14740338.5.1.157

    Article  CAS  PubMed  Google Scholar 

  28. Melkersson K, Khan A, Hilding A, Hulting AL (2001) Different effects of antipsychotic drugs on insulin release in vitro. Eur Neuropsychopharmacol 11:327–332. https://doi.org/10.1016/s0924-977x(01)00108-0

    Article  CAS  PubMed  Google Scholar 

  29. Minder S, Daniel WA, Clausen J, Bickel MH (1994) Adipose tissue storage of drugs as a function of binding competition. In-vitro studies with distribution dialysis. J Pharm Pharmacol 46:313–315. https://doi.org/10.1111/j.2042-7158.1994.tb03801.x

    Article  CAS  PubMed  Google Scholar 

  30. Minet-Ringuet J, Even PC, Valet P, Carpéné C, Visentin V, Prevot D, Daviaud D, Quignard-Boulange A, Tome D, de Beaurepaire R (2007) Alterations of lipid metabolism and gene expression in rat adipocytes during chronic olanzapine treatment. Mol Psychiatry 12:562–571. https://doi.org/10.1038/sj.mp.4001948

    Article  CAS  PubMed  Google Scholar 

  31. Minzenberg MJ, Yoon JH (2011) An index of relative central α-adrenergic receptor antagonism by antipsychotic medications. Exp Clin Psychopharmacol 19:31–39. https://doi.org/10.1037/a0022258

    Article  CAS  PubMed  Google Scholar 

  32. Möller HJ, Volz HP, Reimann IW, Stoll KD (2001) Opipramol for the treatment of generalized anxiety disorder: a placebo-controlled trial including an alprazolam-treated group. J Clin Psychopharmacol 21:59–65. https://doi.org/10.1097/00004714-200102000-00011

    Article  PubMed  Google Scholar 

  33. Moody AJ, Stan MA, Stan M, Gliemann J (1974) A simple free fat cell bioassay for insulin. Horm Metab Res 6:12–16. https://doi.org/10.1055/s-0028-1093895

    Article  CAS  PubMed  Google Scholar 

  34. Mulder H, Sörhede-Winzell M, Contreras JA, Fex M, Ström K, Ploug T, Galbo H, Arner P, Lundberg C, Sundler F, Ahrén B, Holm C (2003) Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact. J Biol Chem 278:36380–36388. https://doi.org/10.1074/jbc.M213032200

    Article  CAS  PubMed  Google Scholar 

  35. Müller WE, Siebert B, Holoubek G, Gentsch C (2004) Neuropharmacology of the anxiolytic drug opipramol, a sigma site ligand. Pharmacopsychiatry 37(Suppl 3):S189–S197. https://doi.org/10.1055/s-2004-832677

    Article  CAS  PubMed  Google Scholar 

  36. Nimura S, Yamaguchi T, Ueda K, Kadokura K, Aiuchi T, Kato R, Obama T, Itabe H (2015) Olanzapine promotes the accumulation of lipid droplets and the expression of multiple perilipins in human adipocytes. Biochem Biophys Res Commun 467:906–912. https://doi.org/10.1016/j.bbrc.2015.10.045

    Article  CAS  PubMed  Google Scholar 

  37. Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, Beck K, Natesan S, Efthimiou O, Cipriani A, Howes OD (2020) Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry 7:64–77. https://doi.org/10.1016/s2215-0366(19)30416-x

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rozanski V, Laux G, Schwarz J (2019) The dopamine receptor antagonism of opipramol: relevance to Parkinsonism? Clin Neuropharmacol 42:77–79. https://doi.org/10.1097/wnf.0000000000000332

    Article  CAS  PubMed  Google Scholar 

  39. Samols E, Stagner JI (1980) Reinterpretation of the effect of haloperidol and ethanol on insulin secretion. Diabetologia 19:81–83. https://doi.org/10.1007/bf00258316

    Article  CAS  PubMed  Google Scholar 

  40. Sarsenbayeva A, Marques-Santos CM, Thombare K, Di Nunzio G, Almby KE, Lundqvist M, Eriksson JW, Pereira MJ (2019) Effects of second-generation antipsychotics on human subcutaneous adipose tissue metabolism. Psychoneuroendocrinol 110:104445–104445. https://doi.org/10.1016/j.psyneuen.2019.104445

    Article  CAS  Google Scholar 

  41. Schulz M, Schmoldt A (2003) Therapeutic and toxic blood concentrations of more than 800 drugs and other xenobiotics. Pharmazie 58:447–474

    CAS  PubMed  Google Scholar 

  42. Sertié AL, Suzuki AM, Sertié RAL, Andreotti S, Lima FB, Passos-Bueno MR, Gattaz WF (2011) Effects of antipsychotics with different weight gain liabilities on human in vitro models of adipose tissue differentiation and metabolism. Prog Neuropsychopharmacol Biol Psychiatry 35:1884–1890. https://doi.org/10.1016/j.pnpbp.2011.07.017

    Article  CAS  PubMed  Google Scholar 

  43. Unger RH (1995) Lipotoxicity in the pathogenesis of obesity-dependent NIDDM. Genetic and clinical implications. Diabetes 44:863–870. https://doi.org/10.2337/diab.44.8.863

    Article  CAS  PubMed  Google Scholar 

  44. Vestri HS, Maianu L, Moellering DR, Garvey WT (2007) Atypical antipsychotic drugs directly impair insulin action in adipocytes: effects on glucose transport, lipogenesis, and antilipolysis. Neuropsychopharmacology 32:765–772. https://doi.org/10.1038/sj.npp.1301142

    Article  CAS  PubMed  Google Scholar 

  45. Vidarsdottir S, de Leeuw van Weenen JE, Frölich M, Roelfsema F, Romijn JA, Pijl H (2010) Effects of olanzapine and haloperidol on the metabolic status of healthy men. J Clin Endocrinol Metab 95:118–125. https://doi.org/10.1210/jc.2008-1815

    Article  CAS  PubMed  Google Scholar 

  46. Wang SP, Laurin N, Himms-Hagen J, Rudnicki MA, Levy E, Robert MF, Pan L, Oligny L, Mitchell GA (2001) The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice. Obes Res 9:119–128. https://doi.org/10.1038/oby.2001.15

    Article  CAS  PubMed  Google Scholar 

  47. Xu H, Zhuang X (2019) Atypical antipsychotics-induced metabolic syndrome and nonalcoholic fatty liver disease: a critical review. Neuropsychiatr Dis Treat 15:2087–2099. https://doi.org/10.2147/ndt.s208061

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Yang C, Chen Y, Tang L, Wang ZJ (2011) Haloperidol disrupts opioid-antinociceptive tolerance and physical dependence. J Pharmacol Exp Ther 338:164–172. https://doi.org/10.1124/jpet.110.175539

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang H, Shen H, Li J, Stanford KI, Guo LW (2020) Sigma-1 receptor ablation impedes adipocyte-like differentiation of mouse embryonic fibroblasts. Cell Signal 75:109732. https://doi.org/10.1016/j.cellsig.2020.109732

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Younce C, Kolattukudy P (2012) MCP-1 induced protein promotes adipogenesis via oxidative stress, endoplasmic reticulum stress and autophagy. Cell Physiol Biochem 30:307–320. https://doi.org/10.1159/000339066

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We hope that in this report we have respected the wishes of our deceased colleague by finalizing the work she had started on the peripheral effects of psychoactive drugs in metabolic diseases. The authors are grateful to all members of the CTPIOD mini-network for helpful discussions (http://obesitydiabetesinctp.weebly.com). All our thanks to G. Tavernier for providing us with HSLKO mice, and to D. Prévot. and M.J. Almaraz for their expert technical assistance.

Author information

Authors and Affiliations

  1. Department of Physiology and Pharmacology, Faculty of Medicine, University of Salamanca, Salamanca, Spain

    Maria Carmen Iglesias-Osma, Maria José García-Barrado & David Hernandez-Gonzalez

  2. Laboratory of Neuroendocrinology, Institute of Neurosciences of Castilla y León (INCyL), and Laboratory of Neuroendocrinology and Obesity, Institute of Biomedical Research of Salamanca (IBSAL), University of Salamanca, Salamanca, Spain

    Maria Carmen Iglesias-Osma, Maria José García-Barrado & David Hernandez-Gonzalez

  3. Inserm UMR1297, Institute of Metabolic and Cardiovascular Diseases, I2MC, CHU Rangueil, BP84225, 1 avenue Jean Poulhès, 31432, Toulouse, cedex 4, France

    Kévin Perrier, Pénélope Viana & Christian Carpéné

  4. University of Toulouse, UMR1297, Paul Sabatier University, Toulouse, France

    Kévin Perrier, Pénélope Viana & Christian Carpéné

Authors
  1. Maria Carmen Iglesias-Osma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maria José García-Barrado
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David Hernandez-Gonzalez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kévin Perrier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Pénélope Viana
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Christian Carpéné
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, C.C, M.C.I.O, and M.J.G.B.; in vitro investigations and data acquisition, P.V. and D.H.G.; biological resource preparation, K.P.; data processing, C.C., M.C.I.O., and M.J.G.B.; data analysis, C.C.; writing, reviewing and editing, C.C. and M.J.G.B. All the authors read and approved the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding author

Correspondence to Christian Carpéné.

Ethics declarations

Research involving human participants and/or animals

Animal procedures were approved with code 12-1048-03-15, by the Animal Ethics Committee of the INSERM unit US006, CREFRE (Toulouse, France) or by the Committee for the Care and Use of Animals of the University of Salamanca (Spain).

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

Opipramol is antilipolytic in rat and mouse fat cells.

Opipramol impairs insulin stimulation of lipid synthesis from glucose in rodent fat cells.

Opipramol and haloperidol inhibit glucose-induced insulin secretion by pancreatic islets.

Maria Carmen Iglesias-Osma passed away on March 15, 2021. The rest of the authors and colleagues want to express their feeling for such a sensitive loss.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Iglesias-Osma, M.C., García-Barrado, M.J., Hernandez-Gonzalez, D. et al. The anxiolytic drug opipramol inhibits insulin-induced lipogenesis in fat cells and insulin secretion in pancreatic islets. J Physiol Biochem 79, 415–425 (2023). https://doi.org/10.1007/s13105-023-00950-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-023-00950-8

Keywords

Search

Navigation