ORIGINAL ARTICLE Feeding Behaviour in Galanin Knockout Mice Supports a Role of Galanin in Fat Intake and Preference A. C. Adams,* J. C. Clapham, D. Wynickà and J. R. Speakman* *Aberdeen Centre for Energy Regulation and Obesity (ACERO), School of Biological Sciences, University of Aberdeen, Aberdeen, UK.  Molecular Pharmacology, AstraZeneca R&D Mo ¨lndal, Mo ¨lndal, Sweden. àDepartments of Pharmacology and Clinical Sciences South Bristol, Bristol University, University Walk, Bristol, UK. The regulation of feeding behaviour is thought to be a key target system for the treatment and prevention of obesity. This regulatory system in vertebrates is currently considered to consist of a net- work comprised of neuropeptides and hormones and appears to reside in the hypothalamus (1); however, other areas of the brain are also thought to play important roles (1). Among the neuro- peptides that are expressed in the hypothalamus and are known to inhibit feeding behaviour, are corticotrophin-releasing factor, cocaine- and amphetamine-regulated transcript (CART), a-melano- cyte-stimulating hormone, pro-opiomelanocortin (POMC) (2, 3). By contrast, neuropeptide Y (NPY), galanin, agouti-related protein (AgRP), melanin-concentrating hormone, and the orexins appear to stimulate food intake in various feeding paradigms (4–6). The physiological pathways involving these neuropeptides have been extensively reviewed (1, 7, 8) and their roles in the development and maintenance of obesity have been determined through the study of a number of obese transgenic mice, as well as various lesion and dietary models (9). Galanin is a 30 amino acid neuropeptide in humans (29 amino acids in other species) (10) and plays a number of roles including effects on cognitive performance (11), pain perception (12, 13) and neuronal protection and regeneration (14, 15). Based on the distri- bution of galanin and its receptors in brain regions that regulate ingestive behaviours, Leibowitz et al. (16) first tested the effects of centrally administered galanin on feeding and drinking in the rat. Microinjection of nanomole doses of galanin into the paraventricu- Journal of Neuroendocrinology Correspondence to: Professor John R. Speakman, School of Biological Sciences, University of Aberdeen, Aberdeen, UK (e-mail: j.speakman@abdn.ac.uk). It has been widely suggested that saturated fat consumption has fuelled the current obesity epi- demic. Macronutrient choices appear to be important not only as potential factors influencing obesity, but also independently as risk factors for diabetes, cardiovascular disease and cancer. The neuropeptide galanin has previously been implicated in the regulation of fat intake, although its precise role has been contested. The present study investigated mice with targeted knockout of the galanin gene (GKO). We demonstrate that, when only a high fat diet (HFD) was available, wild-type (WT) animals consumed significantly more energy than the GKO mice (89.85 Æ 4.57 k J ⁄ day versus 76.84 Æ 3.55 k J ⁄ day, P < 0.001, n = 17 versus 15). Consistent with this, WT animals gained more body weight when fed the HFD than GKO animals (3.48 Æ 0.44 g versus 2.02 Æ 0.62 g, P < 0.001, n = 17 versus 15). In a macronutrient choice scenario, WT mice ate almost three-fold more fat than GKO animals (0.63 Æ 0.02 g versus 0.23 Æ 0.01 g, P < 0.001, n = 18 versus 24).Chronic administration of galanin by mini-osmotic pumps into the lateral ventricle of GKO animals partially reversed the fat avoidance phenotype. Fat intake was significantly lower in the phosphate-buffered saline-treated GKO group compared to galanin-treated GKO animals (0.32 Æ 0.01 g versus 0.38 Æ 0.01 g, P < 0.005, n = 17 versus 17). These data are compatible with the hypothesis that galanin specifically regulates fat intake, and implies that an antagonist to one or more of the galanin receptor subtype(s) may be of use in the treatment of some forms of obesity. Key words: galanin, macronutrient, obesity. doi: 10.1111/j.1365-2826.2007.01638.x Journal of Neuroendocrinology 20, 199–206 ª 2008 The Authors. Journal Compilation ª 2008 Blackwell Publishing Ltd