Invited review The role of the gut/brain axis in modulating food intake Amir H. Sam, Rachel C. Troke, Tricia M. Tan, Gavin A. Bewick * Section of Investigative Medicine, Imperial College London, London, W12 0NN, UK article info Article history: Received 4 August 2011 Received in revised form 28 September 2011 Accepted 13 October 2011 Keywords: Peptide YY (PYY) Glucagon like peptide-1 (GLP-1) Oxyntomodulin Cholecystokinin Ghrelin Obesity abstract Peptide hormones released from the gastrointestinal tract communicate information about the current state of energy balance to the brain. These hormones regulate appetite and energy expenditure via the vagus nerve or by acting on key brain regions implicated in energy homeostasis such as the hypothal- amus and brainstem. This review gives an overview of the main gut hormones implicated in the regu- lation of food intake. Research in this area has provided novel targets for the pharmacological treatment of obesity. This article is part of a Special Issue entitled ‘Central Control Food Intake’ Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. 1. Introduction Hormones released from the gut and adipose tissue play an important role in the regulation of food intake and energy expen- diture. These hormones may exert their effects both via the vagus nerve and by acting directly on areas of the brain implicated in the control of energy homeostasis. Peripheral signals from the gut and adipose tissue constitute feedback mechanisms allowing mainte- nance of a steady body weight, despite daily variations in energy expenditure and nutrient intake. The role of peripheral hormones and the gut/brain axis in the regulation of appetite has become an area of interest in recent years, owing to the growing global obesity crisis. Obesity is a major worldwide public health problem, with a significant burden of morbidity and mortality, as well as having substantial economic consequences. It is an important risk factor for type 2 diabetes, ischaemic heart disease, stroke and cancer, and carries an increased risk of both all cause, and cause-specific mortality (Prospective_Studies_Collaboration, 2009; Ringback Weitoft et al., 2008; Zheng et al., 2011). Peripheral signals controlling satiety may present potential targets for developing novel anti-obesity therapies. The focus of this review is to provide a synopsis of the gut-brain cross talk involved in the regulation of food intake. 2. Neuroendocrine control of appetite (Fig. 1) The hypothalamus and the brainstem are the main central nervous system regions responsible for the regulation of energy homeostasis. These brain areas receive peripheral neural and hormonal signals that relay information about acute nutritional state and adiposity (Murphy and Bloom, 2006). Neural afferents and hormonal signals from the periphery are integrated with higher brain centre signals (e.g. relaying reward drive and mood) to regu- late appetite and control energy expenditure (Schwartz et al., 2000). The arcuate nucleus (ARC) of the hypothalamus is believed to play a crucial role in the regulation of food intake and energy homeostasis. The ARC contains two populations of neurons with opposing effects on food intake (Chaudhri et al., 2008). Medially located orexigenic neurons (i.e. those stimulating appetite) express neuropeptide Y (NPY) and Agouti-related protein (AgRP) (Bewick et al., 2005; Broberger et al., 1998; Hahn et al., 1998). Anorexi- genic neurons (i.e. those inhibiting appetite) in the lateral ARC express alpha-melanocyte stimulating hormone (alpha-MSH) derived from pro-opiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART) (Elias et al., 1998). Abbreviations: AgRP, agouti related peptide; ARC, arcuate nucleus; a-MSH, alpha-melanocyte stimulating hormone; AP, area postrema; CART, cocaine and amphetamine regulated transcript; CCK, cholecystokinin; DPP-IV, dipeptidyl peptidase-4; GLP-1, glucagon like peptide-1; GLP-2, glucagon like peptide-2; NPY, neuropeptide Y; POMC, pro-opiomelanocortin; NT, neurotensin; NTS, nucleus tractus solitarius; OEA, Oleoylethanolamine; OXM, oxyntomodulin; PP, pancreatic polypeptide; PYY, peptide tyrosine tyrosine; PVN, paraventricular nucleus; RYGB, roux-en-Y gastric bypass; SFO, sub fornical organ; VIP, vasoactive intestinal polypeptide. * Corresponding author. Tel.: þ44 2083833086; fax: þ44 2083838320. E-mail address: g.bewick@imperial.ac.uk (G.A. Bewick). Contents lists available at SciVerse ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm 0028-3908/$ e see front matter Crown Copyright Ó 2011 Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2011.10.008 Neuropharmacology 63 (2012) 46e56