Advertisement

Endocrine

, Volume 61, Issue 3, pp 462–472 | Cite as

Serum calcitonin gene-related peptide facilitates adipose tissue lipolysis during exercise via PIPLC/IP3 pathways

  • Malihe Aveseh
  • Maryam Koushkie-JahromiEmail author
  • Javad Nemati
  • Saeed Esmaeili-Mahani
Original Article

Abstract

Purpose

Calcitonin gene-related peptide (CGRP) is formed by alternative transcription of the calcitonin/α-CGRP gene, which also gives rise to calcitonin (CT). Recently, CGRP has been the focus of research for its metabolic effects in vitro. In the present study, the in vivo effects of CGRP on epididymal fat pads lipolysis at rest and during exercise were investigated in trained male Wistar rats.

Methods

Male Wistar rats were assigned to control and trained groups, which underwent endurance training for 12 weeks. The control (at rest) and trained (during acute exercise) animals were subjected to an intravenous injection of rat recombinant CGRP (2 µg kg−1) and CGRP-(8–37), a competitive CGRP receptors antagonist, to evaluate if and how CGRP can affect adipose tissue lipolysis at rest and during exercise.

Results

Intravenous injection of rat CGRP recombinant at rest upregulated major lipolysis pathways (cyclic AMP (cAMP), AMP-activated protein kinase (AMPK), and phospholipase C (PIPLC/IP3)) in fat pads, causing an elevation in plasma-free fatty acid (FFA) and a decrease in plasma triglyceride (TG). All the effects were eliminated by pretreating the animals with CGRP-(8–37), suggesting that CGRP receptors were necessary for lipolytic effects of CGRP in fat pads. In trained animals, acute exercise augmented CGRP in serum, cerebrospinal fluid (CSF), and the cortex. Pretreating the animals with CGRP-(8–37) attenuated PIPLC/IP3 pathway in fat pads and had no effect on cAMP and AMPK pathways.

Conclusions

Epididymal fat pads is a metabolic target for CGRP during exercise and CGRP effects on adipose tissue metabolism during exercise could be related to PIPLC/IP3 pathway.

Keywords

Calcitonin gene-related peptide Endurance training Epididymal fat lipolysis Neuropeptides 

Notes

Acknowledgements

We gratefully acknowledge Kerman Neuroscience Research Center and all our collaborators.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    J.F. Horowitz, Fatty acid mobilization from adipose tissue during exercise. Trends Endocrinol. Metab. 14(8), 386–392 (2003)CrossRefPubMedGoogle Scholar
  2. 2.
    L.L. Spriet, Regulation of skeletal muscle fat oxidation during exercise in humans. Med. Sci. Sports Exerc. 34(9), 1477–1484 (2002)CrossRefPubMedGoogle Scholar
  3. 3.
    R.A. Howlett, M.L. Parolin, D.J. Dyck, E. Hultman, N.L. Jones, G.J. Heigenhauser, L.L. Spriet, Regulation of skeletal muscle glycogen phosphorylase and PDH at varying exercise power outputs. Am. J. Physiol.-Regul., Integr. Comp. Physiol. 275(2), R418–R425 (1998)CrossRefGoogle Scholar
  4. 4.
    L.L. Spriet, New insights into the interaction of carbohydrate and fat metabolism during exercise. Sports Med. 44(1), 87–96 (2014)CrossRefPubMedCentralGoogle Scholar
  5. 5.
    J. Romijn, E. Coyle, L. Sidossis, J. Rosenblatt, R. Wolfe, Substrate metabolism during different exercise intensities in endurance-trained women. J. Appl. Physiol. 88(5), 1707–1714 (2000)CrossRefPubMedGoogle Scholar
  6. 6.
    A. Bolsoni-Lopes, M.I.C. Alonso-Vale, Lipolysis and lipases in white adipose tissue–An update. Arch. Endocrinol. Metab. 59(4), 335–342 (2015)CrossRefPubMedGoogle Scholar
  7. 7.
    R. Zechner, R. Zimmermann, T.O. Eichmann, S.D. Kohlwein, G. Haemmerle, A. Lass, F. Madeo, FAT SIGNALS-lipases and lipolysis in lipid metabolism and signaling. Cell Metab. 15(3), 279–291 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    S. Bijland, S.J. Mancini, I.P. Salt, Role of AMP-activated protein kinase in adipose tissue metabolism and inflammation. Clin. Sci. 124(8), 491–507 (2013)CrossRefPubMedGoogle Scholar
  9. 9.
    S.-J. Kim, T. Tang, M. Abbott, J.A. Viscarra, Y. Wang, H.S. Sul, AMPK phosphorylates desnutrin/ATGL and hormone-sensitive lipase to regulate lipolysis and fatty acid oxidation within adipose tissue. Mol. Cell. Biol. 36(14), 1961–1976 (2016)CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    S. Luquet, C. Magnan, The central nervous system at the core of the regulation of energy homeostasis. Front. Biosci. (Sch. Ed.) 1, 448–465 (2009)CrossRefGoogle Scholar
  11. 11.
    V.-S. Moullé, A. Picard, C. Le Foll, B.-E. Levin, C. Magnan, Lipid sensing in the brain and regulation of energy balance. Diabetes Metab. 40(1), 29–33 (2014)CrossRefPubMedGoogle Scholar
  12. 12.
    M. Meens, N. Mattheij, P. van Loenen, L. Spijkers, P. Lemkens, J. Nelissen, M. Compeer, A. Alewijnse, J. De Mey, G‐protein βγ subunits in vasorelaxing and anti‐endothelinergic effects of calcitonin gene‐related peptide. Br. J. Pharmacol. 166(1), 297–308 (2012)CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    J. McCulloch, R. Uddman, T.A. Kingman, L. Edvinsson, Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc. Natl Acad. Sci. 83(15), 5731–5735 (1986)CrossRefPubMedGoogle Scholar
  14. 14.
    S.-J. Smillie, R. King, X. Kodji, E. Outzen, G. Pozsgai, E. Fernandes, N. Marshall, P. De Winter, R.J. Heads, C. Dessapt-Baradez, An ongoing role of α-calcitonin gene–related peptide as part of a protective network against hypertension, vascular hypertrophy, and oxidative stress. Hypertension 63(5), 1056–1062 (2014)CrossRefPubMedGoogle Scholar
  15. 15.
    F. Russell, R. King, S.-J. Smillie, X. Kodji, S. Brain, Calcitonin gene-related peptide: physiology and pathophysiology. Physiol. Rev. 94(4), 1099–1142 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    R.N. Danaher, K.M. Loomes, B.L. Leonard, L. Whiting, D.L. Hay, L.Y. Xu, E.W. Kraegen, A.R. Phillips, G.J. Cooper, Evidence that α-calcitonin gene-related peptide is a neurohormone that controls systemic lipid availability and utilization. Endocrinology 149(1), 154–160 (2008)CrossRefPubMedGoogle Scholar
  17. 17.
    B. Leighton, G.J. Cooper, Pancreatic amylin and calcitonin gene-related peptide cause resistance to insulin in skeletal muscle in vitro. Nature 335(6191), 632–635 (1988)CrossRefPubMedGoogle Scholar
  18. 18.
    B. Leighton, E. Foot, The role of the sensory peptide calcitonin-gene-related peptide (s) in skeletal muscle carbohydrate metabolism: effects of capsaicin and resiniferatoxin. Biochem. J. 307(3), 707–712 (1995)CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    C.S. Walker, D.L. Hay, S.M. Fitzpatrick, G.J. Cooper, K.M. Loomes, α-Calcitonin gene related peptide (α-CGRP) mediated lipid mobilization in 3T3-L1 adipocytes. Peptides 58, 14–19 (2014)CrossRefPubMedGoogle Scholar
  20. 20.
    K. Chatzipanteli, R.B. Goldbergt, G.A. Howard, B.A. Roos, Calcitonin gene-related peptide is an adipose-tissue neuropeptide with lipolytic actions. Endocrinol. Metab. 3(4), 235–242 (1996)Google Scholar
  21. 21.
    P. Linscheid, D. Seboek, H. Zulewski, U. Keller, B. Muller, Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue. Endocrinology 146(6), 2699–2708 (2005)CrossRefPubMedGoogle Scholar
  22. 22.
    T. Liu, A. Kamiyoshi, T. Sakurai, Y. Ichikawa-Shindo, H. Kawate, L. Yang, M. Tanaka, X. Xian, A. Imai, L. Zhai, Endogenous calcitonin gene-related peptide regulates lipid metabolism and energy homeostasis in male mice. Endocrinology 158(5), 1194–1206 (2017)CrossRefPubMedGoogle Scholar
  23. 23.
    C.S. Walker, X. Li, L. Whiting, S. Glyn-Jones, S. Zhang, A.J. Hickey, M.A. Sewell, K. Ruggiero, A.R. Phillips, E.W. Kraegen, Mice lacking the neuropeptide α-calcitonin gene-related peptide are protected against diet-induced obesity. Endocrinology 151(9), 4257–4269 (2010)CrossRefPubMedGoogle Scholar
  24. 24.
    M. Kjær, T. Mohr, F. Dela, N. Secher, H. Galbo, H.L. Olesen, F.B. Sørensen, S. Schifter, Leg uptake of calcitonin gene‐related peptide during exercise in spinal cord injured humans. Clin. Physiol. Funct. Imaging 21(1), 32–38 (2001)CrossRefGoogle Scholar
  25. 25.
    B. Schuler, G. Rieger, M. Gubser, M. Arras, M. Gianella, O. Vogel, P. Jirkof, N. Cesarovic, J. Klohs, P. Jakob, Endogenous α‐calcitonin‐gene‐related peptide promotes exercise‐induced, physiological heart hypertrophy in mice. Acta Physiol. 211(1), 107–121 (2014)CrossRefGoogle Scholar
  26. 26.
    T. Chiba, A. Yamaguchi, T. Yamatani, A. Nakamura, T. Morishita, T. Inui, M. Fukase, T. Noda, T. Fujita, Calcitonin gene-related peptide receptor antagonist human CGRP-(8–37). Am. J. Physiol.-Endocrinol. Metab. 256(2), E331–E335 (1989)CrossRefGoogle Scholar
  27. 27.
    D.L. Hay, M.L. Garelja, D.R. Poyner, C.S. Walker, Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR Review 25. Br. J. Pharmacol. 175(1), 3–17 (2018)CrossRefPubMedGoogle Scholar
  28. 28.
    S.P. Alexander, A.P. Davenport, E. Kelly, N. Marrion, J.A. Peters, H.E. Benson, E. Faccenda, A.J. Pawson, J.L. Sharman, C. Southan, The Concise Guide to PHARMACOLOGY 2015/16: G protein‐coupled receptors. Br. J. Pharmacol. 172(24), 5744–5869 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    R. Nikooie, S. Samaneh, Exercise-induced lactate accumulation regulates intramuscular triglyceride metabolism via transforming growth factor-β1 mediated pathways. Mol. Cell. Endocrinol. 419, 244–251 (2016)CrossRefPubMedGoogle Scholar
  30. 30.
    M. Mansouri, R. Nikooie, A. Keshtkar, B. Larijani, K. Omidfar, Effect of endurance training on retinol‐binding protein 4 gene expression and its protein level in adipose tissue and the liver in diabetic rats induced by a high‐fat diet and streptozotocin. J. Diabetes Investig. 5(5), 484–491 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    M. Aveseh, R. Nikooie, M. Aminaie, Exercise‐induced changes in tumour LDH‐B and MCT1 expression are modulated by oestrogen‐related receptor alpha in breast cancer‐bearing BALB/c mice. J. Physiol. 593(12), 2635–2648 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    P.C. Emson, M. Zaidi, Further evidence for the origin of circulating calcitonin gene‐related peptide in the rat. J. Physiol. 412(1), 297–308 (1989)CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    M.A. Patestas, L.P. Gartner. A Textbook of Neuroanatomy John Wiley & Sons, New Jersey (2016)Google Scholar
  34. 34.
    M.J. Watt, G.R. Steinberg, Z.P. Chen, B.E. Kemp, M.A. Febbraio, Fatty acids stimulate AMP‐activated protein kinase and enhance fatty acid oxidation in L6 myotubes. J. Physiol. 574(1), 139–147 (2006)CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    H. Drissi, F. Lasmoles, V. Le Mellay, P.J. Marie, M. Lieberherr, Activation of phospholipase C-β1 via Gαq/11during calcium mobilization by calcitonin gene-related peptide. J. Biol. Chem. 273(32), 20168–20174 (1998)CrossRefPubMedGoogle Scholar
  36. 36.
    N. Fukai, T. Yoshimoto, T. Sugiyama, N. Ozawa, R. Sato, M. Shichiri, Y. Hirata, Concomitant expression of adrenomedullin and its receptor components in rat adipose tissues. Am. J. Physiol.-Endocrinol. Metab. 288(1), E56–E62 (2005)CrossRefPubMedGoogle Scholar
  37. 37.
    J. Hoffmann, S. Wecker, L. Neeb, U. Dirnagl, U. Reuter, Primary trigeminal afferents are the main source for stimulus-induced CGRP release into jugular vein blood and CSF. Cephalalgia 32(9), 659–667 (2012)CrossRefPubMedGoogle Scholar
  38. 38.
    P. Hasbak, C. Lundby, N.V. Olsen, S. Schifter, I.-L. Kanstrup, Calcitonin gene-related peptide and adrenomedullin release in humans: effects of exercise and hypoxia. Regul. Pept. 108(2), 89–95 (2002)CrossRefPubMedGoogle Scholar
  39. 39.
    X.-J. Sun, S.-S. Pan, Role of calcitonin gene–related peptide in cardioprotection of short-term and long-term exercise preconditioning. J. Cardiovasc. Pharmacol. 64(1), 53–59 (2014)CrossRefPubMedGoogle Scholar
  40. 40.
    R. Hu, Y.-J. Li, X.-H. Li, An overview of non-neural sources of calcitonin gene-related peptide. Curr. Med. Chem. 23(8), 763–773 (2016)CrossRefPubMedGoogle Scholar
  41. 41.
    M. Sakaguchi, Y. Inaishi, Y. Kashihara, M. Kuno, Release of calcitonin gene‐related peptide from nerve terminals in rat skeletal muscle. J. Physiol. 434(1), 257–270 (1991)CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    M. Yamada, T. Ishikawa, A. Yamanaka, A. Fujimori, K. Goto, Local neurogenic regulation of rat hindlimb circulation: CO2‐induced release of calcitonin gene‐related peptide from sensory nerves. Br. J. Pharmacol. 122(4), 710–714 (1997)CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    W. Brito Vieira, M. Halsberghe, M. Schwantes, S. Perez, V. Baldissera, J. Prestes, D. Farias, N. Parizotto, Increased lactate threshold after five weeks of treadmill aerobic training in rats. Braz. J. Biol. 74(2), 444–449 (2014)CrossRefPubMedGoogle Scholar
  44. 44.
    N. Vollestad, J. Hallen, O. Sejersted, Effect of exercise intensity on potassium balance in muscle and blood of man. J. Physiol. 475(2), 359–368 (1994)CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    P. Arner, E. Kriegholm, P. Engfeldt, J. Bolinder, Adrenergic regulation of lipolysis in situ at rest and during exercise. J. Clin. Investig. 85(3), 893 (1990)CrossRefPubMedGoogle Scholar
  46. 46.
    H.-J. Koh, M.F. Hirshman, H. He, Y. Li, Y. Manabe, J.A. Balschi, L.J. Goodyear, Adrenaline is a critical mediator of acute exercise-induced AMP-activated protein kinase activation in adipocytes. Biochem. J. 403(3), 473–481 (2007)CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    W.G. Aschenbach, K. Sakamoto, L.J. Goodyear, 5’adenosine monophosphate-activated protein kinase, metabolism and exercise. Sports Med. 34(2), 91–103 (2004)CrossRefPubMedGoogle Scholar
  48. 48.
    S.Y. Chou, J.L. Kostyo, N.A. Adamafio, Growth hormone inhibits activation of phosphatidylinositol phospholipase C by insulin in ob/ob mouse adipose tissue. Endocrinology 126(1), 62–66 (1990)CrossRefPubMedGoogle Scholar
  49. 49.
    E. Askew, A. Hecker, V. Coppes, F. Stifel, Cyclic AMP metabolism in adipose tissue of exercise-trained rats. J. Lipid Res. 19(6), 729–736 (1978)PubMedGoogle Scholar
  50. 50.
    R.J. Ho , Dependence of hormone-stimulated lipolysis on ATP and cyclic AMP levels in fat cells. Horm Metab Res 2 (Suppl 2), 83–87 (1970).Google Scholar
  51. 51.
    G. Robison, R. Butcher, E. Sutherland, in Cyclic AMP. Academic Press: New York. (1971) pp. 286–316Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Malihe Aveseh
    • 1
    • 2
  • Maryam Koushkie-Jahromi
    • 1
    Email author
  • Javad Nemati
    • 1
  • Saeed Esmaeili-Mahani
    • 3
    • 4
  1. 1.Sport Sciences DepartmentShiraz UniversityShirazIran
  2. 2.Neuroscience Research Center, Institute of NeuropharmacologyKerman University of Medical SciencesKermanIran
  3. 3.Department of Biology, Faculty of SciencesShahid Bahonar University of KermanKermanIran
  4. 4.Labratory of Molecular Neuroscience, Kerman Neuroscience Reserch CenterInstitute of NeurofarmacologyKermanIran

Personalised recommendations