Target for Smoking Cessation and Weight Control Identified

Megan Brooks

June 10, 2011

June 10, 2011 — New research in mice has revealed a brain mechanism that could lead to novel treatments for smoking cessation and obesity.

In various experiments, scientists found that nicotine decreases food intake and body weight in mice by influencing the hypothalamic melanocortin system, an essential brain pathway involved in regulating energy balance and food intake.

"We found that nicotine reduced eating and body fat through receptors implicated in nicotine aversion and withdrawal rather than reward and reinforcement," senior author Marina Picciotto, PhD, from Yale University School of Medicine in New Haven, Connecticut, said in a statement.

The research is published in the June 10 issue of Science.

It is well-known that smoking suppresses appetite. Smokers are often thinner than nonsmokers and often gain weight when they quit smoking, which may keep some smokers from attempting to kick the habit.

Until now, little was known about the potential central nervous system pathways responsible for nicotine's effects on appetite and weight.

Alleviates Withdrawal

In mice, Dr. Picciotto and colleagues found that activation of hypothalamic α3 β4 nicotinic acetylcholine receptors (nACHRs) leads to activation of pro-opiomelanocortin (POMC) neurons. POMC neurons and subsequent activation of melanocortin 4 receptors proved critical for nicotinic-induced decreases in food intake in mice, they say.

Previous studies, the scientists note, have shown that activation of POMC neurons decreases food intake and increases energy expenditure, and loss of function of the POMC gene leads to obesity in humans and animals.

Dr. Picciotto's team observed that both nicotine and cytisine dose-dependently decreased food intake by up to 50% and lowered body fat mass over time by 10% to 20% in mice treated daily for 30 days. Nicotine binds to nAChRs, and the nicotinic drug cytisine selectively binds to the α3 β4 nAChR.

In contrast, treatment with the nonselective nicotinic antagonist mecamylamine had no significant effect on food intake and weight in the mice, "suggesting that nAChR antagonism alone was not sufficient for the anorexic effects of nicotinic compounds."

Dr. Picciotto and colleagues say selective α3 β4 nAChR agonists may prove "useful for limiting weight gain after smoking cessation."

"These results indicate that medications that specifically target this pathway could alleviate nicotine withdrawal as well as reduce the risk of overeating during smoking cessation," Nora D. Volkow, MD, Director of the National Institute on Drug Abuse, said in a statement.

"Although more research is warranted, such a highly selective compound might be more effective than drugs that act on more than one type of nicotinic receptor," Dr. Volkow said.

The research was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Science. 2011;332:1330-1332. Abstract


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