Serotonin 5-HT2C receptor agonist promotes hypophagia via downstream activation of melanocortin 4 receptors

被引:203
作者
Lam, Daniel D. [1 ,2 ]
Przydzial, Magdalena J. [1 ,2 ]
Ridley, Simon H. [2 ]
Yeo, Giles S. H. [2 ]
Rochford, Justin J. [2 ]
O'Rahilly, Stephen [2 ]
Heisler, Lora K. [1 ,2 ]
机构
[1] Univ Cambridge, Dept Pharmacol, Cambridge CB2 1PD, England
[2] Univ Cambridge, Addenbrookes Hosp, Inst Metab Sci, Dept Clin Biochem,Metab Res Lab, Cambridge CB2 2QQ, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1210/en.2007-1321
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
The neurotransmitter serotonin (5-hydroxytryptamine) is a well-established modulator of energy balance. Both pharmacological and genetic evidence implicate the serotonin 2C receptor (5-HT2CR) as a critical receptor mediator of serotonin's effects on ingestive behavior. Here we characterized the effect of the novel and selective 5-HT2CR agonist BVT.X on energy balance in obese and lean mice and report that BVT.X significantly reduces acute food intake without altering locomotor activity or oxygen consumption. In an effort to elucidate the mechanism of this effect, we examined the chemical phenotype of 5-HT2CR-expressing neurons in a critical brain region affecting feeding behavior, the arcuate nucleus of the hypothalamus. We show that 5-HT(2C)Rs are coexpressed with neurons containing proopiomelanocortin, known to potently affect appetite, in the arcuate nucleus of the hypothalamus of the mouse. We then demonstrate that prolonged infusion with BVT.X in obese mice significantly increases Pomc mRNA and reduces body weight, percent body fat, and initial food intake. To evaluate the functional importance of melanocortin circuitry in the effect of BVT.X on ingestive behavior, we assessed mice with disrupted melanocortin pathways. We report that mice lacking the melanocortin 4 receptor are not responsive to BVT.X-induced hypophagia, demonstrating that melanocortins acting on melanocortin 4 receptor are a requisite downstream pathway for 5-HT2CR agonists to exert effects on food intake. The data presented here not only indicate that the novel 5-HT2CR agonist BVT.X warrants further investigation as a treatment for obesity but also elucidate specific neuronal pathways potently affecting energy balance through which 5-HT2CR agonists regulate ingestive behavior.
引用
收藏
页码:1323 / 1328
页数:6
相关论文
共 31 条
  • [21] AN EXAMINATION OF THE BEHAVIORAL SPECIFICITY OF HYPOPHAGIA INDUCED BY 5-HT1B, 5-HT1C AND 5-HT2 RECEPTOR AGONISTS USING THE POSTPRANDIAL SATIETY SEQUENCE IN RATS
    KITCHENER, SJ
    DOURISH, CT
    [J]. PSYCHOPHARMACOLOGY, 1994, 113 (3-4) : 369 - 377
  • [22] Lam Daniel D., 2007, Expert Reviews in Molecular Medicine, V9, DOI 10.1017/S1462399407000245
  • [23] LEVINE LR, 1987, INT J OBESITY, V11, P185
  • [24] 5-HT1C RECEPTOR IS A PROMINENT SEROTONIN RECEPTOR SUBTYPE IN THE CENTRAL NERVOUS-SYSTEM
    MOLINEAUX, SM
    JESSELL, TM
    AXEL, R
    JULIUS, D
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (17) : 6793 - 6797
  • [25] A negative feedback system between brain serotonin systems and plasma active ghrelin levels in mice
    Nonogaki, K
    Ohashi-Nozue, K
    Oka, Y
    [J]. BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 2006, 341 (03) : 703 - 707
  • [26] Serotonin 5-hydroxytryptamine2C receptor signaling in hypothalamic proopiomelanocortin neurons:: Role in energy homeostasis in females
    Qiu, Jian
    Xue, Changhui
    Bosch, Martha A.
    Murphy, Jonathan G.
    Fan, Wei
    Ronnekleiv, Oline K.
    Kelly, Martin J.
    [J]. MOLECULAR PHARMACOLOGY, 2007, 72 (04) : 885 - 896
  • [27] DISTRIBUTION AND NEUROCHEMICAL PHENOTYPES OF CAUDAL MEDULLARY NEURONS ACTIVATED TO EXPRESS CFOS FOLLOWING PERIPHERAL ADMINISTRATION OF CHOLECYSTOKININ
    RINAMAN, L
    VERBALIS, JG
    STRICKER, EM
    HOFFMAN, GE
    [J]. JOURNAL OF COMPARATIVE NEUROLOGY, 1993, 338 (04) : 475 - 490
  • [28] SALLER CF, 1976, SCIENCE, V192, P385, DOI 10.1126/science.1257774
  • [29] META-CHLOROPHENYLPIPERAZINE - CENTRAL SEROTONIN AGONIST CAUSING POWERFUL ANOREXIA IN RATS
    SAMANIN, R
    MENNINI, T
    FERRARIS, A
    BENDOTTI, C
    BORSINI, F
    GARATTINI, S
    [J]. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 1979, 308 (02) : 159 - 163
  • [30] SIMMONS DM, 1989, J HISTOTECHNOL, V12, P169