Nicotine alters food-cue reactivity via networks extending from the hypothalamus.
ABSTRACT: Obesity and smoking constitute two of the main causes of preventable deaths in the developed countries today. Many smokers motivate consumption as a means to control their body weight because smoking cessation increases the risk to gain weight. Although it is well established that nicotine reduces feeding in animals and that smoking is associated with reduced body weight in quasi-experimental studies of humans, acute nicotine effects are mixed and little is known about the brain networks supporting these effects. Thus, we investigated 26 normal-weighted never-smokers who received either nicotine (2?mg) or placebo gums following a double-blinded randomized cross-over design. We used functional magnetic resonance imaging (fMRI) to investigate reactivity to palatable food cues after both overnight fasting and following a standardized caloric intake (75?g oral glucose tolerance test (OGTT)). Participants viewed food or low-level control pictures in a block design and rated their current appetite after each block. Nicotine had a small- to medium-sized effect on subjective appetite and significantly altered food-cue reactivity in a region sensitive to caloric intake that extended from the right hypothalamus to the basal ganglia. During placebo sessions, the OGTT reduced functional coupling of this region with a 'salience network' (ie, amygdala, ventromedial prefrontal cortex) in processing of food pictures. Furthermore, nicotine reduced coupling with the nucleus accumbens and the OGTT reduced coupling with an 'interoceptive network' (ie, insula, operculum) instead. We conclude that locally restricted acute effects of nicotine in the hypothalamic area have profound effects on food-processing networks.
Project description:Overweight and obesity pose serious challenges to public health and are promoted by our food-rich environment. We used functional magnetic resonance imaging (fMRI) to investigate reactivity to food cues after overnight fasting and following a standardized caloric intake (i.e., a 75 g oral glucose tolerance test, OGTT) in 26 participants (body mass index, BMI between 18.5 and 24.9 kg m(-2)). They viewed pictures of palatable food and low-level control stimuli in a block design and rated their current appetite after each block. Compared to control pictures, food pictures activated a large bilateral network typically involved in homeostatically and hedonically motivated food processing. Glucose ingestion was followed by decreased activation in the basal ganglia and paralimbic regions and increased activation in parietal and occipital regions. Plasma level increases in insulin correlated with cue-induced appetite at the neural and behavioral level. High insulin increases were associated with reduced activation in various bilateral regions including the fusiform gyrus, the superior temporal gyrus, the medial frontal gyrus, and the limbic system in the right hemisphere. In addition, they were accompanied by lower subjective appetite ratings following food pictures and modulated the neural response associated with it (e.g., in the fusiform gyrus). We conclude that individual insulin reactivity is critical to reduce food-cue responsivity after an initial energy intake and thereby may help to counteract overeating.
Project description:Smoking decreases appetite, and smokers often report that they smoke to control their weight. Understanding the neurobiological mechanisms underlying the anorexic effects of smoking would facilitate the development of novel treatments to help with smoking cessation and to prevent or treat obesity. By using a combination of pharmacological, molecular genetic, electrophysiological, and feeding studies, we found that activation of hypothalamic ?3?4 nicotinic acetylcholine receptors leads to activation of pro-opiomelanocortin (POMC) neurons. POMC neurons and subsequent activation of melanocortin 4 receptors were critical for nicotinic-induced decreases in food intake in mice. This study demonstrates that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identifies critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite.
Project description:The action of nicotine to suppress body weight is often cited as a factor impacting smoking initiation and the failure to quit. Despite the weight-suppressant effects of nicotine, smokers and nonsmokers report equal daily caloric intake. The weight-suppressive effects of nicotine in animal models of smoking are poorly understood. Furthermore, the Food and Drug Administration has authority to implement a policy markedly reducing nicotine levels in cigarettes; such a reduction could reduce smoking behavior, but have detrimental effects on body weight. The aim of this investigation was to examine the effects of self-administered nicotine on body weight and food intake in rats.In Experiment 1, rats with ad libitum access to chow responded for intravenous infusions of nicotine (60 µg/kg/infusion) or saline in daily 1-hour sessions; body weight and 24-hour food intake were measured. Experiment 2 tested the effects of subcutaneous injections of nicotine on food intake. In Experiment 3, rats were food restricted and self-administered nicotine across a range of doses (3.75-60 µg/kg/infusion) while body weight was measured. In Experiment 4, rats self-administered 60 µg/kg/infusion nicotine before reduction to one of several doses (1.875-15 µg/kg/infusion) for 50 days.Self-administered nicotine suppressed weight gain independent of food intake. In food restricted rats, self-administered nicotine dose-dependently suppressed body weight gain. In rats self-administering 60 µg/kg/infusion nicotine, dose reduction increased body weight.Self-administered nicotine, even at low doses, suppressed body independent of food intake; this may have important implications for nicotine reduction policy.The results of the present studies demonstrate that self-administered nicotine suppresses body weight independent of food intake in rats. Further, the present studies establish that self-administered nicotine suppresses body weight even at very low doses and that reduction of nicotine dose results in weight gain. These results have important implications for nicotine reduction policy.
Project description:Despite health risks associated with smoking, up to 20% of the US population persist in this behavior; many smoke to control body weight or appetite, and fear of post-cessation weight gain can motivate continued smoking. Nicotine and tobacco use is associated with lower body weight, and cessation yields an average weight gain of about 4 kg, which is thought to reflect a return to the body weight of a typical nonsmoker. Nicotine replacement therapies can delay this weight gain but do not prevent it altogether, and the underlying mechanism for how nicotine is able to reduce weight is not fully understood. In rodent models, nicotine reduces weight gain, reduces food consumption, and alters energy expenditure, but these effects vary with duration and route of nicotine administration. Nicotine, acting through nicotinic acetylcholine receptors (nAChRs), increases the firing rate of both orexigenic agouti-related peptide and anorexigenic proopiomelanocortin neurons in the arcuate nucleus of the hypothalamus (ARC). Manipulation of nAChR subunit expression within the ARC can block the ability of nicotine and the nicotinic agonist cytisine from decreasing food intake; however, it is unknown exactly how this reduces food intake. This review summarizes the clinical and preclinical work on nicotine, food intake, and weight gain, then explores the feeding circuitry of the ARC and how it is regulated by nicotine. Finally, we propose a novel hypothesis for how nicotine acts on this hypothalamic circuit to reduce food intake. Implications: This review provides a comprehensive and updated summary of the clinical and preclinical work examining nicotine and food intake, as well as a summary of recent work examining feeding circuits of the hypothalamus. Synthesis of these two topics has led to new understanding of how nAChR signaling regulates food intake circuits in the hypothalamus.
Project description:Smoking influences body weight such that smokers weigh less than non-smokers and smoking cessation often leads to weight increase. The relationship between body weight and smoking is partly explained by the effect of nicotine on appetite and metabolism. However, the brain reward system is involved in the control of the intake of both food and tobacco. We evaluated the effect of single-nucleotide polymorphisms (SNPs) affecting body mass index (BMI) on smoking behavior, and tested the 32 SNPs identified in a meta-analysis for association with two smoking phenotypes, smoking initiation (SI) and the number of cigarettes smoked per day (CPD) in an Icelandic sample (N=34,216 smokers). Combined according to their effect on BMI, the SNPs correlate with both SI (r=0.019, P=0.00054) and CPD (r=0.032, P=8.0 × 10(-7)). These findings replicate in a second large data set (N=127,274, thereof 76,242 smokers) for both SI (P=1.2 × 10(-5)) and CPD (P=9.3 × 10(-5)). Notably, the variant most strongly associated with BMI (rs1558902-A in FTO) did not associate with smoking behavior. The association with smoking behavior is not due to the effect of the SNPs on BMI. Our results strongly point to a common biological basis of the regulation of our appetite for tobacco and food, and thus the vulnerability to nicotine addiction and obesity.
Project description:The ability of smoking to reduce body weight serves as motivation for continued smoking. It is unclear to what extent non-nicotine constituents in cigarettes are contributing to the weight-reducing effect of smoking. The purpose of the current study was to examine the effects of nicotine and four minor tobacco alkaloids (nornicotine, cotinine, anatabine, and anabasine) on food intake, one of the key regulators of body weight. In addition, a smokeless tobacco extract (STE) and e-cigarette (EC) refill liquid were used to model the effects of actual tobacco product exposure on food intake. Male Holztman rats were trained to lever press for food pellets during daily 2h sessions in operant chambers. In Experiment 1, the effects of subcutaneous injections of saline, nicotine (0.25-1.00mg/kg), nornicotine (0.50-6.00mg/kg), cotinine (1.00-100.00mg/kg), anatabine (0.25-3.00mg/kg), and anabasine (0.50-4.00mg/kg) were assessed. In Experiment 2, rats from Experiment 1 were used to examine the effects of nicotine, STE, and EC liquid. All alkaloids, except cotinine, produced a dose-dependent reduction in overall food intake. The highest doses of all drugs significantly reduced latency and response rate to obtain the first pellet. At some doses, nicotine, anatabine, and nornicotine reduced food intake within the first 45min without compensatory increases in intake later in the session. STE and EC liquid produced dose dependent decreases in food intake similar to nicotine alone. These data suggest that minor tobacco alkaloids have appetite suppressant effects and warrant further investigation into their effects on body weight, energy intake, and energy expenditure under free-feeding conditions. However, findings with STE and EC liquid suggest that nicotine is the primary constituent in these products to affect food intake, whereas levels of minor alkaloids in these products may be too low to influence food intake.
Project description:Smoking leads to the development of automatic tendencies that promote approach behavior toward smoking-related stimuli which in turn may maintain addictive behavior. The present study examined whether automatic approach tendencies toward smoking-related stimuli can be measured by using an adapted version of the Approach-Avoidance Task (AAT). Given that progression of addictive behavior has been associated with a decreased reactivity of the brain reward system for stimuli signaling natural rewards, we also used the AAT to measure approach behavior toward natural rewarding stimuli in smokers. During the AAT, 92 smokers and 51 non-smokers viewed smoking-related vs. non-smoking-related pictures and pictures of natural rewards (i.e. highly palatable food) vs. neutral pictures. They were instructed to ignore image content and to respond to picture orientation by either pulling or pushing a joystick. Within-group comparisons revealed that smokers showed an automatic approach bias exclusively for smoking-related pictures. Contrary to our expectations, there was no difference in smokers' and non-smokers' approach bias for nicotine-related stimuli, indicating that non-smokers also showed approach tendencies for this picture category. Yet, in contrast to non-smokers, smokers did not show an approach bias for food-related pictures. Moreover, self-reported smoking attitude could not predict approach-avoidance behavior toward nicotine-related pictures in smokers or non-smokers. Our findings indicate that the AAT is suited for measuring smoking-related approach tendencies in smokers. Furthermore, we provide evidence for a diminished approach tendency toward food-related stimuli in smokers, suggesting a decreased sensitivity to natural rewards in the course of nicotine addiction. Our results indicate that in contrast to similar studies conducted in alcohol, cannabis and heroin users, the AAT might only be partially suited for measuring smoking-related approach tendencies in smokers. Nevertheless, our findings are of special importance for current etiological models and smoking cessation programs aimed at modifying nicotine-related approach tendencies in the context of a nicotine addiction.
Project description:Increased appetite and weight gain after cessation is a deterrent for quitting smoking. Attempts to understand the mechanism for these effects using animals have been hampered by the difficulty or inconsistency of modeling the effects seen in humans.To examine the effects of extended daily access to intravenous nicotine, via programmed infusions, on body weight and meal patterns in rats.Intravenous (IV) nicotine infusions (0.06 mg/kg/inf) were administered noncontingently, every 30 min throughout the dark cycle and the last 3 h of the light cycle, to emulate self-administration. The effect of these infusions on food intake, meal patterns, and weight change were examined relative to a control group during treatment and in a post-nicotine phase.Nicotine-treated rats gained half the weight that vehicle treated animals gained and ate approximately 20 % less food overall than vehicle-treated rats. Whereas a compensatory increase in meal frequency occurred during the dark period to account for smaller meals, no compensation was observed throughout the light period. In a post-nicotine phase, the nicotine group maintained a lower weight for 1 week and then gained weight back to control levels. The rate of weight gain post-cessation was faster in animals that had received nicotine compared to controls.Compared to previous studies examining the effects of minipump or intraperitoneal injections of nicotine on food intake, the present study was able to detect previously unknown circadian differences in meal patterns which will be important in the development of smoking cessation and weight gain prevention drugs.
Project description:Obesity and tobacco smoking represent the largest challenges to public health, but the causal relationship between nicotine and obesity is poorly understood. Nicotine suppresses body weight gain, a factor impacting smoking initiation and the failure to quit, particularly among obese smokers. The impact of nicotine on body weight regulation in obesity-prone and obesity-resistant populations consuming densely caloric diets is unknown. In the current experiment, body weight gain of adult male rats maintained on a high energy diet (31.8% kcal from fat) distributed into obesity-prone (OP), obesity-resistant (OR) and an intermediate group, which was placed on standard rodent chow (Chow). These rats were surgically implanted with intravenous catheters and allowed to self-administer nicotine (0 or 60?g/kg/infusion, a standard self-administration dose) in 1-h sessions for 20 consecutive days. Self-administered nicotine significantly suppressed body weight gain but not food intake in OP and Chow rats. Self-administered nicotine had no effect on body weight gain in OR rats. These data suggest that: 1) OR rats are also resistant to nicotine-induced suppression of body weight gain; and 2) nicotine may reduce levels of obesity in a subset of smokers prone to obesity.
Project description:Carbohydrate intake, preference, and taste thresholds may be altered in current and former cigarette smokers, which may mediate weight gain and risk for obesity in individuals who quit smoking. Attempts to model these effects in rodents have primarily used noncontingent nicotine administration. The purpose of this research was to characterize changes in chow and sucrose intake in rats during a 23-h access model of i.v. nicotine self-administration (NSA), in which rats lever-pressed for chow, sucrose, and nicotine under concurrent fixed-ratio (FR) 1 schedules. Male rats were assigned to one of three groups that differed in food and drug availability. The Nicotine C+S group had concurrent access to nicotine, chow, and sucrose. The Saline C+S group had access to saline, chow, and sucrose. The Nicotine C-Only group had access to nicotine and chow, but not sucrose. Changes in food intake and weight gain were assessed during baseline, NSA, and nicotine withdrawal (i.e., saline extinction). Weight gain was significantly slowed during NSA and increased during withdrawal, but did not differ between the nicotine groups. NSA produced a significant decrease in both chow and sucrose intake. Gradual tolerance to nicotine's effects on sucrose, but not chow intake, occurred. During withdrawal, chow and sucrose intake increased, with a larger percent increase in sucrose intake compared to chow. The proportion of total food intake from sucrose was greater at the end of withdrawal compared to baseline, indicating a history of nicotine intake changed dietary preference. Combined, these results indicate that sucrose intake is more resistant to nicotine's appetite suppressant effects and withdrawal from nicotine produces a greater increase in sweet food intake alongside general increases in chow intake. Changes in overall food intake in current and ex-smokers may lead to increased risk for obesity and other health problems, potentially limiting the benefit of quitting smoking.