A number of studies have demonstrated a role for BDNF/TrkB in hedonic feeding, regulating motivation and the reward (see Cordeira and Rios,2011). concerns. Manipulation of central peptidergic systems poses a number of therapeutic problems, including brain access and side effects. Given that the homeostatic defence of body weight may limit the effectiveness of any single-target therapy developed, a combination therapy approach may offer the best hope for the effective prevention and treatment of obesity. == LINKED ARTICLES == This article is a part of a themed section on Neuropeptides. To view the other articles in Rifaximin (Xifaxan) this section visithttp://dx.doi.org/10.1111/bph.2013.170.issue-7 Keywords:obesity, neuropeptides, hypothalamus, orexigenic, anorectic == Introduction == Obesity is a major public health issue worldwide. It is estimated that more than 1.5 billion individuals are overweight and more than 400 million adults are obese (World Health Organization,2011). These figures are anticipated to rise, with predictions that by 2050, 60% of men, 50% of women and 25% of children under 16 in the UK will be obese (Foresight Report,2007). Increased weight predisposes to and can aggravate many clinical conditions, including cardiovascular disease, type II diabetes mellitus, restrictive lung disease, certain cancers and infertility (Kopelman,2000). Obesity is usually a multifactorial condition in which genetic, environmental, behavioural and socio-economic conditions all contribute to determine body weight, adipose tissue mass and distribution (Bray,1992). == Current therapeutic options == For a new drug to be considered efficacious in the treatment of obesity by the US Food and Drug Administration (FDA), it must meet certain criteria in randomized controlled trials carried out over a minimum period of 1 year. The mean placebo-subtracted weight loss must be at least 5% from baseline, or alternatively, at least 35% of patients in the drug-treated group must drop more than 5% of baseline body weight (and the loss must be statistically significant and double that of the placebo group; FDA,2007). The European Medicine Agency (EMEA) suggests that efficacy is demonstrated with a loss of at least 10% baseline body weight, statistically significant compared to placebo, following a minimum 1 year treatment period (EMEA,2006). Currently, the only approved drug for the long-term treatment of obesity in the UK is usually orlistat (Xenical), which reduces the absorption of dietary fat by inhibiting intestinal lipases (Hauptmanet al.,1992; Sjstrmet al.,1998). There are a number of anti-obesity drugs, which are internationally approved but which are not licensed for use in the UK. These include appetite-suppressing amphetamine analogues such as phentermine, which are only approved for short periods (less than 12 weeks) due to concerns regarding tolerance and dependency (Ioannides-Demoset al.,2011). Qsymia, a Rifaximin (Xifaxan) combination of phentermine and topiramate, and lorcaserin, a selective 5-HT2Creceptor agonist (receptor nomenclature follows Alexanderet al.,2011), have recently been approved for the treatment of obesity by the FDA (FDA,2012). Two drugs previously approved for the treatment of obesity, which target the CNS, have been withdrawn in recent years due to their unacceptable side effects. Sibutramine (Reductil), a 5-HT and noradrenaline reuptake inhibitor was withdrawn in 2010 2010 due to its cardiovascular side effects including increased blood pressure and heart rate associated with an increased risk of stroke and myocardial infarction (Jameset al.,2000; Kimet al.,2003). Rimonabant, an inverse agonist for the cannabinoid CB1receptor was withdrawn in 2009 2009 due to reports of severe depressive disorder and suicidal ideation (Van Gaalet al.,2005; Topolet al.,2010). H4 The withdrawal of these drugs illustrates the need for more selective drug targets in order to minimize adverse effects. Obesity is associated with numerous co-morbidities and any treatment for obesity is likely to be required long term; the therapeutic windows of any new pharmacotherapy must therefore be closely scrutinized before approval. The classical neurotransmitter and endocannabinoid systems are widespread within the CNS, reflecting multiple physiological functions, and manipulation of these systems carries the risk of unwanted effects. Neuropeptides can act in the CNS as neuromodulators Rifaximin (Xifaxan) of the classical neurotransmitter systems. Typically expressed by discrete clusters of neurons, they project diffusely throughout the CNS, and modulate postsynaptic neurons in a way that can alter their responses to classical neurotransmitters. All CNS neurons that produce.