Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2009 Jan 15;587(1):49-60.
doi: 10.1113/jphysiol.2008.164152. Epub 2008 Nov 24.

Pharmacological targeting of the serotonergic system for the treatment of obesity

Alastair S Garfield  1 , Lora K Heisler
Affiliations
Review

Pharmacological targeting of the serotonergic system for the treatment of obesity

Alastair S Garfield et al. J Physiol. .

Abstract

The attenuation of food intake as induced by an increase in serotonergic (5-hydroxytryptamine, 5-HT) efficacy has been a target of antiobesity pharmacotherapies. However, the induction of tolerance and/or side-effects limited the clinical utility of the earliest serotonin-related medications. With the global prevalence of obesity rising, there has been renewed interest in the manipulation of the serotonergic system as a point of pharmacological intervention. The serotonin(2C) receptor (5-HT(2C)R), serotonin(1B) (rodent)/serotonin(1Dbeta) (human) receptor (5-HT(1B/1Dbeta)R) and serotonin(6) receptor (5-HT(6)R) represent the most promising serotonin receptor therapeutic targets. Canonical serotonin receptor compounds have given way to a myriad of novel receptor-selective ligands, many of which have observable anorectic effects. Here we review serotonergic compounds reducing ingestive behaviour and discuss their clinical potential for the treatment of obesity.

PubMed Disclaimer

Figures

Figure 1
Figure 1. Proposed model of a serotonergic pathway modulating food intake
An increase in serotonin bioavailability (due to food intake or pharmacological compounds such as sibutramine and fenfluramine) or direct agonism of 5HT2CRs and 5HT1BRs modulates firing of pro-opiomelanocortin (POMC)/cocaine and amphetamine regulated transcript (CART) and agouti related protein (AgRP)/neuropeptide Y (NPY) neurones within the arcuate nucleus of the of the hypothalamus (ARC). Anorectic POMC neurones expressing 5HT2CR depolarize on receptor activation and release α-melanocyte-stimulating hormone (α-MSH), which in turn activates second-order melanocortin 4 receptor (MC4R) expressing neurones, principally within the paraventricular nucleus of the hypothalamus (PVH; Balthasar et al. 2005). Concomitant activation of 5HT1BRs expressed on orexigenic AgRP/NPY neurones within the ARC causes membrane hyperpolarization and subsequent inhibition of neuropeptide release. Inhibitory 5HT1BR activation also attenuates inhibitory postsynaptic currents onto POMC/CART neurones further potentiating anorexigenesis. Subsequent downstream neuroendocrine signalling promotes satiety and the cessation of food intake.
See this image and copyright information in PMC

References

    1. Abenhaim L, Moride Y, Brenot F, Rich S, Benichou J, Kurz X, Higenbottam T, Oakley C, Wouters E, Aubier M, Simonneau G, Begaud B. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996;335:609–616. - PubMed
    1. Adams DR, Bentley JM, Benwell KR, Bickerdike MJ, Bodkin CD, Cliffe IA, Dourish CT, George AR, Kennett GA, Knight AR, Malcolm CS, Mansell HL, Misra A, Quirk K, Roffey JR, Vickers SP. Pyrrolo (iso) quinoline derivatives as 5-HT (2C) receptor agonists. Bioorg Med Chem Lett. 2006;16:677–680. - PubMed
    1. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med. 1999;106:179–184. - PubMed
    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. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123:493–505. - PubMed
    1. Barkeling B, Elfhag K, Rooth P, Rossner S. Short-term effects of sibutramine (Reductil) on appetite and eating behaviour and the long-term therapeutic outcome. Int J Obes Relat Metab Disord. 2003;27:693–700. - PubMed

Publication types

MeSH terms

LinkOut - more resources