Pflügers Archiv - European Journal of Physiology

, Volume 465, Issue 12, pp 1687–1699 | Cite as

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

  • Priscila Cassolla
  • Ernane Torres Uchoa
  • Frederico Sander Mansur Machado
  • Juliana Bohnen Guimarães
  • Maria Antonieta Rissato Garófalo
  • Nilton de Almeida Brito
  • Lucila Leico Kagohara Elias
  • Cândido Celso Coimbra
  • Isis do Carmo Kettelhut
  • Luiz Carlos Carvalho NavegantesEmail author
Integrative physiology


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.


Brown adipose tissue Fatty acid synthase inhibitors Thermogenesis Sympathetic activation 



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).


  1. 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):734–737PubMedCrossRefGoogle Scholar
  2. 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–E869PubMedCrossRefGoogle Scholar
  3. 3.
    Cannon B, Lindberg O (1979) Mitochondria from brown adipose tissue: isolation and properties. Meth Enzimol 55:65–78CrossRefGoogle Scholar
  4. 4.
    Cannon B, Nedergaard J (2004) Brown adipose tissue: function and physiological significance. Physiol Rev 84:277–359PubMedCrossRefGoogle Scholar
  5. 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):303–326PubMedCrossRefGoogle Scholar
  6. 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):41–79PubMedCrossRefGoogle Scholar
  7. 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 317:301–308PubMedCrossRefGoogle Scholar
  8. 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):14557–14562PubMedCrossRefGoogle Scholar
  9. 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):15410–15415PubMedCrossRefGoogle Scholar
  10. 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 8:113–127PubMedCrossRefGoogle Scholar
  11. 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):1509–1517PubMedCrossRefGoogle Scholar
  12. 12.
    Dimicco JA, Zaretsky DV (2007) The dorsomedial hypothalamus: a new player in thermoregulation. Am J Physiol Regul Integr Comp Physiol 292(1):R47–R63PubMedCrossRefGoogle Scholar
  13. 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 l57:257–270PubMedCrossRefGoogle Scholar
  14. 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):5628–5633PubMedCrossRefGoogle Scholar
  15. 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 60:206–208PubMedCrossRefGoogle Scholar
  16. 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):1–21PubMedCrossRefGoogle Scholar
  17. 17.
    Himms-Hagen J (1989) Brown adipose tissue thermogenesis and obesity. Prog Lipid Res 28(2):67–115PubMedCrossRefGoogle Scholar
  18. 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):159–169PubMedCrossRefGoogle Scholar
  19. 19.
    Hirata K (1982) Blood flow to brown adipose tissue and norepinephrine-induced calorigenesis in physically trained rats. Jpn J Physiol 32(2):279–291PubMedCrossRefGoogle Scholar
  20. 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–E879PubMedGoogle Scholar
  21. 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):19970–19976PubMedCrossRefGoogle Scholar
  22. 22.
    Krauss S, Zhang C-Y, Lowell BB (2005) The mitochondrial uncoupling-protein homologues. Nat Rev Mol Cell Biol 6:248–261PubMedCrossRefGoogle Scholar
  23. 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):462–479PubMedCrossRefGoogle Scholar
  24. 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 288:2379–2381PubMedCrossRefGoogle Scholar
  25. 25.
    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275PubMedGoogle Scholar
  26. 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):119–160PubMedCrossRefGoogle Scholar
  27. 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–R805CrossRefGoogle Scholar
  28. 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 l77:1084–1095PubMedCrossRefGoogle Scholar
  29. 29.
    Miller I, Ronnett GV, Moran TH, Aja S (2004) Anorexigenic C75 alters c-Fos in mouse hypothalamic and hindbrain subnuclei. Neuro Report 15:925–929Google Scholar
  30. 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):277–288PubMedCrossRefGoogle Scholar
  31. 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. 32.
    Nakamura K, Matsumura K, Kobayashi S, Kaneko T (2005) Sympathetic premotor neurons mediating thermoregulatory functions. Neurosci Res 51(1):1–8PubMedCrossRefGoogle Scholar
  33. 33.
    Nicholls DG, Locke RM (1984) Thermogenic mechanisms in brown fat. Physiol Rev 64:1–64PubMedGoogle Scholar
  34. 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 236:1274–1281CrossRefGoogle Scholar
  35. 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 1:233–241CrossRefGoogle Scholar
  36. 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):515–526PubMedCrossRefGoogle Scholar
  37. 37.
    Paxinos G, Watson C (1982) The rat brain in stereotaxic coordinates, 2nd edn. Academic, SydneyGoogle Scholar
  38. 38.
    Paxinos G, Watson C (1997) The rat brain in stereotaxic coordinates, 3rd edn. Academic, San DiegoGoogle Scholar
  39. 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 57:3231–3238PubMedCrossRefGoogle Scholar
  40. 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. 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):134–142PubMedCrossRefGoogle Scholar
  42. 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):237–242PubMedCrossRefGoogle Scholar
  43. 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):235–253PubMedCrossRefGoogle Scholar
  44. 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):543–556PubMedCrossRefGoogle Scholar
  45. 45.
    Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG (2000) Central nervous system control of food intake. Nature 404(6778):661–671PubMedGoogle Scholar
  46. 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):66–71PubMedCrossRefGoogle Scholar
  47. 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):367–374PubMedCrossRefGoogle Scholar
  48. 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):1042–1048PubMedCrossRefGoogle Scholar
  49. 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):9498–9502PubMedCrossRefGoogle Scholar
  50. 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):486–493PubMedCrossRefGoogle Scholar
  51. 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):596–604PubMedCrossRefGoogle Scholar
  52. 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):1500–1508PubMedCrossRefGoogle Scholar
  53. 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):1518–1525PubMedCrossRefGoogle Scholar
  54. 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):1848–1860PubMedCrossRefGoogle Scholar
  55. 55.
    Yoshida K, Li X, Cano G, Lazarus M, Saper CB (2009) Parallel preoptic pathways for thermoregulation. J Neurosci 29(38):11954–11964PubMedCrossRefGoogle Scholar
  56. 56.
    Young AA, Dawson NJ (1982) Evidence for on-off control of heat dissipation from the tail of the rat. Can J Physiol Pharmacol 60:392–398PubMedCrossRefGoogle Scholar
  57. 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):1873–1884PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Priscila Cassolla
    • 1
  • Ernane Torres Uchoa
    • 1
  • Frederico Sander Mansur Machado
    • 2
  • Juliana Bohnen Guimarães
    • 2
  • Maria Antonieta Rissato Garófalo
    • 1
  • Nilton de Almeida Brito
    • 3
  • Lucila Leico Kagohara Elias
    • 1
  • Cândido Celso Coimbra
    • 2
  • Isis do Carmo Kettelhut
    • 4
  • Luiz Carlos Carvalho Navegantes
    • 1
    Email author
  1. 1.Department of Physiology, School of Medicine of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil
  2. 2.Department of Physiology and Biophysics, Institute of Biological SciencesFederal University of Minas GeraisBelo HorizonteBrazil
  3. 3.Department of Physiological Sciences, Biological Sciences CenterState University of MaringáParanáBrazil
  4. 4.Department of Biochemistry and Immunology, School of Medicine of Ribeirão PretoUniversity of São PauloRibeirão PretoBrazil

Personalised recommendations