New central targets for the treatment of obesity

Abstract

The review focuses on the central neuronal circuits involved in energy homeostasis and the opportunities these offer for pharmacological intervention to decrease feeding behaviour and reduce weight. This article is based on the presentation 'New central targets for the treatment of obesity' (Sargent, British Pharmacological society, Clinical Section Symposium, December 2008). Central neuronal substrates controlling weight offer numerous opportunities for pharmacological intervention. These opportunities range from non-specific enhancement of monoamine signalling (triple reuptake inhibitors) to targeting specific monoamine receptor subtypes (5-HT(2c) and 5-HT(6)). The data reviewed suggest that these approaches will lead to weight loss; whether this is sufficient to produce clinically meaningful effect remains to be determined. Combination therapy targeting more than one mechanism may be a means of increasing the magnitude of the response. Preclinical studies also suggest that novel approaches targeting specific neuronal pathways within the hypothalamus, e.g. MCH(1) receptor antagonism, offer an opportunity for weight reduction. However, these approaches are at an early stage and clinical studies will be needed to determine if these novel approaches lead to clinically meaningful weight loss and improvements in co-morbid conditions such as diabetes and cardiovascular disorders.

Figure 1

Multivariate relative risk of death from all causes among men and women according to body mass index, smoking status, and disease status. The four subgroups are mutually exclusive. Nonsmokers had never smoked. The reference category was made up of subjects with a body mass index of 23.5–24.9. Calle et al. N Engl J Med 1999; 341: 1097–105. Current or former smokers with a history of disease (----); Current or former smokers with on history of disease (– –); Nonsmokers with a history of disease (—); Nonsmokers with no history of disease ()

Figure 2

Circuits implicated in the central control of feeding. AcbSH, nucleus accumbens shell; AgRP, agouti gene-related peptide; ARC, arcuate nucleus; CART, cocaine-amphetamine regulated transcript; CCK, cholecystokinin; CRH, corticotrophin releasing hormone; LHA, lateral hypothalamus; α-MSH, alpha-melanocyte stimulating hormone; MCH, melanin-concentrating hormone; MC4R, melanocortin 4 receptor; NPY, neuropeptide Y; NTS, tractus solitari; ORX-orexin (hypocretin); OXY, oxytocin; POMC, pro-opiomelanocortin; PVN, periventricular nucleus