Neuroscience Letters 411 (2007) 72–76 Nicotine withdrawal increases body weight, neuropeptide Y and Agouti-related protein expression in the hypothalamus and decreases uncoupling protein-3 expression in the brown adipose tissue in high-fat fed mice Alice Fornari a , Patrizia Pedrazzi a,b , Giordano Lippi a , Marina R. Picciotto c , Michele Zoli a,∗ , Isabella Zini a,b a Department of Biomedical Sciences, Section of Physiology, University of Modena and Reggio Emilia, Italy b School of Dietetics, University of Modena and Reggio Emilia, Italy c Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA Received 19 July 2006; received in revised form 20 September 2006; accepted 3 October 2006 Abstract Nicotine is known to decrease body weight in normal rodents and human smokers, whereas nicotine withdrawal or smoking cessation can increase body weight. We have found that mice fed a high fat diet do not show the anorectic effect of chronic nicotine treatment, but do increase their body weight following nicotine withdrawal. Nicotine withdrawal is accompanied by increased expression of the orexigenic peptides neuropeptide Y and Agouti-related protein in the hypothalamus, and decreased expression of the metabolic protein uncoupling protein-3 in brown adipose tissue. These data suggest that diet can influence the ability of nicotine to modulate body weight regulation and demonstrate that chronic nicotine exposure results in adaptive changes in central and peripheral molecules which regulate feeding behavior and energy metabolism. © 2006 Elsevier Ireland Ltd. All rights reserved. Keywords: Neuropeptide Y; Agouti-related protein; Appetite; Feeding; Addiction; Smoking Epidemiological studies have revealed a link between smoking cessation and increased body weight (for review see [9]). Indeed, concern over weight gain decreases motivation for smoking ces- sation while weight gain increases the risk of relapse [11,22]. The biological mechanisms of smoking cessation-related weight gain are not known, although changes in metabolic rate and food intake have been reported [9]. Nicotine is thought to be involved in mediating smoking effects on body weight. Nicotine decreases body weight in rats [12], mice [4] and humans [13,16], while nicotine withdrawal in animals chronically treated with nicotine increases body weight [15,3,4]. In addition, mice demonstrate increased motivation to work for food even after several weeks of withdrawal from nicotine [8]. ∗ Corresponding author at: Department of Biomedical Sciences, Section of Physiology, University of Modena and Reggio Emilia, via Campi 287, 41100 Modena, Italy. Tel.: +39 059 205 5668; fax: +39 059 205 5363. E-mail address: mzoli@unimo.it (M. Zoli). Less research has been devoted to differential effects of nico- tine withdrawal on lean or overweight individuals. A recent paper shows that hedonic effects of tobacco are decreased in obese compared to lean humans, and nicotine conditioned place- preference is diminished in mice fed a high-fat diet [7]. The current study examined the effects of chronic oral nicotine treat- ment and withdrawal on body weight, food intake and molecular markers of hypothalamic and endocrine signaling in C57Bl6 mice fed a high-fat (HF) diet. Eight-week old male C57Bl/6J mice (n = 40, Charles River Laboratories, Lecco, Italy) were randomly divided into 3 groups and housed in a temperature controlled vivarium (25 ◦ C) with a 12:12 h light–dark cycle (lights on 6:30 A.M.). All animal exper- iments were conducted in accordance with the European Com- munities Council Directive of 24 November 1986 (86/609/EEC) Laboratory Animals. Animals had free access to water and food over the course of treatment. They were fed a HF or a low fat (LF) diet (Research Diets Inc., New Brunswick, NJ) with the same source of fat (soybean oil and lard): 0304-3940/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2006.10.014