Anatabine, Nornicotine, and Anabasine Reduce Weight Gain and Body Fat through Decreases in Food Intake and Increases in Physical Activity

Abstract

Obesity is a leading cause of preventable death in the United States. Currently approved pharmacotherapies for the treatment of obesity are associated with rebound weight gain, negative side effects, and the potential for abuse. There is a need for new treatments with fewer side effects. Minor tobacco alkaloids (MTAs) are potential candidates for novel obesity pharmacotherapies. These alkaloids are structurally related to nicotine, which can help reduce body weight, but without the same addictive potential. The purpose of the current study was to examine the effects of three MTAs (nornicotine, anatabine, and anabasine) and nicotine on weight gain, body composition, chow intake, and physical activity. We hypothesized that the MTAs and nicotine would reduce weight gain through reductions in chow intake and increases in physical activity. To test this, male Sprague Dawley rats were housed in metabolic phenotyping chambers. Following acclimation to these chambers and to (subcutaneous (sc)) injections of saline, animals received daily injections (sc) of nornicotine, anabasine, anatabine, or nicotine for one week. Compared to saline-injected animals that gained body weight and body fat during the treatment phase, injections of nornicotine and anatabine prevented additional weight gain, alongside reductions in body fat. Rats receiving anabasine and nicotine gained body weight at a slower rate relative to rats receiving saline injections, and body fat remained unchanged. All compounds reduced the intake of chow pellets. Nornicotine and nicotine produced consistent increases in physical activity 6 h post-injection, whereas anabasine's and anatabine's effects on physical activity were more transient. These results show that short-term, daily administration of nornicotine, anabasine, and anatabine has positive effects on weight loss, through reductions in body fat and food intake and increases in physical activity. Together, these findings suggest that MTAs are worthy of further investigations as anti-obesity pharmacotherapies.

Keywords: body weight; minor tobacco alkaloids; nicotine; obesity.

Figure 1

Mean (±S.E.M.) change in body weight over six days, following injections of either saline (orange; n = 8), nicotine (blue; n = 10), nornicotine (green; n = 10), anabasine (red; n = 10), or anatabine (purple; n = 10). Weight change is expressed relative to the mean body weight during the final day of the baseline phase (day 0) as absolute cumulative weight gain in grams (panel A) and as a percent change in body weight (panel B). * p < 0.05, ** p < 0.01 difference from baseline (day 0) body weight at the indicated day. # p < 0.05, ## p < 0.01 difference from weight gain in the saline group at the indicated day. Significance marks are color-coded to reflect which drug group experienced significant changes.

Figure 2

Mean (±S.E.M.) change in body composition before and after drug treatment, on the final day of saline injections (day 0; pre-drug) and the final day of the treatment phase (day 7; post-drug) in animals that received daily injections of either saline (n = 8), nicotine (n = 10), nornicotine (n = 10), anabasine (n = 10), or anatabine (n = 10) for 6 consecutive days. Body composition change is expressed as the contributions of fat mass (g; panel A) and lean mass (g; panel B) to overall body weight, as measured by EchoMRI. * p < 0.05, ** p < 0.01 difference from pre-drug to post-drug. # p < 0.05 difference from the saline group at the indicated timepoint.

Figure 3

Mean (±S.E.M.) of changes in food (chow) intake over six days, following injections of either saline (orange; n = 8), nicotine (blue; n = 10), nornicotine (green; n = 10), anabasine (red; n = 10), or anatabine (purple; n = 10). Changes in food intake are expressed relative to the mean food intake during the final day of the baseline phase (day 0), as absolute cumulative change (panel A) and as a percent change (panel B) in food intake. * p < 0.05, ** p < 0.01 difference from baseline food intake (day 0) at the indicated day. # p < 0.05, ## p < 0.01 difference from food intake in the saline group at the indicated day. Significance marks are color-coded to reflect which drug group experienced significant changes.

Figure 4

Mean (±S.E.M.) of changes in physical activity over six days, measured as the mean distance traveled in meters, following injections of saline (orange; n = 8), nicotine (blue; n = 10), nornicotine (green; n = 10), anabasine (red; n = 10), or anatabine (purple; n = 10). Changes in physical activity are expressed relative to the mean activity during the final day of the baseline phase (day 0), as absolute cumulative change (panel A) and as a percent change (panel B) in activity. * p < 0.05 difference from the saline group on the indicated day; # p < 0.05 difference from baseline physical activity (day 0) at the indicated day. Significance marks are color- coded to reflect which drug group experienced significant changes.

Figure 5

Mean (±S.E.M.) of changes in physical activity during the dark (panel A) and light (panel B) cycles, as well as the full 24 h period (panel C), for the final day of baseline (day 0), and days 1 of 6 of treatment injections of saline (n = 8), nicotine (n = 10), nornicotine (n = 10), anabasine (n = 10), or anatabine (n = 10). * p < 0.05, ** p < 0.01 difference from baseline activity (day 0) at the indicated day.

Figure 6

Mean (±S.E.M.) of cumulative changes in physical activity, measured as the mean distance traveled in meters during the 6 h following injections of saline (panel A; n = 8), nicotine (panel B; n = 10), nornicotine (panel C; n = 10), anabasine (panel D; n = 10), or anatabine (panel E; n = 10) for the final day of baseline (day 0), and days 1 and 6 of treatment injections. * p < 0.05, ** p < 0.01 difference from baseline activity (day 0) at the indicated hour.

Figure 7

Mean (±S.E.M.) of absolute changes in physical activity, measured as the mean distance traveled in meters during the 6 h following injections of saline (panel A; n = 8), nicotine (panel B; n = 10), nornicotine (panel C; n = 10), anabasine (panel D; n = 10), or anatabine (panel E; n = 10) for the final day of baseline (day 0), and days 1 and 6 of treatment injections. * p < 0.05, ** p < 0.01 difference from baseline activity (day 0) at the indicated hour.