Skip to main content
SpringerLink
Log in

The central administration of C75, a fatty acid synthase inhibitor, activates sympathetic outflow and thermogenesis in interscapular brown adipose tissue

  • Integrative physiology
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

Abstract

The present work investigated the participation of interscapular brown adipose tissue (IBAT), which is an important site for thermogenesis, in the anti-obesity effects of C75, a synthetic inhibitor of fatty acid synthase (FAS). We report that a single intracerebroventricular (i.c.v.) injection of C75 induced hypophagia and weight loss in fasted male Wistar rats. Furthermore, C75 induced a rapid increase in core body temperature and an increase in heat dissipation. In parallel, C75 stimulated IBAT thermogenesis, which was evidenced by a marked increase in the IBAT temperature that preceded the rise in the core body temperature and an increase in the mRNA levels of uncoupling protein-1. As with C75, an i.c.v. injection of cerulenin, a natural FAS inhibitor, increased the core body and IBAT temperatures. The sympathetic IBAT denervation attenuated all of the thermoregulatory effects of FAS inhibitors as well as the C75 effect on weight loss and hypophagia. C75 induced the expression of Fos in the paraventricular nucleus, preoptic area, dorsomedial nucleus, ventromedial nucleus, and raphé pallidus, all of which support a central role of FAS in regulating IBAT thermogenesis. These data indicate a role for IBAT in the increase in body temperature and hypophagia that is induced by FAS inhibitors and suggest new mechanisms explaining the weight loss induced by these compounds.

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

Similar content being viewed by others

References

  1. Aston-Jones G, Ennis M, Pieribone VA, Nickell WT, Shipley MT (1986) The brain nucleus locus coeruleus: restricted afferent control of a broad efferent network. Science 234(4777):734–737

    Article  PubMed  CAS  Google Scholar 

  2. Borges BC, Rorato R, Avraham Y, da Silva LE, Castro M, Vorobiav L, Berry E, Antunes-Rodrigues J, Elias LL (2011) Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge. Am J Physiol Endocrinol Metab 300(5):E858–E869

    Article  PubMed  CAS  Google Scholar 

  3. Cannon B, Lindberg O (1979) Mitochondria from brown adipose tissue: isolation and properties. Meth Enzimol 55:65–78

    Article  CAS  Google Scholar 

  4. Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359

    Article  PubMed  CAS  Google Scholar 

  5. Cano G, Passerin AM, Schiltz JC, Card JP, Morrison SF, Sved AF (2003) Anatomical substrates for the central control of sympathetic outflow to interscapular adipose tissue during cold exposure. J Comp Neurol 460(3):303–326

    Article  PubMed  Google Scholar 

  6. Canteras NS, Simerly RB, Swanson LW (1994) Organization of projections from the ventromedial nucleus of the hypothalamus: a Phaseolus vulgaris-leucoagglutinin study in the rat. J Comp Neurol 348(1):41–79

    Article  PubMed  CAS  Google Scholar 

  7. Cha S-H, Hu Z, Lane MD (2004) Long-term effects of a fatty acid synthase inhibitor on obese mice: food intake, hypothalamic neuropeptides and UCP3. Biochem Biophys Res Commun 317:301–308

    Article  PubMed  CAS  Google Scholar 

  8. Cha S-H, Hu Z, Chohnan S, Lane MD (2005) Inhibition of hypothalamic fatty acid synthase triggers rapid activation of fatty acid oxidation in skeletal muscle. Proc Natl Acad Sci USA 102(41):14557–14562

    Article  PubMed  CAS  Google Scholar 

  9. Cha S-H, Rodgers JT, Puigserver P, Chohnan S, Lane MD (2006) Hypothalamic malonyl-CoA triggers mitochondrial biogenesis and oxidative gene expression in skeletal muscle: role of PGC-1α. Proc Natl Acad Sci USA 103(42):15410–15415

    Article  PubMed  CAS  Google Scholar 

  10. Cikos S, Bukovska A, Koppel J (2007) Relative quantification of mRNA: comparison of methods currently used for real-time PCR data analysis. BMC Mol Biol 8:113–127

    Article  PubMed  Google Scholar 

  11. Cypess AM, Lehman S, Williams G, Tal I, Rodman D, Goldfine AB, Kuo FC, Palmer EL, Tseng Y-H, Doria A, Kolodny GM, Kahn CR (2009) Identification and importance of brown adipose tissue in adult humans. N Engl J Med 360(15):1509–1517

    Article  PubMed  CAS  Google Scholar 

  12. Dimicco JA, Zaretsky DV (2007) The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol 292(1):R47–R63

    Article  PubMed  CAS  Google Scholar 

  13. Foster DO, Frydman ML (1979) Tissue distribution of cold-induced thermogenesis in conscious warm- or cold-acclimated rats reevaluated from changes in tissue blood flow: the dominant role of brown adipose tissue in the replacement of shivering by nonshivering thermogenesis. Can J Physiol Pharmaco l57:257–270

    Article  PubMed  CAS  Google Scholar 

  14. Gao S, Lane MD (2003) Effect of the anorectic fatty acid synthase inhibitor C75 on neuronal activity in the hypothalamus and brainstem. Proc Natl Acad Sci USA 100(10):5628–5633

    Article  PubMed  CAS  Google Scholar 

  15. Garófalo MAR, Kettelhut IC, Roselino JES, Migliorini RH (1996) Effect of acute cold exposure on norepinephrine turnover rates in rat white adipose tissue. J Auton Nerv Syst 60:206–208

    Article  PubMed  Google Scholar 

  16. Hermann DM, Luppi PH, Peyron C, Hinckel P, Jouvet M (1997) Afferent projections to the rat nuclei raphe magnus, raphe pallidus and reticularis gigantocellularis pars alpha demonstrated by iontophoretic application of choleratoxin (subunit b). J Chem Neuroanat 13(1):1–21

    Article  PubMed  CAS  Google Scholar 

  17. Himms-Hagen J (1989) Brown adipose tissue thermogenesis and obesity. Prog Lipid Res 28(2):67–115

    Article  PubMed  CAS  Google Scholar 

  18. Himms-Hagen J (1995) Role of brown adipose tissue thermogenesis in control of thermoregulatory feeding in rats: a new hypothesis that links thermostatic and glucostatic hypotheses for control of food intake. Proc Soc Exp Biol Med 208(2):159–169

    Article  PubMed  CAS  Google Scholar 

  19. Hirata K (1982) Blood flow to brown adipose tissue and norepinephrine-induced calorigenesis in physically trained rats. Jpn J Physiol 32(2):279–291

    Article  PubMed  CAS  Google Scholar 

  20. Kim EK, Miller I, Landree LE, Borisy-Rudin FF, Brown P, Tihan T, Townsend CA, Witters LA, Moran TH, Kuhajda FP, Ronnett GV (2002) Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. Am J Physiol Endocrinol Metab 283(5):E867–E879

    PubMed  CAS  Google Scholar 

  21. Kim E-K, Miller I, Aja S, Landree LE, Pinn M, McFadden J, Kuhajda FP, Moran TH, Ronnett GV (2004) C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J Biol Chem 279(19):19970–19976

    Article  PubMed  CAS  Google Scholar 

  22. Krauss S, Zhang C-Y, Lowell BB (2005) The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6:248–261

    Article  PubMed  CAS  Google Scholar 

  23. Larsen PJ, Møller M, Mikkelsen JD (1991) Efferent projections from the periventricular and medial parvicellular subnuclei of the hypothalamic paraventricular nucleus to circumventricular organs of the rat: a Phaseolus vulgaris-leucoagglutinin (PHA-L) tracing study. J Comp Neurol 306(3):462–479

    Article  PubMed  CAS  Google Scholar 

  24. Loftus TM, Jaworsky DE, Frehywot GL, Townsend CA, Ronnett GV, Lane MD, Kahajda FP (2000) Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288:2379–2381

    Article  PubMed  CAS  Google Scholar 

  25. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    PubMed  CAS  Google Scholar 

  26. Luppi PH, Aston-Jones G, Akaoka H, Chouvet G, Jouvet M (1995) Afferent projections to the rat locus coeruleus demonstrated by retrograde and anterograde tracing with cholera-toxin B subunit and Phaseolus vulgaris leucoagglutinin. Neuroscience 65(1):119–160

    Article  PubMed  CAS  Google Scholar 

  27. Mansouri A, Aja S, Moran TH, Ronnett G, Kuhajda FP, Arnold M, Geary N, Langhans W, Leonhardt M (2008) Intraperitoneal injections of low doses of C75 elicit a behaviorally specific and vagal afferent-independent inhibition of eating in rats. Am Physiol Regul Integr Comp Physiol 295:R799–R805

    Article  CAS  Google Scholar 

  28. Mera P, Bentebibel A, López-Viñas E, Cordente AG, Gurunathan C, Sebastián D, Vázquez I, Herrero L, Ariza X, Gómez-Puertas P, Asins G, Serra D, Garcí J, Hegardt FG (2009) C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochem Pharmaco l77:1084–1095

    Article  PubMed  CAS  Google Scholar 

  29. Miller I, Ronnett GV, Moran TH, Aja S (2004) Anorexigenic C75 alters c-Fos in mouse hypothalamic and hindbrain subnuclei. Neuro Report 15:925–929

    CAS  Google Scholar 

  30. Mönnikes H, Lauer G, Arnold R (1997) Peripheral administration of cholecystokinin activates c-fos expression in the locus coeruleus/subcoeruleus nucleus, dorsal vagal complex and paraventricular nucleus via capsaicin-sensitive vagal afferents and CCK-A receptors in the rat. Brain Res 770(1–2):277–288

    Article  PubMed  Google Scholar 

  31. Morrison SF, Madden CJ, Tupone D (2012) Central control of brown adipose tissue thermogenesis. Front Endocrinol (Lausanne). doi:10.3389/fendo.2012.00005

  32. Nakamura K, Matsumura K, Kobayashi S, Kaneko T (2005) Sympathetic premotor neurons mediating thermoregulatory functions. Neurosci Res 51(1):1–8

    Article  PubMed  Google Scholar 

  33. Nicholls DG, Locke RM (1984) Thermogenic mechanisms in brown fat. Physiol Rev 64:1–64

    PubMed  CAS  Google Scholar 

  34. Okamatsu-Ogura Y, Nio-Kobayashi J, Iwanaga T, Terao A, Kimura K, Saito M (2011) Possible involvement of uncoupling protein 1 in appetite control by leptin. Exp Biol Med 236:1274–1281

    Article  CAS  Google Scholar 

  35. Okamatsu-Ogura Y, Uozumi A, Toda C, Kimura K, Yamashita H, Saito M (2007) Uncoupling protein 1 contributes to fat-reducing effect of leptin. Obes Res Clin Pract 1:233–241

    Article  Google Scholar 

  36. Oldfield BJ, Giles ME, Watson A, Anderson C, Colvill LM, McKinley MJ (2002) The neurochemical characterisation of hypothalamic pathways projecting polysynaptically to brown adipose tissue in the rat. Neuroscience 110(3):515–526

    Article  PubMed  CAS  Google Scholar 

  37. Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates, 2nd edn. Academic, Sydney

    Google Scholar 

  38. Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San Diego

    Google Scholar 

  39. Proulx K, Cota D, Woods SC, Seeley RJ (2008) Fatty acid synthase inhibitors modulate energy balance via mammalian target of rapamycin complex 1 signaling in the central nervous system. Diabetes 57:3231–3238

    Article  PubMed  CAS  Google Scholar 

  40. Richard D, Monge-Roffarello B, Chechi K, Labbé SM, Turcotte EE (2012) Control and physiological determinants of sympathetically mediated brown adipose tissue thermogenesis. Front Endocrinol (Lausanne). doi:10.3389/fendo.2012.00036

  41. Rorato R, Castro M, Borges BC, Benedetti M, Germano CM, Antunes-Rodrigues J, Elias LL (2008) Adrenalectomy enhances endotoxemia-induced hypophagia: higher activation of corticotrophin-releasing-factor and proopiomelanocortin hypothalamic neurons. Horm Behav 54(1):134–142

    Article  PubMed  CAS  Google Scholar 

  42. Rothwell NJ, Stock MJ (1981) Influence of noradrenaline on blood flow to brown adipose tissue in rats exhibiting diet-induced thermogenesis. Pflügers Arch 389(3):237–242

    Article  PubMed  CAS  Google Scholar 

  43. Samuels ER, Szabadi E (2008) Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr Neuropharmacol 6(3):235–253

    Article  PubMed  CAS  Google Scholar 

  44. Sangiao-Alvarellos S, Varela L, Vázquez MJ, Da Boit K, Saha AK, Cordido F, Diéguez C, López M (2010) Influence of ghrelin and growth hormone deficiency on AMP-activated protein kinase and hypothalamic lipid metabolism. J Neuroendocrinol 22(6):543–556

    Article  PubMed  CAS  Google Scholar 

  45. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671

    PubMed  CAS  Google Scholar 

  46. Shimokawa T, Kumar MV, Lane D (2002) Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc Natl Acad Sci USA 99(1):66–71

    Article  PubMed  CAS  Google Scholar 

  47. Thornhill J, Halvorson I (1994) Activation of shivering and non-shivering thermogenesis by electrical stimulation of the lateral and medial preoptic areas. Brain Res 656(2):367–374

    Article  PubMed  CAS  Google Scholar 

  48. Thornhill J, Jugnauth A, Halvorson I (1994) Brown adipose tissue thermogenesis evoked by medial preoptic stimulation is mediated via the ventromedial hypothalamic nucleus. Can J Physiol Pharmaco l72(9):1042–1048

    Article  PubMed  CAS  Google Scholar 

  49. Thupari JN, Landree LE, Ronnett GV, Kuhadja FP (2002) C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proc Natl Acad Sci USA 99(14):9498–9502

    Article  PubMed  CAS  Google Scholar 

  50. Tu Y, Thupari JN, Kim E-K, Pinn ML, Moran TH, Ronnett GV, Kuhajda FP (2005) C75 alters central and peripheral gene expression to reduce food intake and increase energy expenditure. Endocrinology 146(1):486–493

    Article  PubMed  CAS  Google Scholar 

  51. Uchoa ET, Sabino HA, Ruginsk SG, Antunes-Rodrigues J, Elias LL (2009) Hypophagia induced by glucocorticoid deficiency is associated with an increased activation of satiety-related responses. J Appl Physiol 106(2):596–604

    Article  PubMed  Google Scholar 

  52. van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JMAFL, Kemerink GJ, Bouvy ND, Schrauwen P, Teule GJJ (2009) Cold-activated brown adipose tissue in healthy men. N Engl J Med 360(15):1500–1508

    Article  PubMed  Google Scholar 

  53. Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, Taittonen M, Laine J, Savisto N-J, Enerbäck S, Nuutila P (2009) Functional brown adipose tissue in healthy adults. N Engl J Med 360(15):1518–1525

    Article  PubMed  CAS  Google Scholar 

  54. Yoshida K, Nakamura K, Matsumura K, Kanosue K, König M, Thiel HJ, Boldogköi Z, Toth I, Roth J, Gerstberger R, Hübschle T (2003) Neurons of the rat preoptic area and the raphe pallidus nucleus innervating the brown adipose tissue express the prostaglandin E receptor subtype EP3. Eur J Neurosci 18(7):1848–1860

    Article  PubMed  Google Scholar 

  55. Yoshida K, Li X, Cano G, Lazarus M, Saper CB (2009) Parallel preoptic pathways for thermoregulation. J Neurosci 29(38):11954–11964

    Article  PubMed  CAS  Google Scholar 

  56. Young AA, Dawson NJ (1982) Evidence for on-off control of heat dissipation from the tail of the rat. Can J Physiol Pharmacol 60:392–398

    Article  PubMed  CAS  Google Scholar 

  57. Zhang Y, Kerman IA, Laque A, Nguyen P, Faouzi M, Louis GW, Jones JC, Rhodes C, Münzberg H (2011) Leptin-receptor-expressing neurons in the dorsomedial hypothalamus and median preoptic area regulate sympathetic brown adipose tissue circuits. J Neurosci 31(5):1873–1884

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank José Roberto da Silva (Laboratory of Endocrinology; HCFMRP-USP) for the determination of plasma corticosterone, and Dr. Léa Maria Zanini Maciel and Giselle Aparecida Caixe de Carvalho Paixão (Laboratory of Thyroid and Neonatal Screening; HCFMRP-USP) for the determination of plasma total thyroxine. We are also indebted to Elza Aparecida Filippin, Neusa Maria Zanon, Lilian Zorzenon Carmo de Paula, Maria Valci Aparecida dos Santos, and Victor Diaz Galban for their technical assistance. This work was supported by grants from the Fundação de Amparoà Pesquisa do Estado de São Paulo (Fapesp 08/06694–6, 09/07584–2, 10/11083–6, and 10/11015–0) and from the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 140094/07–5, 306101/09–2, 303786/08–6, and 305149/12–1).

Author information

Authors and Affiliations

  1. Department of Physiology, School of Medicine of Ribeirão Preto, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Priscila Cassolla, Ernane Torres Uchoa, Maria Antonieta Rissato Garófalo, Lucila Leico Kagohara Elias & Luiz Carlos Carvalho Navegantes

  2. Department of Physiology and Biophysics, Institute of Biological Sciences, Federal University of Minas Gerais, 6627 Antonio Carlos Avenue, Belo Horizonte, Minas Gerais, 31270-901, Brazil

    Frederico Sander Mansur Machado, Juliana Bohnen Guimarães & Cândido Celso Coimbra

  3. Department of Physiological Sciences, Biological Sciences Center, State University of Maringá, 6790 Colombo Avenue Maringá, Paraná, 87020-900, Brazil

    Nilton de Almeida Brito

  4. Department of Biochemistry and Immunology, School of Medicine of Ribeirão Preto, University of São Paulo, 3900 Bandeirantes Avenue, Ribeirão Preto, São Paulo, 14049-900, Brazil

    Isis do Carmo Kettelhut

Authors
  1. Priscila Cassolla
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ernane Torres Uchoa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Frederico Sander Mansur Machado
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Juliana Bohnen Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Maria Antonieta Rissato Garófalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nilton de Almeida Brito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Lucila Leico Kagohara Elias
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Cândido Celso Coimbra
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Isis do Carmo Kettelhut
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Luiz Carlos Carvalho Navegantes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Luiz Carlos Carvalho Navegantes.

Additional information

Ethical approval

All of the experimental protocols followed the Ethical principles in animal research adopted by the Brazilian College of Animal Experimentation, and they were approved by the Ethical Commission of Ethics in Animal Research (no. 116/2006) at the Ribeirão Preto School of Medicine at the University of São Paulo, Brazil.

Conflict of interest

No conflicts of interest, financial or otherwise, are reported by the authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cassolla, P., Uchoa, E.T., Mansur Machado, F.S. et al. The central administration of C75, a fatty acid synthase inhibitor, activates sympathetic outflow and thermogenesis in interscapular brown adipose tissue. Pflugers Arch - Eur J Physiol 465, 1687–1699 (2013). https://doi.org/10.1007/s00424-013-1301-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-013-1301-5

Keywords

Search

Navigation