Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Effects of pain controlling neuropeptides on human fat cell lipolysis

International Journal of Obesity volume 34, pages 1333–1340 (2010)Cite this article

Subjects

Abstract

Objective:

Neuropeptides NPFF and NPSF are involved in pain control, acting through the G-protein coupled receptors (GPR)74 (high affinity for NPFF) and GPR147 (equal affinity for NPFF and NPSF). GPR74 also inhibits catecholamine-induced adipocyte lipolysis and regulates fat mass in humans. The aim of this study was to compare the effects of NPFF and NPSF on noradrenaline-induced lipolysis and to determine the expression of their receptors in human fat cells.

Design:

Adipose tissue was obtained during surgery. Adipocytes were prepared and kept in primary culture. Lipolysis, protein expression and gene expression were determined.

Results:

NPFF counteracted noradrenaline-induced lipolysis, which was more marked after 48 h than after 4 h exposure and was solely attributed to inhibition of β-adrenoceptor signalling. NPSF counteracted noradrenaline-induced lipolysis maximally after 4 h of exposure, which was attributed to a combination of inhibition of β-adrenoceptor signalling and decreased activation of the protein kinase-A hormone sensitive lipase complex by cyclic AMP. Both neuropeptides were effective in nanomolar concentrations. NPFF and NPSF had no effects on the expression of genes involved in catecholamine signal transduction. Both GPR74 and GPR147 were expressed at the protein level in fat cells from various adipose regions. GPR74 mRNA levels were higher in adipose tissue from obese as compared with non-obese subjects. High gene expression of either receptor correlated with low noradrenaline-induced lipolysis (P<0.05).

Conclusions:

Pain controlling neuropeptides NPFF and NPSF may be important for the regulation of lipolysis in man probably acting through GPR74 and GPR147. At low concentrations they inhibit catecholamine-induced lipolysis through rapid and long-term post-transcriptional effects at several steps in adrenoceptor signalling in fat cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Panula P, Aarnisalo AA, Wasowicz K . Neuropeptide FF, a mammalian neuropeptide with multiple functions. Prog Neurobiol 1996; 48: 461–487.

    Article  CAS  Google Scholar 

  2. Prokai L, Zharikova AD, Juhasz A, Prokai-Tatrai K . Cardiovascular effects of neuropeptide FF antagonists. Peptides 2006; 27: 1015–1019.

    Article  CAS  Google Scholar 

  3. Murase T, Arima H, Kondo K, Oiso Y . Neuropeptide FF reduces food intake in rats. Peptides 1996; 17: 353–354.

    Article  CAS  Google Scholar 

  4. Nicklous DM, Simansky KJ . Neuropeptide FF exerts pro- and anti-opioid actions in the parabrachial nucleus to modulate food intake. Am J Physiol Regul Integr Comp Physiol 2003; 285: R1046–R1054.

    Article  CAS  Google Scholar 

  5. Sundblom DM, Hyrkko A, Fyhrquist F . Pulsatile secretion of neuropeptide FF into human blood. Peptides 1998; 19: 1165–1170.

    Article  CAS  Google Scholar 

  6. Elshourbagy NA, Ames RS, Fitzgerald LR, Foley JJ, Chambers JK, Szekeres PG et al. Receptor for the pain modulatory neuropeptides FF and AF is an orphan G protein-coupled receptor. J Biol Chem 2000; 275: 25965–25971.

    Article  CAS  Google Scholar 

  7. Bonini JA, Jones KA, Adham N, Forray C, Artymyshyn R, Durkin MM et al. Identification and characterization of two G protein-coupled receptors for neuropeptide FF. J Biol Chem 2000; 275: 39324–39331.

    Article  CAS  Google Scholar 

  8. Hinuma S, Shintani Y, Fukusumi S, Iijima N, Matsumoto Y, Hosoya M et al. New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol 2000; 2: 703–708.

    Article  CAS  Google Scholar 

  9. Parker RM, Copeland NG, Eyre HJ, Liu M, Gilbert DJ, Crawford J et al. Molecular cloning and characterisation of GPR74 a novel G-protein coupled receptor closest related to the Y-receptor family. Brain Res Mol Brain Res 2000; 77: 199–208.

    Article  CAS  Google Scholar 

  10. Gouarderes C, Mazarguil H, Mollereau C, Chartrel N, Leprince J, Vaudry H et al. Functional differences between NPFF1 and NPFF2 receptor coupling: high intrinsic activities of RFamide-related peptides on stimulation of [35S]GTPgammaS binding. Neuropharmacology 2007; 52: 376–386.

    Article  CAS  Google Scholar 

  11. Dahlman I, Dicker A, Jiao H, Kere J, Blomqvist L, van Harmelen V et al. A common haplotype in the G-protein-coupled receptor gene GPR74 is associated with leanness and increased lipolysis. Am J Hum Genet 2007; 80: 1115–1124.

    Article  CAS  Google Scholar 

  12. Lefrere I, De Coppet P, Camelin JC, Le Lay S, Mercier N, Elshourbagy N et al. Neuropeptide AF and FF modulation of adipocyte metabolism. Primary insights from functional genomics and effects on beta-adrenergic responsiveness. J Biol Chem 2002; 277: 39169–39178.

    Article  CAS  Google Scholar 

  13. Liu Q, Guan XM, Martin WJ, McDonald TP, Clements MK, Jiang Q et al. Identification and characterization of novel mammalian neuropeptide FF-like peptides that attenuate morphine-induced antinociception. J Biol Chem 2001; 276: 36961–36969.

    Article  CAS  Google Scholar 

  14. Mollereau C, Mazarguil H, Marcus D, Quelven I, Kotani M, Lannoy V et al. Pharmacological characterization of human NPFF(1) and NPFF(2) receptors expressed in CHO cells by using NPY Y(1) receptor antagonists. Eur J Pharmacol 2002; 451: 245–256.

    Article  CAS  Google Scholar 

  15. Dicker A, Ryden M, Naslund E, Muehlen IE, Wiren M, Lafontan M et al. Effect of testosterone on lipolysis in human pre-adipocytes from different fat depots. Diabetologia 2004; 47: 420–428.

    Article  CAS  Google Scholar 

  16. Hellmer J, Arner P, Lundin A . Automatic luminometric kinetic assay of glycerol for lipolysis studies. Anal Biochem 1989; 177: 132–137.

    Article  CAS  Google Scholar 

  17. Nordstrom EA, Ryden M, Backlund EC, Dahlman I, Kaaman M, Blomqvist L et al. A human-specific role of cell death-inducing DFFA (DNA fragmentation factor-alpha)-like effector A (CIDEA) in adipocyte lipolysis and obesity. Diabetes 2005; 54: 1726–1734.

    Article  Google Scholar 

  18. Vyas N, Mollereau C, Cheve G, McCurdy CR . Structure-activity relationships of neuropeptide FF and related peptidic and non-peptidic derivatives. Peptides 2006; 27: 990–996.

    Article  CAS  Google Scholar 

  19. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP et al. International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev 2005; 57: 279–288.

    Article  CAS  Google Scholar 

  20. Lafontan M, Berlan M . Fat cell adrenergic receptors and the control of white and brown fat cell function. J Lipid Res 1993; 34: 1057–1091.

    CAS  PubMed  Google Scholar 

  21. Carey GB . Mechanisms regulating adipocyte lipolysis. Adv Exp Med Biol 1998; 441: 157–170.

    Article  CAS  Google Scholar 

  22. Arner P . Differences in lipolysis between human subcutaneous and omental adipose tissues. Ann Med 1995; 27: 435–438.

    Article  CAS  Google Scholar 

  23. Arner P . Role of antilipolytic mechanisms in adipose tissue distribution and function in man. Acta Med Scand Suppl 1988; 723: 147–152.

    CAS  PubMed  Google Scholar 

  24. Arner P . Human fat cell lipolysis: biochemistry, regulation and clinical role. Best Pract Res Clin Endocrinol Metab 2005; 19: 471–482.

    Article  CAS  Google Scholar 

  25. Sengenes C, Berlan M, De Glisezinski I, Lafontan M, Galitzky J . Natriuretic peptides: a new lipolytic pathway in human adipocytes. FASEB J 2000; 14: 1345–1351.

    Article  CAS  Google Scholar 

  26. Ryden M, Dicker A, van Harmelen V, Hauner H, Brunnberg M, Perbeck L et al. Mapping of early signaling events in tumor necrosis factor-alpha-mediated lipolysis in human fat cells. J Biol Chem 2002; 277: 1085–1091.

    Article  CAS  Google Scholar 

  27. Ryden M, Arvidsson E, Blomqvist L, Perbeck L, Dicker A, Arner P . Targets for TNF-alpha-induced lipolysis in human adipocytes. Biochem Biophys Res Commun 2004; 318: 168–175.

    Article  CAS  Google Scholar 

  28. Ryden M, Arner P . Tumour necrosis factor-alpha in human adipose tissue—from signalling mechanisms to clinical implications. J Intern Med 2007; 262: 431–438.

    Article  CAS  Google Scholar 

  29. Sundblom DM, Heikman P, Naukkarinen H, Fyhrquist F . Blood concentrations of vasopressin, neuropeptide FF and prolactin are increased by high-dose right unilateral ECT. Peptides 1999; 20: 319–326.

    Article  CAS  Google Scholar 

  30. Devillers JP, Labrouche SA, Castes E, Simonnet G . Release of neuropeptide FF, an anti-opioid peptide, in rat spinal cord slices is voltage- and Ca(2+)-sensitive: possible involvement of P-type Ca2+ channels. J Neurochem 1995; 64: 1567–1575.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Gaby Åström and Kerstin Wåhlén for excellent technical assistance. The study was supported by Grants from the Swedish Research Council, Swedish Diabetes Association, Swedish Heart and Lung Foundation, Novo Nordic Foundation and King Gustaf V and Queen Victoria Foundation. This work is part of the project ‘Hepatic and adipose tissue and functions in the metabolic syndrome’ (HEPADIP, see http://www.hepadip.org/), which is supported by the European Commission as an Integrated Project under the 6th Framework Programme (Contract LSHM-Ct-2005-018734).

Author information

Author notes

  1. V van Harmelen and A Dicker: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, Karolinska Institutet, Karolinska University Hospital—Huddinge, Stockholm, Sweden

    V van Harmelen, A Dicker, E Sjölin, J Hoffstedt, M Rydén & P Arner

  2. Department of Surgery, Karolinska University Hospital—Huddinge, Stockholm, Sweden

    L Blomqvist & M Wirén

Authors
  1. V van Harmelen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A Dicker
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E Sjölin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. L Blomqvist
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M Wirén
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. J Hoffstedt
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. M Rydén
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. P Arner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P Arner.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

van Harmelen, V., Dicker, A., Sjölin, E. et al. Effects of pain controlling neuropeptides on human fat cell lipolysis. Int J Obes 34, 1333–1340 (2010). https://doi.org/10.1038/ijo.2010.46

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ijo.2010.46

Keywords

This article is cited by

Search

Advanced search

Quick links