A serotonin and melanocortin circuit mediates D-fenfluramine anorexia

Journal of Neuroscience

Volumn 30, Issue 44, 2010, Pages 14630-14634

  Xu, Yong ^a   Jones, Juli E ^b   Lauzon, Danielle A ^a   Anderson, Jason G ^a   Balthasar, Nina ^c   Heisler, Lora K ^d   Zinn, Andrew R ^a   Lowell, Bradford B ^b   Elmquist, Joel K ^a  

^a UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^b HARVARD MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF BRISTOL   (United Kingdom)

^d UNIVERSITY OF CAMBRIDGE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DEXFENFLURAMINE; MELANOCORTIN; MELANOCORTIN 4 RECEPTOR; PROOPIOMELANOCORTIN; SEROTONIN; SEROTONIN 2C RECEPTOR;

AMYGDALOID NUCLEUS; ANIMAL EXPERIMENT; ANOREXIA; ANTERIOR HYPOTHALAMUS; APPETITE; ARTICLE; BODY WEIGHT; BRAIN NERVE CELL; CONTROLLED STUDY; GENE DELETION; GENETIC MODEL; HYPOPHAGIA; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN EXPRESSION;

ANIMALS; ANOREXIA; FENFLURAMINE; MALE; MELANOCORTINS; MICE; MICE, INBRED C57BL; MICE, KNOCKOUT; NEURAL PATHWAYS; PRO-OPIOMELANOCORTIN; RECEPTOR, MELANOCORTIN, TYPE 4; RECEPTOR, SEROTONIN, 5-HT2C; SEROTONIN; SEROTONIN UPTAKE INHIBITORS; WEIGHT LOSS;

EID: 78049500472     PISSN: 02706474     EISSN: 15292401     Source Type: Journal    
DOI: 10.1523/JNEUROSCI.5412-09.2010     Document Type: Article

References (27)

1. Balthasar N, Dalgaard LT, Lee CE, Yu J, Funahashi H, Williams T, Ferreira M, Tang V, McGovern RA, Kenny CD, Christiansen LM, Edelstein E, Choi B, Boss O, Aschkenasi C, Zhang CY, Mountjoy K, Kishi T, Elmquist JK, Lowell BB (2005) Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell 123:493-505.
2. Clifton PG, Lee MD, Dourish CT (2000) Similarities in the action of Ro 60-0175, a 5-HT2C receptor agonist and d-fenfluramine on feeding patterns in the rat. Psychopharmacology (Berl) 152:256-267.
3. Connolly HM, Crary JL, McGoon MD, Hensrud DD, Edwards BS, Edwards WD, Schaff HV (1997) Valvular heart disease associated with fenfluramine- phentermine. N Engl J Med 337:581-588.
4. Cremers TI, Giorgetti M, Bosker FJ, Hogg S, Arnt J, Mørk A, Honig G, Bøgesø KP, Westerink BH, den Boer H, Wikstrom HV, Tecott LH (2004) Inactivation of 5-HT(2C) receptors potentiates consequences of serotonin reuptake blockade. Neuropsychopharmacology 29:1782-1789.
5. Garfield AS, Heisler LK (2009) Pharmacological targeting of the serotonergic system for the treatment of obesity. J Physiol 587:49-60.
6. Heisler LK, Cowley MA, Tecott LH, Fan W, Low MJ, Smart JL, Rubinstein M, Tatro JB, Marcus JN, Holstege H, Lee CE, Cone RD, Elmquist JK (2002) Activation of central melanocortin pathways by fenfluramine. Science 297:609-611.
7. Heisler LK, Jobst EE, Sutton GM, Zhou L, Borok E, Thornton-Jones Z, Liu HY, Zigman JM, Balthasar N, Kishi T, Lee CE, Aschkenasi CJ, Zhang CY, Yu J, Boss O, Mountjoy KG, Clifton PG, Lowell BB, Friedman JM, Horvath T, et al. (2006) Serotonin reciprocally regulates melanocortin neurons to modulate food intake. Neuron 51:239-249.
8. Holder JL Jr, Butte NF, Zinn AR (2000) Profound obesity associated with a balanced translocation that disrupts the SIM1 gene. Hum Mol Genet 9:101-108.
9. Holder JL Jr, Zhang L, Kublaoui BM, DiLeone RJ, Oz OK, Bair CH, Lee YH, Zinn AR (2004) Sim1 gene dosage modulates the homeostatic feeding response to increased dietary fat in mice. Am J Physiol Endocrinol Metab 287:E105-E113.
10. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F (1997) Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131-141.
11. Kiss J, Léránth C, Halász B (1984) Serotoninergic endings on VIP-neurons in the suprachiasmatic nucleus and on ACTH-neurons in the arcuate nucleus of the rat hypothalamus. A combination of high resolution autoradiography and electron microscopic immunocytochemistry. Neurosci Lett 44:119-124.
12. Lam DD, Przydzial MJ, Ridley SH, Yeo GS, Rochford JJ, O'Rahilly S, Heisler LK (2008) Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors. Endocrinology 149:1323-1328.
13. Lucas JJ, Yamamoto A, Scearce-Levie K, Saudou F, Hen R (1998) Absence of fenfluramine-induced anorexia and reduced c-Fos induction in the hypothalamus and central amygdaloid complex of serotonin 1B receptor knock-out mice. J Neurosci 18:5537-5544.
14. McGuirk J, Goodall E, Silverstone T, Willner P (1991) Differential effects of d-fenfluramine, l-fenfluramine and d-amphetamine on the microstructure of human eating behaviour. Behav Pharmacol 2:113-119.
15. Michaud JL, Boucher F, Melnyk A, Gauthier F, Goshu E, Lévy E, Mitchell GA, Himms-Hagen J, Fan CM (2001) Sim1 haploinsufficiency causes hyperphagia, obesity and reduction of the paraventricular nucleus of the hypothalamus. Hum Mol Genet 10:1465-1473.
16. Molineaux SM, Jessell TM, Axel R, Julius D (1989) 5-HT1c receptor is a prominent serotonin receptor subtype in the central nervous system. Proc Natl Acad Sci U S A 86:6793-6797.
17. Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone RD (1994) Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol 8:1298-1308.
18. Nonogaki K, Strack AM, Dallman MF, Tecott LH (1998) Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 4:1152-1156.
19. Qiu J, Xue C, Bosch MA, Murphy JG, Fan W, Rønnekleiv OK, Kelly MJ (2007) Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons: role in energy homeostasis in females. Mol Pharmacol 72:885-896.
20. Rothman RB, Clark RD, Partilla JS, Baumann MH (2003) (+)-Fenfluramine and its major metabolite, (+)-norfenfluramine, are potent substrates for norepinephrine transporters. J Pharmacol Exp Ther 305:1191-1199.
21. Rowland NE, Carlton J (1986) Neurobiology of an anorectic drug: fenfluramine. Prog Neurobiol 27:13-62.
22. Tong Q, Ye CP, Jones JE, Elmquist JK, Lowell BB (2008) Synaptic release of GABA by AgRP neurons is required for normal regulation of energy balance. Nat Neurosci 11:998-1000.
23. Vaisse C, Clement K, Guy-Grand B, Froguel P (1998) A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat Genet 20:113-114.
24. Vickers SP, Clifton PG, Dourish CT, Tecott LH (1999) Reduced satiating effect of d-fenfluramine in serotonin 5-HT(2C) receptor mutant mice. Psychopharmacology (Berl) 143:309-314.
25. Williams DL, Schwartz MW (2005) The melanocortin system as a central integrator of direct and indirect controls of food intake. Am J Physiol Regul Integr Comp Physiol 289:R2-R3.
26. Xu Y, Jones JE, Kohno D, Williams KW, Lee CE, Choi MJ, Anderson JG, Heisler LK, Zigman JM, Lowell BB, Elmquist JK (2008) 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate energy homeostasis. Neuron 60:582-589.
27. Zhou L, Sutton GM, Rochford JJ, Semple RK, Lam DD, Oksanen LJ, Thornton-Jones ZD, Clifton PG, Yueh CY, Evans ML, McCrimmon RJ, Elmquist JK, Butler AA, Heisler LK (2007) Serotonin 2C receptor agonists improve type 2 diabetes via melanocortin-4 receptor signaling pathways. Cell Metab 6:398-405.