Effect of nicotine on body composition in mice

in Journal of Endocrinology

Nicotine induces weight loss in both humans and rodents consuming a regular diet; however, the effect of nicotine on body weight and fat composition in rodents consuming a high-fat diet (HFD) has not been well studied. Thus, this study examined the effect of nicotine vs saline on body weight and fat composition in mice fed with either an HFD (62% of kcal from fat) or a standard normal chow diet (NCD) for 7 weeks. Nicotine dose dependently reduced body weight gain in mice that consumed both diets, but this effect was significantly greater in mice on the HFD. Caloric intake was decreased in nicotine-treated mice. Estimates of energy intake suggested that decreased caloric intake accounted for all the reduced weight gain in mice on an NCD and 66% of the reduced weight gain on an HFD. Computed tomography analysis for fat distribution demonstrated that nicotine was effective in reducing abdominal fat in mice that consumed the HFD, with nicotine treatment leading to lower visceral fat. The effect of nicotine on weight loss in mice on an HFD was completely blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor (nAChR) antagonist, but only partially blocked by the α4β2 nAChR partial agonist/antagonist, varenicline. We conclude that nicotine is effective in preventing HFD-induced weight gain and abdominal fat accumulation.

Abstract

Nicotine induces weight loss in both humans and rodents consuming a regular diet; however, the effect of nicotine on body weight and fat composition in rodents consuming a high-fat diet (HFD) has not been well studied. Thus, this study examined the effect of nicotine vs saline on body weight and fat composition in mice fed with either an HFD (62% of kcal from fat) or a standard normal chow diet (NCD) for 7 weeks. Nicotine dose dependently reduced body weight gain in mice that consumed both diets, but this effect was significantly greater in mice on the HFD. Caloric intake was decreased in nicotine-treated mice. Estimates of energy intake suggested that decreased caloric intake accounted for all the reduced weight gain in mice on an NCD and 66% of the reduced weight gain on an HFD. Computed tomography analysis for fat distribution demonstrated that nicotine was effective in reducing abdominal fat in mice that consumed the HFD, with nicotine treatment leading to lower visceral fat. The effect of nicotine on weight loss in mice on an HFD was completely blocked by mecamylamine, a nonselective nicotinic acetylcholine receptor (nAChR) antagonist, but only partially blocked by the α4β2 nAChR partial agonist/antagonist, varenicline. We conclude that nicotine is effective in preventing HFD-induced weight gain and abdominal fat accumulation.

Introduction

In a recent assessment of the mortality attributable to modifiable risk factors in the US adult population, it was found that tobacco use was responsible for 467 000 deaths (approximately one out of five) in 2005 (Fiore et al. 1999). Reduction in the rate of smoking could decrease over $50 billion in health care costs within the United States (McGinnis & Foege 1999). Smoking is a major risk factor for devastating cardiovascular events such as myocardial infarction, sudden death, stroke, and peripheral vascular disease (Robbins et al. 1994, Murray & Lopez 1997, Wilson 1997), with a positive correlation between morbidity and mortality related to cardiovascular diseases and the number of cigarettes smoked per day (Kannel 1981). Importantly, the health risk associated with smoking is exaggerated by obesity, and smoking and obesity are the leading causes of morbidity and mortality worldwide (Haslam & James 2005, Chiolero et al. 2008). The life expectancy of an obese smoker was 13 years less than that of a normal-weight nonsmoker (Chiolero et al. 2008). Furthermore, smoking lowers body weight (BW) and BMI, which makes many people reluctant to quit (Chiolero et al. 2008). The finding that smoking lowers body weight but increases rates of diabetes, insulin resistance, and cardiovascular disease is an intriguing paradox that our laboratory is studying using both human and rodent models.

Smokers weigh less than nonsmokers of the same age and sex (Albanes et al. 1987), while cessation of smoking is usually accompanied by weight gain (Grunberg 1986, Klesges et al. 1989, Williamson et al. 1991). A comparison of 1911 homozygotic male twins, where only one of the siblings smoked, demonstrated that smokers weighed 2.5–5.0 kg less than nonsmokers (Eisen et al. 1993). Cigarette smoking is perceived as an effective strategy for weight control for many smokers. Approximately 75% of women and 35% of men reported that they would not tolerate a weight gain of more than 2.5 kg if they quit smoking (Pomerleau & Kurth 1996). One explanation for the reduction in body weight with tobacco smoking may result from decreased caloric intake and/or increased energy expenditure (Wager-Srdar et al. 1984, Grunberg 1986).

Although numerous rodent studies have provided convincing evidence for the inverse association between smoking/nicotine and body weight, the mechanisms underlying this relationship are not well understood. Furthermore, smoking and nicotine intake are not equivalent; a number of studies suggest that nicotine has beneficial effects on body weight control, food intake, energy expenditure, as well as on improving cognition and preventing inflammation, whereas cigarette smoking is associated with increased risk factors for cardiovascular diseases and other morbidity and mortalities (Kannel 1981, Filozof et al. 2004, Wang et al. 2011). The effect of cigarettes can not only be solely explained by nicotine but also by many other components in the cigarettes, as well as by unhealthy lifestyles often exhibited by smokers (Grunberg 1985, Filozof et al. 2004). Some human and animal studies suggest that nicotine suppresses food intake (Bowen et al. 1986, Frankish et al. 1995), while other studies show that nicotine increases metabolic rate (Schechter & Cook 1976, Wager-Srdar et al. 1984, Hofstetter et al. 1986, Sztalryd et al. 1996). Winders & Grunberg (1990) showed that nicotine decreased weight gain and carcass fat, but did not affect food intake in rats.

We are concerned that some smokers know that smoking leads to lower weight and may erroneously conclude that they can eat whatever they want while smoking. Given that obesity is epidemic and that smoking/nicotine use is on the rise in many developing countries, it is clear that the co-occurrence of the smoking and weight gain has devastating effects on overall heath throughout the world (Chiolero et al. 2008, Flegal et al. 2010). Additionally, there are two types of abdominal fat, visceral and subcutaneous, with the former being more metabolically active and associated with cardiovascular risk factors (Fox et al. 2007). Smokers have a lower amount of visceral fat than nonsmokers (Matsushita et al. 2010), although the effect of nicotine on fat distribution (visceral vs subcutaneous) in an animal model has not been determined.

To address these issues, in this study, we treated mice with different doses of nicotine or saline while they were on either a normal chow diet (NCD) or a high-fat diet (HFD) and examined changes in body weight, caloric intake, as well as measured fat distribution by computed tomography (CT) analysis and dual-energy X-ray absorption (DXA) scan analysis. Additionally, to determine the potential mechanism of nicotine action on alterations in body weight, we examined the ability of a nonselective nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, and a partial nAChR agonist/antagonist, varenicline, to reverse the effects of nicotine on weight loss.

Materials and Methods

Animals and treatments

Male C57BL/6 mice weighing 22–24 g obtained from Taconic farm (Germantown, NY, USA) were used for all experiments. Mice were housed four per cage until the beginning of the experiments at which time they were individually housed with the exception that animals were housed two per cage during the nicotine antagonists/partial agonist experiment. All mice had free access to water and food. All experiments using animals were performed in compliance with the NIH Guidelines for the Use of Animals in Research and approved by the Institutional Animal Care and Use Committee at Charles Drew University School of Medicine & Sciences (Los Angeles, CA, USA).

Mice were fed either an NCD with 5% fat (2.03 kcal/g; laboratory rodent diet #5001, LabDiet, Richmond, IN, USA) or an HFD with 60% of calories derived from fat consisting of 26.2% protein, 26.3% carbohydrate, and 34.9% fat (5.24 kcal/g; D12492, Research Diets, New Brunswick, NJ, USA) for 7 weeks. Mice on either diet received twice daily i.p. injections of either low-nicotine dose (0.5 mg/kg per BW per day, given twice daily) or high-nicotine dose (1.5 mg/kg per day, given twice daily), an escalating dose of nicotine (starting at 0.25 mg/kg per day, given twice daily and going up to 4.5 mg/kg per day by an increment of 0.5 mg/kg per day every 3 days), or saline. The escalating dose was designed to compensate for the development of nicotine tolerance. The 1.5 mg/kg per day dose is approximately equal to the amount of nicotine that a smoker smoking 50 cigarettes a day (2.5 packs) might be exposed to over the whole day (Armitage et al. 1968). For experiments using nAChR antagonists/partial agonists, mice were given twice daily i.p. injections of mecamylamine (2 mg/kg per day) or varenicline (2 mg/kg per day) concurrently with the nicotine injections and were only exposed to the HFD. In this experiment, mice were placed on the HFD 11 days before starting the injections.

Animals were weighed daily and the weight change from baseline was calculated. The amount of food consumed per mouse was measured daily. The cumulative caloric intake was calculated based on the kcal/g of each diet. For the antagonist study, mice were weighed and food consumption was determined every 3 days.

Drugs

(−)Nicotine liquid, mecamylamine hydrochloride, varenicline tartrate, and ketamine hydrochloride/xylazine hydrochloride solution were purchased from Sigma/Aldrich. Isoflurane was purchased from Attane (Bethlehem, PA, USA). Nicotine, mecamylamine, and varenicline were all diluted in saline and each injection was administered in a volume of around 200 μl, after adjusting for body weight. The nicotine solution was covered with aluminum foil during storage to prevent light exposure.

DXA scan

Body composition experiments to measure fat depots were carried out by DXA densitometry using a LUNAR PIXImus II Densitometer (GE Medical Systems, New York, NY, USA) with software (version 2.10) and procedures, as described previously (Nagy & Clair 2000) and performed on mice that were treated with nicotine or saline and HFD or NCD for 10 weeks. Mice were anesthetized with ketamine (100 mg/kg) and xylazine (10 mg/kg) before scanning.

CT scan

CT scans were performed on mice treated with nicotine or saline and receiving HFD or NCD for 10 weeks. Mice received isoflurane (2% by inhalation) anesthesia before imaging in a MicroCAT II small animal CT system (Siemens Preclinical Solutions, Knoxville, TN, USA), as described previously (Suckow & Stout 2008, Suckow et al. 2009). A heated anesthesia chamber was used to maintain body temperature and mice were positioned in the center of the field of view. Exposure settings were 70 kVp, 500 mAs, 500 ms exposure time, and 360° rotation in 1° steps with 2.0 mm aluminum filtration. Images were reconstructed using a modified Feldkamp process to a cubic voxel size of 0.20 mm in a 256×256×496 matrix. CT values were converted into Hounsfield units using the formula: HU=(μt−μw)/(μw−μa)×1000) where μw and μa are the linear attenuation coefficients of water and air, respectively, and μt is the linear attenuation coefficient of tissue. Using the freely available software AMIDE (http://amide.sourceforge.net/), images were analyzed to separate fat (low density) from other soft tissues based on Hounsfield units. The imaging chamber was removed from the CT images using elliptic cylinder region of interest (ROI). The mouse abdominal region was selected from the liver/lung interface to the top of the pelvic horn. An isocontour value selection above −350 Hounsfield units was used to determine the region volume. Adipose tissue volume was selected using isocontour value selection between −268 and −48. Separation of visceral and subcutaneous fat was performed in draw mode by editing the adipose region to contain only one fat type. ROI volumes were calculated using AMIDE and converted to mass assuming an average density of 1.0 g/cm3.

Data analyses

Data are expressed as mean±s.e.m. Changes in body weight and caloric intake were analyzed using repeated measures ANOVA. DXA scan and CT scan data were analyzed by two-way ANOVA. The Newman–Keuls post hoc test was used to reveal significant differences between various treatments. All statistical tests were two tailed and the significance level was set at P≤0.05.

Results

Nicotine blunted weight gain in mice on NCD and HFD and decreased caloric intake

Figure 1A illustrates the effect of nicotine (1.5 mg/kg per day) vs saline on body weight gain in mice fed with NCD or HFD. Repeated measures ANOVA revealed a significant treatment by time interaction (F141,490=9.37; P<0.000001). Post hoc analysis of the data showed that HFD led to more weight gain than NCD (P<0.000001) and nicotine (compared with saline) significantly decreased the weight gain in mice on the NCD (P<0.000001) or HFD (P<0.000001). The weight-blunting effects of nicotine on the HFD were much more robust than on the NCD. Tolerance to the weight-blunting effects of nicotine did not occur in any of the nicotine-treated groups.

Figure 1

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Figure 1

Changes in body weight from baseline in mice receiving either nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline fed with the HFD or NCD (A); in mice on the HFD receiving saline or either high (1.5 mg/kg per day, given twice daily, i.p.), low (0.5 mg/kg per day, given twice daily, i.p.), or escalating dose of nicotine (starting at 0.25 mg/kg per day given twice daily and going up to 4.5 mg/kg per day by an increment of 0.5 mg/kg per day every 3 days, i.p.) (B); and in mice with the NCD receiving either saline or high (1.5 mg/kg per day, given twice daily, i.p.), low (0.5 mg/kg per day, given twice daily, i.p.), or an escalating dose of nicotine (starting at 0.25 mg/kg per day given twice daily and increasing up to 4.5 mg/kg per day by an increment of 0.5 mg/kg per day every 3 days, i.p.) (C). Depicted figure (n=3–4/condition) represents mean (±s.e.m.) and is representative of experiment performed on three occasions. *P<0.00001 vs saline/NCD; #P<0.00001 vs saline/HFD.

Citation: Journal of Endocrinology 212, 3; 10.1530/JOE-11-0350

Figure 1B illustrates the effect of low (0.5 mg/kg per day), high (1.5 mg/kg per day), or an escalating dose of nicotine vs saline on changes in body weight in mice fed with the HFD. Repeated measures ANOVA revealed a significant treatment by time interaction (F141,489=4.08; P<0.000001). Post hoc analysis of the data showed a significant decrease in weight gain in mice treated with the high (1.5 mg/kg per day; P<0.000001) or escalating (P<0.000001) dose of nicotine, but not in those treated with the low (0.5 mg/kg per day) dose of nicotine (P=NS) compared with saline-treated controls.

Figure 1C illustrates the effect of low (0.5 mg/kg per day), high (1.5 mg/kg per day), or an escalating dose of nicotine vs saline on changes in body weight in mice fed with the NCD. Repeated measures ANOVA revealed a significant treatment by time interaction (F141,534=4.08; P<0.000001). Post hoc analysis of the data showed that nicotine at high (1.5 mg/kg per day; P<0.000001) or escalating dose (P<0.000001), but not at the 0.5 mg/kg per day dose (P=NS), compared with saline, significantly blunted weight gain induced by the consumption of the NCD. Thus, higher dose nicotine blocks weight gain in mice on both the HFD and the NCD.

Figure 2A shows that the difference in weight gain between mice on nicotine compared to those on saline was accentuated when mice were placed on the HFD after being on the NCD for 45 days. In fact, the saline-treated animals gained about 2 g on the NCD for 45 days and 8 g when placed on the HFD for the next 23 days, whereas the nicotine-treated animals lost about 2 g when fed with the NCD for 45 days and gained only 2 g when placed on the HFD for the next 23 days. Repeated measures ANOVA revealed a significant treatment by time interaction (F26,196=22.23; P<0.000001).

Figure 2

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Figure 2

Changes in body weight from baseline in mice on the HFD (A) after receiving the NCD for 45 days and given either higher dose nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline; or (B) in mice on the NCD following nicotine cessation after receiving a higher dose nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline for 23 days. The data represent mean (±s.e.m.) of five mice per time point in each treatment group. *P<0.00001 vs saline; **P<0.00001 vs saline for days 1–23; ##P<0.00001 vs saline for days 24–38.

Citation: Journal of Endocrinology 212, 3; 10.1530/JOE-11-0350

Figure 2B shows that there was a significant difference in body weight gain in mice on the NCD that were treated with nicotine compared to saline (compare the two groups up to day 23). Repeated measures ANOVA from days 0 to 23 revealed a significant treatment by time interaction (F22,154=3.61; P<0.000001). Figure 2B also shows that the difference in weight gain between mice receiving nicotine compared with saline was reduced when nicotine treatment was stopped on day 23 (compare the two groups after day 23). Repeated measures ANOVA from days 24 to 38 revealed a significant treatment by time interaction (F15,105=3.47; P<0.0001).

Figure 3 shows that mecamylamine completely and varenicline partially blocked the weight-reducing action of nicotine in mice fed with the HFD. Repeated measures ANOVA revealed a significant treatment by time interaction (F65,220=4.85; P<0.000001). Post hoc analysis of the data showed that mecamylamine (nicotine/mecamylamine vs nicotine/saline; P<0.000001) and varenicline (nicotine/varenicline vs nicotine/saline; P<0.00005) each significantly blunted the weight-reducing action of nicotine. The nicotine/varenicline group was significantly different from the saline/saline group (P<0.000001), showing that varenicline only partially blocked the weight-reducing action of nicotine, while there was no difference between the nicotine/mecamylamine group and the saline/saline group (P=0.27), indicating a complete inhibition by mecamylamine. Post hoc analysis of the data showed that saline/mecamylamine and saline/varenicline groups were not statistically different from the saline/saline group (P=0.09 and 0.69 respectively), indicating that mecamylamine and varenicline do not significantly affect body weight by themselves.

Figure 3

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Figure 3

Changes in body weight from baseline in mice on an HFD receiving either nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline with concurrent treatment with either mecamylamine (2 mg/kg per day, given twice daily, i.p.) or varenicline (2 mg/kg per day, given twice daily, i.p.). The data represent mean (±s.e.m.) of three to four mice per time point in each treatment group and is representative of data performed on two occasions. *P<0.00005 vs nicotine/saline; #P<0.000005 vs saline/saline.

Citation: Journal of Endocrinology 212, 3; 10.1530/JOE-11-0350

Figure 4 illustrates that cumulative caloric intake was mildly reduced by different doses of nicotine compared with saline in mice fed with NCD and HFD, with HFD-treated mice consuming more calories. For NCD, repeated measures ANOVA revealed a significant treatment by time interaction (F141,520=1.38; P=0.006). Post hoc analysis of the data showed that nicotine at low (0.5 mg/kg per day; P=0.001) and escalating dose (P=0.006) but not at high dose (1.5 mg/kg per day; P=0.96) significantly decreased the cumulative caloric intake in mice on the NCD. For HFD, cumulative caloric intake was mildly reduced in mice on the HFD treated with different doses of nicotine compared with saline. In HFD-treated mice, the effect of the escalating dose was minimal initially but increased as the dose of nicotine increased. Repeated measures ANOVA revealed a significant treatment by time interaction (F=1.66; P=0.0001). Post hoc analysis of the data showed that nicotine at the 1.5 mg/kg per day dose (P=0.002), but not at the escalating (P=0.07) or low (0.5 mg/kg per day; P=0.5) dose significantly decreased caloric intake.

Figure 4

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Figure 4

Cumulative caloric intake in mice fed with the NCD or HFD receiving either saline, high (1.5 mg/kg per day, given twice daily, i.p.), low (0.5 mg/kg per day, given twice daily, i.p.), or an escalating (ESC) dose of nicotine (starting at 0.25 mg/kg per day given twice daily and going up to 4.5 mg/kg per day by an increment of 0.5 mg/kg per day every 3 days, i.p.). The data represent mean (±s.e.m.) of three to four mice per time point and is representative of data performed on three separate occasions. *P<0.01 vs saline.

Citation: Journal of Endocrinology 212, 3; 10.1530/JOE-11-0350

The cumulative caloric intake over the 42 days of the study (Fig. 4) between saline-treated mice and nicotine-treated (1.5 mg/kg per day) mice was 41.2 kcal for mice on the NCD and 48.2 kcal for mice on the HFD. It is estimated that for every 10 kcal reduction in caloric intake, an average mouse loses 1 g of weight (Dalan Jensen, University of Colorado, and Joseph Bass, Northwestern University, personal communication). Thus, the decreased caloric intake possibly accounts for 65% of the reduced weight gain in nicotine-treated (1.5 mg/kg per day) mice on the HFD (7.3 g less weight gained over the first 42 days, Fig. 1) and all of the reduced weight gain in the NCD (2.6 g less weight gained over the first 42 days, Fig. 1).

Nicotine decreased body fat as determined by DXA and CT scan

Two-way ANOVA revealed a significant effect of diet (F1,12=38.8; P=0.00004), treatment (F1,12=6.26; P=0.03), and interaction between the two factors (F1,12=5.03; P=0.04) for body fat (g) using DXA scan analysis (Fig. 5A). Post hoc analysis of the data demonstrated that nicotine (1.5 mg/kg per day) compared with saline decreased the amount of fat (P<0.05) in mice on the HFD, but not in mice fed with NCD (P=NS). As expected, mice on the HFD had a greater amount of fat compared with mice on the NCD (P<0.001).

Figure 5

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Figure 5

DXA scan showing the total amount of fat (g) (A) and lean mass (muscle plus bone) (B) in mice receiving nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline fed with the NCD or HFD. *P<0.05 vs HFD-saline group, **P<0.01 vs HFD-saline group. The data represent mean (±s.e.m.) of four mice in each group.

Citation: Journal of Endocrinology 212, 3; 10.1530/JOE-11-0350

As shown in Fig. 5B, while two-way ANOVA revealed no significant effect of treatment (F1,12=3.04; P=0.11) on lean mass (muscle plus bone), as measured by DXA, there was a significant effect of diet (F1,12=103.6; P<0.0001) and a significant interaction between the diet and treatment (F1,12=11.5; P=0.0053). Post hoc analysis of the data demonstrated that nicotine (1.5 mg/kg per day) compared with saline decreased the amount of lean mass (P<0.01) in mice on the HFD, but not in mice fed with NCD (P>0.05).

Using a two-way ANOVA for the CT scan data for total body fat (Fig. 6A), we found a significant effect of diet (F1,12=97; P<0.0001), indicating that the HFD resulted in higher total fat than NCD, a significant effect of treatment (F1,12=5.8; P<0.05), indicating that the nicotine-treated group had lower total fat than the saline-treated group, and a trend toward a significant interaction between the two factors (F1,12=4.4; P=0.08) showing that nicotine altered the amount of fat more in mice on HFD, although it did not reach significance. Post hoc analysis of the data showed that nicotine significantly reduced total fat in the HFD-treated mice (P<0.05), but not in the NCD-treated mice (P=NS). For visceral fat (Fig. 6B), we found a significant effect of diet (F1,12=106; P<0.0001), a significant effect of treatment (F1,12=7.2; P<0.05), and a trend toward a significant interaction between the two factors (F1,12=4.4; P=0.06), showing that nicotine altered the amount of visceral fat more in mice on HFD, although it did not reach significance. Post hoc analysis of the data showed that nicotine significantly reduced visceral fat in the HFD-treated mice (P<0.05), but not in the NCD-treated mice (P=NS). For subcutaneous fat (Fig. 6C), we found a significant effect of diet (F1,12=72; P<0.0001), but no significant effect of treatment (F1,12=3.1; P=NS) and no significant interaction between the two factors (F1,12=1.95; P=NS). Thus, nicotine selectively reduced visceral fat, but not subcutaneous fat, in mice on an HFD.

Figure 6

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Figure 6

CT scans in mice receiving nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline and fed with the NCD or HFD showing total fat (A), visceral fat (B), and subcutaneous fat (C), and representative view of visceral and subcutaneous fat using coronal, sagittal, and transverse sections (D). The data represent mean (±s.e.m.) of four mice per group. *P<0.05 vs saline.

Citation: Journal of Endocrinology 212, 3; 10.1530/JOE-11-0350

Representative coronal, sagittal, and transverse views of the CT scans of mice on the HFD receiving saline or nicotine (1.5 mg/kg per day) showed a decrease in fat content after combined treatments with HFD plus nicotine compared with HFD plus saline (Fig. 6D).

Discussion

Obesity and cigarette smoking are the leading preventable causes of death in developed societies. Both obesity and cigarette smoking are also important risk factors in many age-related diseases, accelerating the aging process via increasing oxidative stress and inflammation (Valdes et al. 2005). Both smoking and consumption of an HFD are risk factors for insulin resistance and type 2 diabetes, and the two habits together can increase the risk of developing these conditions even higher. With an increasing prevalence of obesity, many people report that smoking can be used to control weight gain (Cavallo et al. 2010) and adolescent smokers frequently engage in unhealthy dietary restrictions (fasting, diet pills, or vomiting) (Cavallo et al. 2010). Once they start smoking, some people may develop an erroneous belief that they can eat unhealthy diets. Thus, understanding the combined effects of nicotine, the main ingredient in cigarettes that affects body weight (Schechter & Cook 1976, Grunberg 1982) and body fat distribution has important public health consequences.

Our study showed that nicotine reduced weight gain in mice, an effect that was much more pronounced in mice fed with the HFD compared with those on the NCD. The effect was more robust at the higher dose of nicotine. We also found that when mice were switched from an NCD to HFD, the weight loss properties of nicotine were accentuated. Furthermore, nicotine cessation led to weight gain and therefore a reduction in the difference observed on weight gain between nicotine- and saline-treated mice on the NCD. The accelerated weight gain following nicotine cessation is consistent with previous animal (Schechter & Cook 1976, Grunberg et al. 1984, 1985, 1986, Winders & Grunberg 1990) and human (Grunberg 1982, Grunberg & Morse 1984) studies, although other studies reported that body weight remained attenuated following smoking cessation (Bellinger et al. 2010). This result may also suggest that the weight-reducing action of nicotine is dependent on nicotine intake and may involve some rapidly reversible processes that may be turned off following the cessation of nicotine treatment.

The nicotine-induced changes in body weight may be due to decreased energy intake, increased energy expenditure, or a combination of the two processes. The literature provides support for decreased food intake (Munster & Battig 1975, Grunberg 1982, Clarke & Kumar 1984, Grunberg et al. 1985, Chen et al. 2007b), but there is also some evidence showing no effect on food intake (Schechter & Cook 1976, Grunberg et al. 1984), especially in male rats (Grunberg et al. 1987, Winders & Grunberg 1990). A recent article found that nicotine, given to mice on an HFD, decreased food intake and increased energy expenditure, while nicotine withdrawal resulted in weight gain due to a decrease in energy expenditure (Hur et al. 2010). The relative effect of food intake vs energy expenditure may have to do with species, gender, type of food (bland vs sweet food), time of nicotine exposure (light or dark cycle), method of nicotine administration (pump vs injections), or dose of nicotine. Additional studies demonstrated increased metabolism in rodents exposed to nicotine (Bizzi et al. 1972, Ilebekk et al. 1975, Bellinger et al. 2010). We found that caloric intake was decreased in nicotine-treated mice. Estimates of energy intake suggested that decreased caloric intake accounted for all the weight loss in mice on an NCD and 66% on an HFD. This suggests that some of the weight loss in mice on an HFD may be due to increased energy expenditure. It is worth noting that the conversion between reduced caloric intake and decreased body weight is only an estimate.

In both humans and rats, nicotine administration or cigarette smoking has been shown to selectively depress the consumption of sweet-tasting high-caloric foods (Grunberg & Morse 1984, Grunberg et al. 1985). The hypophagic and weight-reducing actions of nicotine in rats depend mainly on the sweet taste rather than the caloric content of the food, when these two variables are independently manipulated (Grunberg et al. 1985). Female rats are more sensitive to the weight-reducing effects of nicotine than male rats (Grunberg et al. 1986). Additionally, female rats gain more weight following smoking cessation than male rats (Grunberg et al. 1986). Thus, future work is needed to examine whether the present results extend to female mice.

Our studies as well as most studies looking at weight-reducing effects of nicotine used nicotine and not cigarette smoke. Chen et al. (2007a), however, found that cigarette smoke exposure reduced body weight more substantially in Balb/c mice on a regular chow compared with mice on the HFD. In that study, smoke exposure reduced weight gain without significantly reducing fat mass and the authors found a reduction in food intake with smoke exposure.

An important issue that our study begins to address is which nAChR mediates the nicotine-induced weight loss and change in body composition. nAChRs are divided into muscle (α1, β1, γ/ϵ, and δ) and neuronal subtypes (α2–10 and β2–4) (Dani 2001). In addition, nonneuronal cells express functional nAChR, including keratinocytes, bronchial epithelial cells and aortic endothelial cells, and lymphocytes (Maslinski et al. 1992, Nguyen et al. 2000, Liu et al. 2004). Recently, Liu et al. (2004) found that rat adipocytes express α1–7, α9, α10, β1–4, δ, and ϵ subunit mRNA. Immunocytochemical analysis also suggested the presence of α7 and β2 subunits in adipocytes and receptor binding studies showed high-affinity binding for nicotine in adipocytes (Liu et al. 2004).

Our finding that mecamylamine completely blocked the effects of nicotine implies that nicotine receptors are involved, although we are unable to determine whether the effect is mediated via the central or peripheral nAChRs. In the future, we may perform experiments with antagonists that do not cross the blood–brain barrier to help determine whether the effects are mediated via the central or peripheral nAChRs. It is possible that nicotine is having a direct effect on the adipocyte, which expresses nAChRs as discussed above, or may be an effect at sites related to increased metabolism, such as via the adrenal medulla where nAChR activation may lead to increased catecholamine release (Sala et al. 2008) or brown fat, where nAChR activation may stimulate expression of uncoupling proteins 1 and 3 promoting thermogenesis (Chen et al. 2008).

Our study also examined the effects of varenicline, an α4β2 nAChR partial agonist/antagonist that is used clinically for smoking cessation under the trade name of Chantix (Gonzales et al. 2006, Siu & Tyndale 2007) on nicotine-induced weight loss. Varenicline partially blocked the nicotine-induced weight loss, suggesting that α4β2 nAChR is partially involved in the weight-reducing properties of nicotine, but other nAChRs are also likely to be involved. None of the antagonists/partial agonists altered body weight in mice given saline, although a trend toward weight gain was seen with saline plus varenicline. Clinically, weight gain has been found with varenicline (Physicians' Desk Reference 2011. http://www.pdr.net/, Accessed October 26, 2011), although this may be due to the weight gain observed following smoking cessation.

Smokers are leaner yet paradoxically have increased rates of cardiovascular disease and type 2 diabetes. This may be explained by the type of fat distribution in smokers. Visceral fat is known to be more detrimental in terms of cardiovascular disease, diabetes, and overall mortality (Lapidus et al. 1984, Larsson et al. 1984, Sparrow et al. 1986, Fujioka et al. 1987). Smokers have an elevated risk of having a high waist–hip ratio (WHR) with increased central obesity/visceral fat even with a low BMI (Moffatt & Owens 1991, Jee et al. 2002) and a graded dose–response relationship was found between the number of cigarettes smoked and WHR (Shimokata et al. 1989). The WHR in those who started smoking actually increased despite their loss of weight. These paradoxical changes in WHR indicate that there are harmful effects of cigarette smoking on the pattern of distribution of body fat (Shimokata et al. 1989). However, other studies have found that smokers have a lower amount of visceral fat than nonsmokers (Matsushita et al. 2010). Because of the effect of cigarettes on fat distribution in humans, we determined how nicotine affects fat distribution in mice fed with the HFD compared with the NCD. We hypothesized that we would see an increase in the amount of visceral fat in nicotine-treated mice, similar to subjects using cigarettes. DXA scan showed that nicotine did not alter the amount of fat in mice on the NCD but did substantially reduce the amount of fat in mice fed with the HFD. CT scan analysis confirmed that nicotine led to a substantial reduction in fat stores, but only in mice on the HFD diet. Surprisingly, nicotine treatment resulted in a decreased amount of visceral fat in mice on HFD, which is similar to the above study (Matsushita et al. 2010). Thus, the more detrimental fat appears to be selectively reduced by nicotine.

Our DXA scan analysis demonstrated a decrease in both fat and lean body mass in mice receiving HFD and treated with nicotine compared with their saline-treated controls. The reduction in fat mass is expected and is consistent with a decreased body weight found in this group. The decreased lean mass quantitated by DXA may be due to ectopic fat deposition in the muscle of mice treated with nicotine/HFD, as we have reported in a preliminary study (Shin et al. 2011). Our DXA finding showing a lack of an effect of nicotine on both fat and lean body mass in mice receiving NCD might be due to the small overall differences in weight between the two groups that might not be detected by DXA scan.

Our study has some limitations. Nicotine was delivered by twice daily i.p. injections. We recognize that this system does not incorporate voluntary consumption and also that only twice a day peak of nicotine is nonphysiological, compared with how smokers receive nicotine. However, other models have their own drawbacks. For example, Alzet pump to deliver nicotine or saline continuously is not clinically relevant either and our unpublished data demonstrate that it can lead to increased corticosterone levels due to the postoperative pain and distress associated with osmotic minipump implantation. Thus, we are confident that this model is a realistic choice to study the effects of nicotine on body weight and fat redistribution.

In conclusion, we observed that nicotine exposure reduced HFD-induced weight gain and further led to lower amounts of body fat and a more favorable distribution of body fat (a trend toward more subcutaneous and less visceral fat). Thus, superficially, it might appear that the HFD plus nicotine is actually a more beneficial combination than HFD alone. However, several recent animal studies have shown that cigarette smoking exacerbates hepatic steatosis triggered by HFD (Liu et al. 2003, Chen et al. 2007a, Yuan et al. 2009, Azzalini et al. 2010). In preliminary studies, our laboratory has found that nicotine plus the HFD leads to impaired glucose tolerance (Friedman et al. 2009), increased oxidative stress, and hepatic and muscle steatosis (Mangubat et al. 2011). Therefore, we certainly do not advocate smoking or nicotine use to combat the untoward consequences of consumption of the HFD as it is likely that these two insults can act synergistically to exhibit severely detrimental metabolic effects, more than each insult alone.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. None of the authors has a relationship with the tobacco industry and no funding from any tobacco company was received for this work.

Funding

This work was supported by NIH grants R01 DA14659 and K21 DA00276 to T C F, RCMI Program grant G21 RR03026-13, an NIH (R24DA017298) Minority Institution Drug Abuse Research Program (MIDARP) Program, and an Endowment grant S21MD000103–NIH/NCMHD to Charles Drew University of Medicine & Sciences. K L was supported by NIH grant R01 DA16682. Y L was supported by NIH grant K01 DK073272 and SC1DK087655.

Acknowledgements

The authors thank the UCLA Biosciences Core Facilities program for performing the DXA scans and the UCLA Crump Imaging Center for performing the CT scans.

References

  • AlbanesDJonesDYMicozziMSMattsonME1987Associations between smoking and body weight in the US population: analysis of NHANES II. American Journal of Public Health77439444. doi:10.2105/AJPH.77.4.439.

  • ArmitageAKHallGHMorrisonCF1968Pharmacological basis for the tobacco smoking habit. Nature217331334. doi:10.1038/217331a0.

  • AzzaliniLFerrerERamalhoLNMorenoMDominguezMColmeneroJPeinadoVIBarberaJAArroyoVGinesP2010Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Hepatology5115671576. doi:10.1002/hep.23516.

  • BellingerLLWellmanPJHarrisRBKelsoEWKramerPR2010The effects of chronic nicotine on meal patterns, food intake, metabolism and body weight of male rats. Pharmacology Biochemistry and Behavior959299. doi:10.1016/j.pbb.2009.12.012.

  • BizziATacconiMTMedeaAGarattiniS1972Some aspects of the effect of nicotine on plasma FFA and tissue triglycerides. Pharmacology7216224. doi:10.1159/000136292.

  • BowenDJEurySEGrunbergNE1986Nicotine's effects on female rats' body weight: caloric intake and physical activity. Pharmacology Biochemistry and Behavior2511311136. doi:10.1016/0091-3057(86)90099-7.

  • CavalloDASmithAESchepisTSDesaiRPotenzaMNKrishnan-SarinS2010Smoking expectancies, weight concerns, and dietary behaviors in adolescence. Pediatrics126e66e72. doi:10.1542/peds.2009-2381.

  • ChenHHansenMJJonesJEVlahosRAndersonGPMorrisMJ2007aDetrimental metabolic effects of combining long-term cigarette smoke exposure and high-fat diet in mice. American Journal of Physiology Endocrinology and Metabolism293E1564E1571. doi:10.1152/ajpendo.00442.2007.

  • ChenHHansenMJJonesJEVlahosRBozinovskiSAndersonGPMorrisMJ2007bRegulation of hypothalamic NPY by diet and smoking. Peptides28384389. doi:10.1016/j.peptides.2006.07.034.

  • ChenHHansenMJJonesJEVlahosRAndersonGPMorrisMJ2008Long-term cigarette smoke exposure increases uncoupling protein expression but reduces energy intake. Brain Research12288188. doi:10.1016/j.brainres.2008.06.067.

  • ChioleroAFaehDPaccaudFCornuzJ2008Consequences of smoking for body weight, body fat distribution, and insulin resistance. American Journal of Clinical Nutrition87801809.

  • ClarkePBKumarR1984Some effects of nicotine on food and water intake in undeprived rats. British Journal of Pharmacology82233239.

  • DaniJA2001Overview of nicotinic receptors and their roles in the central nervous system. Biological Psychiatry49166174. doi:10.1016/S0006-3223(00)01011-8.

  • EisenSALyonsMJGoldbergJTrueWR1993The impact of cigarette and alcohol consumption on weight and obesity. An analysis of 1911 monozygotic male twin pairs. Archives of Internal Medicine15324572463. doi:10.1001/archinte.1993.00410210081009.

  • FilozofCFernandez PinillaMCFernandez-CruzA2004Smoking cessation and weight gain. Obesity Reviews595103. doi:10.1111/j.1467-789X.2004.00131.x.

  • FioreMCFlemingMFBurnsME1999Tobacco and alcohol abuse: clinical opportunities for effective intervention. Proceedings of the Association of American Physicians111131140. doi:10.1046/j.1525-1381.1999.09249.x.

  • FlegalKMCarrollMDOgdenCLCurtinLR2010Prevalence and trends in obesity among US adults, 1999–2008. Journal of the American Medical Association303235241. doi:10.1001/jama.2009.2014.

  • FoxCSMassaroJMHoffmannUPouKMMaurovich-HorvatPLiuCYVasanRSMurabitoJMMeigsJBCupplesLA2007Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation1163948. doi:10.1161/CIRCULATIONAHA.106.675355.

  • FrankishHMDrydenSHopkinsDWangQWilliamsG1995Neuropeptide Y, the hypothalamus, and diabetes: insights into the central control of metabolism. Peptides16757771. doi:10.1016/0196-9781(94)00200-P.

  • FriedmanTCWangWGhodsDLutfyKLiuY2009The mechanisms of nicotine-induced glucose intolerance: role in the high prevalence of cardiovascular disease in smokers. Endocrine Society91P2476.

  • FujiokaSMatsuzawaYTokunagaKTaruiS1987Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism365459. doi:10.1016/0026-0495(87)90063-1.

  • GonzalesDRennardSINidesMOnckenCAzoulaySBillingCBWatskyEJGongJWilliamsKEReevesKR2006Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. Journal of the American Medical Association2964755. doi:10.1001/jama.296.1.47.

  • GrunbergNE1982The effects of nicotine and cigarette smoking on food consumption and taste preferences. Addictive Behaviors7317331. doi:10.1016/0306-4603(82)90001-6.

  • GrunbergNE1985Nicotine, cigarette smoking, and body weight. British Journal of Addiction80369377. doi:10.1111/j.1360-0443.1985.tb03008.x.

  • GrunbergNE1986Nicotine as a psychoactive drug: appetite regulation. Psychopharmacology Bulletin22875881.

  • GrunbergNEMorseDE1984Cigarette smoking and food consumption in the United States. Journal of Applied Social Psychology14310317. doi:10.1111/j.1559-1816.1984.tb02239.x.

  • GrunbergNEBowenDJMorseDE1984Effects of nicotine on body weight and food consumption in rats. Psychopharmacology839398. doi:10.1007/BF00427430.

  • GrunbergNEBowenDJMaycockVANesporSM1985The importance of sweet taste and caloric content in the effects of nicotine on specific food consumption. Psychopharmacology87198203. doi:10.1007/BF00431807.

  • GrunbergNEBowenDJWindersSE1986Effects of nicotine on body weight and food consumption in female rats. Psychopharmacology90101105. doi:10.1007/BF00172879.

  • GrunbergNEWindersSEPoppKA1987Sex differences in nicotine's effects on consummatory behavior and body weight in rats. Psychopharmacology91221225. doi:10.1007/BF00217067.

  • HaslamDWJamesWP2005Obesity. Lancet36611971209. doi:10.1016/S0140-6736(05)67483-1.

  • HofstetterASchutzYJequierEWahrenJ1986Increased 24-hour energy expenditure in cigarette smokers. New England Journal of Medicine3147982. doi:10.1056/NEJM198601093140204.

  • HurYNHongGHChoiSHShinKHChunBG2010High fat diet altered the mechanism of energy homeostasis induced by nicotine and withdrawal in C57BL/6 mice. Molecules and Cells30219226. doi:10.1007/s10059-010-0110-3.

  • IlebekkAMillerNEMjosOD1975Effects of nicotine and inhalation of cigarette smoke on total body oxygen consumption in dogs. Scandinavian Journal of Clinical and Laboratory Investigation356772. doi:10.3109/00365517509068007.

  • JeeSHLeeSYNamCMKimSYKimMT2002Effect of smoking on the paradox of high waist-to-hip ratio and low body mass index. Obesity Research10891895. doi:10.1038/oby.2002.122.

  • KannelWB1981Update on the role of cigarette smoking in coronary artery disease. American Heart Journal101319328. doi:10.1016/0002-8703(81)90197-6.

  • KlesgesRCMeyersAWKlesgesLMLa VasqueME1989Smoking, body weight, and their effects on smoking behavior: a comprehensive review of the literature. Psychological Bulletin106204230. doi:10.1037/0033-2909.106.2.204.

  • LapidusLBengtssonCLarssonBPennertKRyboESjostromL1984Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. British Medical Journal28912571261. doi:10.1136/bmj.289.6454.1257.

  • LarssonBSvardsuddKWelinLWilhelmsenLBjorntorpPTibblinG1984Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. British Medical Journal28814011404. doi:10.1136/bmj.288.6428.1401.

  • LiuRHMizutaMMatsukuraS2003Long-term oral nicotine administration reduces insulin resistance in obese rats. European Journal of Pharmacology458227234. doi:10.1016/S0014-2999(02)02726-7.

  • LiuRHMizutaMMatsukuraS2004The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. Journal of Pharmacology and Experimental Therapeutics3105258. doi:10.1124/jpet.103.065037.

  • MangubatMLyzlovANzenwaIShenRSinha HikimAPFriedmanTCSinha-HikimI2011Nicotine induces oxidative stress and exacerbates high fat diet (HFD)-induced hepatic steatosis in a mouse mode of diet-induced obesity. Endocrine Society93OR0401.

  • MaslinskiWLaskowska-BozekHRyzewskiJ1992Nicotinic receptors of rat lymphocytes during adjuvant polyarthritis. Journal of Neuroscience Research31336340. doi:10.1002/jnr.490310215.

  • MatsushitaYNakagawaTYamamotoSTakahashiYNodaMMizoueT2010Associations of smoking cessation with visceral fat area and prevalence of metabolic syndrome in men: the Hitachi Health Study. Obesity19647651. doi:10.1038/oby.2010.237.

  • McGinnisJMFoegeWH1999Mortality and morbidity attributable to use of addictive substances in the United States. Proceedings of the Association of American Physicians111109118. doi:10.1046/j.1525-1381.1999.09256.x.

  • MoffattRJOwensSG1991Cessation from cigarette smoking: changes in body weight, body composition, resting metabolism, and energy consumption. Metabolism40465470. doi:10.1016/0026-0495(91)90225-L.

  • MunsterGBattigK1975Nicotine-induced hypophagia and hypodipsia in deprived and in hypothalamically stimulated rats. Psychopharmacologia41211217. doi:10.1007/BF00428926.

  • MurrayCJLopezAD1997Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet34914981504. doi:10.1016/S0140-6736(96)07492-2.

  • NagyTRClairAL2000Precision and accuracy of dual-energy X-ray absorptiometry for determining in vivo body composition of mice. Obesity Research8392398. doi:10.1038/oby.2000.47.

  • NguyenVTNdoyeAGrandoSA2000Novel human alpha9 acetylcholine receptor regulating keratinocyte adhesion is targeted by Pemphigus vulgaris autoimmunity. American Journal of Pathology15713771391. doi:10.1016/S0002-9440(10)64651-2.

  • PomerleauCSKurthCL1996Willingness of female smokers to tolerate postcessation weight gain. Journal of Substance Abuse8371378. doi:10.1016/S0899-3289(96)90215-1.

  • RobbinsASMansonJELeeIMSatterfieldSHennekensCH1994Cigarette smoking and stroke in a cohort of U.S. male physicians. Annals of Internal Medicine120458462.

  • SalaFNistriACriadoM2008Nicotinic acetylcholine receptors of adrenal chromaffin cells. Acta Physiologica192203212. doi:10.1111/j.1748-1716.2007.01804.x.

  • SchechterMDCookPG1976Nicotine-induced weight loss in rats without an effect on appetite. European Journal of Pharmacology386369. doi:10.1016/0014-2999(76)90201-6.

  • ShimokataHMullerDCAndresR1989Studies in the distribution of body fat. III. Effects of cigarette smoking. Journal of the American Medical Association26111691173. doi:10.1001/jama.1989.03420080089037.

  • ShinCSMangubatMLyzlovASinha HikimAPSinha-HikimIFriedmanTC2011Nicotine plus a high-fat diet leads to intramyocellular fat deposition in a mouse model of diet-induced obesity. American Diabetes Association712633PO.

  • SiuECTyndaleRF2007Non-nicotinic therapies for smoking cessation. Annual Review of Pharmacology and Toxicology47541564. doi:10.1146/annurev.pharmtox.47.120505.105354.

  • SparrowDBorkanGAGerzofSGWisniewskiCSilbertCK1986Relationship of fat distribution to glucose tolerance. Results of computed tomography in male participants of the Normative Aging Study. Diabetes35411415. doi:10.2337/diabetes.35.4.411.

  • SuckowCEStoutDB2008MicroCT liver contrast agent enhancement over time, dose, and mouse strain. Molecular Imaging and Biology10114120. doi:10.1007/s11307-007-0128-x.

  • SuckowCKuntnerCChowPSilvermanRChatziioannouAStoutD2009Multimodality rodent imaging chambers for use under barrier conditions with gas anesthesia. Molecular Imaging and Biology11100106. doi:10.1007/s11307-008-0165-0.

  • SztalrydCHamiltonJHorwitzBAJohnsonPKraemerFB1996Alterations of lipolysis and lipoprotein lipase in chronically nicotine-treated rats. American Journal of Physiology270E215E223.

  • ValdesAMAndrewTGardnerJPKimuraMOelsnerECherkasLFAvivASpectorTD2005Obesity, cigarette smoking, and telomere length in women. Lancet366662664. doi:10.1016/S0140-6736(05)66630-5.

  • Wager-SrdarSALevineASMorleyJEHoidalJRNiewoehnerDE1984Effects of cigarette smoke and nicotine on feeding and energy. Physiology and Behavior32389395. doi:10.1016/0031-9384(84)90252-X.

  • WangXYangZXueBShiH2011Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance. Endocrinology152836846. doi:10.1210/en.2010-0855.

  • WilliamsonDFMadansJAndaRFKleinmanJCGiovinoGAByersT1991Smoking cessation and severity of weight gain in a national cohort. New England Journal of Medicine324739745. doi:10.1056/NEJM199103143241106.

  • WilsonPW1997An epidemiologic perspective of systemic hypertension, ischemic heart disease, and heart failure. American Journal of Cardiology803J8J. doi:10.1016/S0002-9149(97)00831-X.

  • WindersSEGrunbergNE1990Effects of nicotine on body weight, food consumption and body composition in male rats. Life Sciences4615231530. doi:10.1016/0024-3205(90)90425-Q.

  • YuanHShyyJYMartins-GreenM2009Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1. Journal of Hepatology51535547. doi:10.1016/j.jhep.2009.03.026.

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    Changes in body weight from baseline in mice receiving either nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline fed with the HFD or NCD (A); in mice on the HFD receiving saline or either high (1.5 mg/kg per day, given twice daily, i.p.), low (0.5 mg/kg per day, given twice daily, i.p.), or escalating dose of nicotine (starting at 0.25 mg/kg per day given twice daily and going up to 4.5 mg/kg per day by an increment of 0.5 mg/kg per day every 3 days, i.p.) (B); and in mice with the NCD receiving either saline or high (1.5 mg/kg per day, given twice daily, i.p.), low (0.5 mg/kg per day, given twice daily, i.p.), or an escalating dose of nicotine (starting at 0.25 mg/kg per day given twice daily and increasing up to 4.5 mg/kg per day by an increment of 0.5 mg/kg per day every 3 days, i.p.) (C). Depicted figure (n=3–4/condition) represents mean (±s.e.m.) and is representative of experiment performed on three occasions. *P<0.00001 vs saline/NCD; #P<0.00001 vs saline/HFD.

  • View in gallery

    Changes in body weight from baseline in mice on the HFD (A) after receiving the NCD for 45 days and given either higher dose nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline; or (B) in mice on the NCD following nicotine cessation after receiving a higher dose nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline for 23 days. The data represent mean (±s.e.m.) of five mice per time point in each treatment group. *P<0.00001 vs saline; **P<0.00001 vs saline for days 1–23; ##P<0.00001 vs saline for days 24–38.

  • View in gallery

    Changes in body weight from baseline in mice on an HFD receiving either nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline with concurrent treatment with either mecamylamine (2 mg/kg per day, given twice daily, i.p.) or varenicline (2 mg/kg per day, given twice daily, i.p.). The data represent mean (±s.e.m.) of three to four mice per time point in each treatment group and is representative of data performed on two occasions. *P<0.00005 vs nicotine/saline; #P<0.000005 vs saline/saline.

  • View in gallery

    Cumulative caloric intake in mice fed with the NCD or HFD receiving either saline, high (1.5 mg/kg per day, given twice daily, i.p.), low (0.5 mg/kg per day, given twice daily, i.p.), or an escalating (ESC) dose of nicotine (starting at 0.25 mg/kg per day given twice daily and going up to 4.5 mg/kg per day by an increment of 0.5 mg/kg per day every 3 days, i.p.). The data represent mean (±s.e.m.) of three to four mice per time point and is representative of data performed on three separate occasions. *P<0.01 vs saline.

  • View in gallery

    DXA scan showing the total amount of fat (g) (A) and lean mass (muscle plus bone) (B) in mice receiving nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline fed with the NCD or HFD. *P<0.05 vs HFD-saline group, **P<0.01 vs HFD-saline group. The data represent mean (±s.e.m.) of four mice in each group.

  • View in gallery

    CT scans in mice receiving nicotine (1.5 mg/kg per day, given twice daily, i.p.) or saline and fed with the NCD or HFD showing total fat (A), visceral fat (B), and subcutaneous fat (C), and representative view of visceral and subcutaneous fat using coronal, sagittal, and transverse sections (D). The data represent mean (±s.e.m.) of four mice per group. *P<0.05 vs saline.

References

AlbanesDJonesDYMicozziMSMattsonME1987Associations between smoking and body weight in the US population: analysis of NHANES II. American Journal of Public Health77439444. doi:10.2105/AJPH.77.4.439.

ArmitageAKHallGHMorrisonCF1968Pharmacological basis for the tobacco smoking habit. Nature217331334. doi:10.1038/217331a0.

AzzaliniLFerrerERamalhoLNMorenoMDominguezMColmeneroJPeinadoVIBarberaJAArroyoVGinesP2010Cigarette smoking exacerbates nonalcoholic fatty liver disease in obese rats. Hepatology5115671576. doi:10.1002/hep.23516.

BellingerLLWellmanPJHarrisRBKelsoEWKramerPR2010The effects of chronic nicotine on meal patterns, food intake, metabolism and body weight of male rats. Pharmacology Biochemistry and Behavior959299. doi:10.1016/j.pbb.2009.12.012.

BizziATacconiMTMedeaAGarattiniS1972Some aspects of the effect of nicotine on plasma FFA and tissue triglycerides. Pharmacology7216224. doi:10.1159/000136292.

BowenDJEurySEGrunbergNE1986Nicotine's effects on female rats' body weight: caloric intake and physical activity. Pharmacology Biochemistry and Behavior2511311136. doi:10.1016/0091-3057(86)90099-7.

CavalloDASmithAESchepisTSDesaiRPotenzaMNKrishnan-SarinS2010Smoking expectancies, weight concerns, and dietary behaviors in adolescence. Pediatrics126e66e72. doi:10.1542/peds.2009-2381.

ChenHHansenMJJonesJEVlahosRAndersonGPMorrisMJ2007aDetrimental metabolic effects of combining long-term cigarette smoke exposure and high-fat diet in mice. American Journal of Physiology Endocrinology and Metabolism293E1564E1571. doi:10.1152/ajpendo.00442.2007.

ChenHHansenMJJonesJEVlahosRBozinovskiSAndersonGPMorrisMJ2007bRegulation of hypothalamic NPY by diet and smoking. Peptides28384389. doi:10.1016/j.peptides.2006.07.034.

ChenHHansenMJJonesJEVlahosRAndersonGPMorrisMJ2008Long-term cigarette smoke exposure increases uncoupling protein expression but reduces energy intake. Brain Research12288188. doi:10.1016/j.brainres.2008.06.067.

ChioleroAFaehDPaccaudFCornuzJ2008Consequences of smoking for body weight, body fat distribution, and insulin resistance. American Journal of Clinical Nutrition87801809.

ClarkePBKumarR1984Some effects of nicotine on food and water intake in undeprived rats. British Journal of Pharmacology82233239.

DaniJA2001Overview of nicotinic receptors and their roles in the central nervous system. Biological Psychiatry49166174. doi:10.1016/S0006-3223(00)01011-8.

EisenSALyonsMJGoldbergJTrueWR1993The impact of cigarette and alcohol consumption on weight and obesity. An analysis of 1911 monozygotic male twin pairs. Archives of Internal Medicine15324572463. doi:10.1001/archinte.1993.00410210081009.

FilozofCFernandez PinillaMCFernandez-CruzA2004Smoking cessation and weight gain. Obesity Reviews595103. doi:10.1111/j.1467-789X.2004.00131.x.

FioreMCFlemingMFBurnsME1999Tobacco and alcohol abuse: clinical opportunities for effective intervention. Proceedings of the Association of American Physicians111131140. doi:10.1046/j.1525-1381.1999.09249.x.

FlegalKMCarrollMDOgdenCLCurtinLR2010Prevalence and trends in obesity among US adults, 1999–2008. Journal of the American Medical Association303235241. doi:10.1001/jama.2009.2014.

FoxCSMassaroJMHoffmannUPouKMMaurovich-HorvatPLiuCYVasanRSMurabitoJMMeigsJBCupplesLA2007Abdominal visceral and subcutaneous adipose tissue compartments: association with metabolic risk factors in the Framingham Heart Study. Circulation1163948. doi:10.1161/CIRCULATIONAHA.106.675355.

FrankishHMDrydenSHopkinsDWangQWilliamsG1995Neuropeptide Y, the hypothalamus, and diabetes: insights into the central control of metabolism. Peptides16757771. doi:10.1016/0196-9781(94)00200-P.

FriedmanTCWangWGhodsDLutfyKLiuY2009The mechanisms of nicotine-induced glucose intolerance: role in the high prevalence of cardiovascular disease in smokers. Endocrine Society91P2476.

FujiokaSMatsuzawaYTokunagaKTaruiS1987Contribution of intra-abdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity. Metabolism365459. doi:10.1016/0026-0495(87)90063-1.

GonzalesDRennardSINidesMOnckenCAzoulaySBillingCBWatskyEJGongJWilliamsKEReevesKR2006Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. Journal of the American Medical Association2964755. doi:10.1001/jama.296.1.47.

GrunbergNE1982The effects of nicotine and cigarette smoking on food consumption and taste preferences. Addictive Behaviors7317331. doi:10.1016/0306-4603(82)90001-6.

GrunbergNE1985Nicotine, cigarette smoking, and body weight. British Journal of Addiction80369377. doi:10.1111/j.1360-0443.1985.tb03008.x.

GrunbergNE1986Nicotine as a psychoactive drug: appetite regulation. Psychopharmacology Bulletin22875881.

GrunbergNEMorseDE1984Cigarette smoking and food consumption in the United States. Journal of Applied Social Psychology14310317. doi:10.1111/j.1559-1816.1984.tb02239.x.

GrunbergNEBowenDJMorseDE1984Effects of nicotine on body weight and food consumption in rats. Psychopharmacology839398. doi:10.1007/BF00427430.

GrunbergNEBowenDJMaycockVANesporSM1985The importance of sweet taste and caloric content in the effects of nicotine on specific food consumption. Psychopharmacology87198203. doi:10.1007/BF00431807.

GrunbergNEBowenDJWindersSE1986Effects of nicotine on body weight and food consumption in female rats. Psychopharmacology90101105. doi:10.1007/BF00172879.

GrunbergNEWindersSEPoppKA1987Sex differences in nicotine's effects on consummatory behavior and body weight in rats. Psychopharmacology91221225. doi:10.1007/BF00217067.

HaslamDWJamesWP2005Obesity. Lancet36611971209. doi:10.1016/S0140-6736(05)67483-1.

HofstetterASchutzYJequierEWahrenJ1986Increased 24-hour energy expenditure in cigarette smokers. New England Journal of Medicine3147982. doi:10.1056/NEJM198601093140204.

HurYNHongGHChoiSHShinKHChunBG2010High fat diet altered the mechanism of energy homeostasis induced by nicotine and withdrawal in C57BL/6 mice. Molecules and Cells30219226. doi:10.1007/s10059-010-0110-3.

IlebekkAMillerNEMjosOD1975Effects of nicotine and inhalation of cigarette smoke on total body oxygen consumption in dogs. Scandinavian Journal of Clinical and Laboratory Investigation356772. doi:10.3109/00365517509068007.

JeeSHLeeSYNamCMKimSYKimMT2002Effect of smoking on the paradox of high waist-to-hip ratio and low body mass index. Obesity Research10891895. doi:10.1038/oby.2002.122.

KannelWB1981Update on the role of cigarette smoking in coronary artery disease. American Heart Journal101319328. doi:10.1016/0002-8703(81)90197-6.

KlesgesRCMeyersAWKlesgesLMLa VasqueME1989Smoking, body weight, and their effects on smoking behavior: a comprehensive review of the literature. Psychological Bulletin106204230. doi:10.1037/0033-2909.106.2.204.

LapidusLBengtssonCLarssonBPennertKRyboESjostromL1984Distribution of adipose tissue and risk of cardiovascular disease and death: a 12 year follow up of participants in the population study of women in Gothenburg, Sweden. British Medical Journal28912571261. doi:10.1136/bmj.289.6454.1257.

LarssonBSvardsuddKWelinLWilhelmsenLBjorntorpPTibblinG1984Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. British Medical Journal28814011404. doi:10.1136/bmj.288.6428.1401.

LiuRHMizutaMMatsukuraS2003Long-term oral nicotine administration reduces insulin resistance in obese rats. European Journal of Pharmacology458227234. doi:10.1016/S0014-2999(02)02726-7.

LiuRHMizutaMMatsukuraS2004The expression and functional role of nicotinic acetylcholine receptors in rat adipocytes. Journal of Pharmacology and Experimental Therapeutics3105258. doi:10.1124/jpet.103.065037.

MangubatMLyzlovANzenwaIShenRSinha HikimAPFriedmanTCSinha-HikimI2011Nicotine induces oxidative stress and exacerbates high fat diet (HFD)-induced hepatic steatosis in a mouse mode of diet-induced obesity. Endocrine Society93OR0401.

MaslinskiWLaskowska-BozekHRyzewskiJ1992Nicotinic receptors of rat lymphocytes during adjuvant polyarthritis. Journal of Neuroscience Research31336340. doi:10.1002/jnr.490310215.

MatsushitaYNakagawaTYamamotoSTakahashiYNodaMMizoueT2010Associations of smoking cessation with visceral fat area and prevalence of metabolic syndrome in men: the Hitachi Health Study. Obesity19647651. doi:10.1038/oby.2010.237.

McGinnisJMFoegeWH1999Mortality and morbidity attributable to use of addictive substances in the United States. Proceedings of the Association of American Physicians111109118. doi:10.1046/j.1525-1381.1999.09256.x.

MoffattRJOwensSG1991Cessation from cigarette smoking: changes in body weight, body composition, resting metabolism, and energy consumption. Metabolism40465470. doi:10.1016/0026-0495(91)90225-L.

MunsterGBattigK1975Nicotine-induced hypophagia and hypodipsia in deprived and in hypothalamically stimulated rats. Psychopharmacologia41211217. doi:10.1007/BF00428926.

MurrayCJLopezAD1997Alternative projections of mortality and disability by cause 1990–2020: Global Burden of Disease Study. Lancet34914981504. doi:10.1016/S0140-6736(96)07492-2.

NagyTRClairAL2000Precision and accuracy of dual-energy X-ray absorptiometry for determining in vivo body composition of mice. Obesity Research8392398. doi:10.1038/oby.2000.47.

NguyenVTNdoyeAGrandoSA2000Novel human alpha9 acetylcholine receptor regulating keratinocyte adhesion is targeted by Pemphigus vulgaris autoimmunity. American Journal of Pathology15713771391. doi:10.1016/S0002-9440(10)64651-2.

PomerleauCSKurthCL1996Willingness of female smokers to tolerate postcessation weight gain. Journal of Substance Abuse8371378. doi:10.1016/S0899-3289(96)90215-1.

RobbinsASMansonJELeeIMSatterfieldSHennekensCH1994Cigarette smoking and stroke in a cohort of U.S. male physicians. Annals of Internal Medicine120458462.

SalaFNistriACriadoM2008Nicotinic acetylcholine receptors of adrenal chromaffin cells. Acta Physiologica192203212. doi:10.1111/j.1748-1716.2007.01804.x.

SchechterMDCookPG1976Nicotine-induced weight loss in rats without an effect on appetite. European Journal of Pharmacology386369. doi:10.1016/0014-2999(76)90201-6.

ShimokataHMullerDCAndresR1989Studies in the distribution of body fat. III. Effects of cigarette smoking. Journal of the American Medical Association26111691173. doi:10.1001/jama.1989.03420080089037.

ShinCSMangubatMLyzlovASinha HikimAPSinha-HikimIFriedmanTC2011Nicotine plus a high-fat diet leads to intramyocellular fat deposition in a mouse model of diet-induced obesity. American Diabetes Association712633PO.

SiuECTyndaleRF2007Non-nicotinic therapies for smoking cessation. Annual Review of Pharmacology and Toxicology47541564. doi:10.1146/annurev.pharmtox.47.120505.105354.

SparrowDBorkanGAGerzofSGWisniewskiCSilbertCK1986Relationship of fat distribution to glucose tolerance. Results of computed tomography in male participants of the Normative Aging Study. Diabetes35411415. doi:10.2337/diabetes.35.4.411.

SuckowCEStoutDB2008MicroCT liver contrast agent enhancement over time, dose, and mouse strain. Molecular Imaging and Biology10114120. doi:10.1007/s11307-007-0128-x.

SuckowCKuntnerCChowPSilvermanRChatziioannouAStoutD2009Multimodality rodent imaging chambers for use under barrier conditions with gas anesthesia. Molecular Imaging and Biology11100106. doi:10.1007/s11307-008-0165-0.

SztalrydCHamiltonJHorwitzBAJohnsonPKraemerFB1996Alterations of lipolysis and lipoprotein lipase in chronically nicotine-treated rats. American Journal of Physiology270E215E223.

ValdesAMAndrewTGardnerJPKimuraMOelsnerECherkasLFAvivASpectorTD2005Obesity, cigarette smoking, and telomere length in women. Lancet366662664. doi:10.1016/S0140-6736(05)66630-5.

Wager-SrdarSALevineASMorleyJEHoidalJRNiewoehnerDE1984Effects of cigarette smoke and nicotine on feeding and energy. Physiology and Behavior32389395. doi:10.1016/0031-9384(84)90252-X.

WangXYangZXueBShiH2011Activation of the cholinergic antiinflammatory pathway ameliorates obesity-induced inflammation and insulin resistance. Endocrinology152836846. doi:10.1210/en.2010-0855.

WilliamsonDFMadansJAndaRFKleinmanJCGiovinoGAByersT1991Smoking cessation and severity of weight gain in a national cohort. New England Journal of Medicine324739745. doi:10.1056/NEJM199103143241106.

WilsonPW1997An epidemiologic perspective of systemic hypertension, ischemic heart disease, and heart failure. American Journal of Cardiology803J8J. doi:10.1016/S0002-9149(97)00831-X.

WindersSEGrunbergNE1990Effects of nicotine on body weight, food consumption and body composition in male rats. Life Sciences4615231530. doi:10.1016/0024-3205(90)90425-Q.

YuanHShyyJYMartins-GreenM2009Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1. Journal of Hepatology51535547. doi:10.1016/j.jhep.2009.03.026.

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