Yale scientists have thrown new light on an ugly truth about smoking: though cigarettes can kill you, most smokers are thinner than their non-smoking peers. Many people take up smoking, or resist quitting, because nicotine lowers body weight.

“We have known for a very long time that some smokers use cigarettes to try to control their weight,” says Marina Picciotto, Ph.D., Charles B.G. Murphy Professor of Psychiatry and professor of neurobiology and pharmacology. “And we have now identified one of the molecular mechanisms underlying this effect.”

A major subset of the brain’s nerve cells are studded with “nicotinic” receptors, which activate the cells when coupled with nicotine molecules. Tobacco addiction is thought to result from the interaction of these neurons with other neural circuits that govern the brain’s reward systems. But the physiological link between nicotine and weight loss has been poorly understood.

During research on the potential antidepressant effects of several nicotine-like drugs, some of which is reported in the current issue of Behavioural Pharmacology, Associate Research Scientist Yann S. Mineur, Ph.D., M.Sc., noticed that, like smokers, mice treated with the drugs ate less than the control mice and gained less weight. The robustness of these effects hinted at a possible mechanism, and Mineur obtained a pilot grant from Yale’s Transdisciplinary Tobacco Use Research Center to undertake further studies.

For this research, Picciotto and Mineur teamed up with Xiao-Bing Gao, Ph.D., associate professor of comparative medicine, and Tamas Horvath, D.V.M., Ph.D., the Jean and David W. Wallace Professor of Biomedical Research and chair of the Section of Comparative Medicine (see related story).

In the June 10 issue of Science, the group describes experiments demonstrating that a specific type of nicotinic receptor found on cells known as POMC neurons is the crucial trigger for nicotine’s effects on eating and weight gain in the mice. When the scientists disabled this particular receptor, the mice ate as much as normal mice, even when given a nicotine-like drug.

POMC neurons are located in the hypothalamus, a brain region known to regulate feeding and metabolism, where they generate hunger and fullness cues that direct us when to seek food and when to put the fork down. “The interesting aspect of our finding,” says Picciotto, “is that the receptors that are expressed in the POMC neurons are not the same ones that are responsible for nicotine reward.”

Smokers are about 10 pounds lighter than non-smoking peers on average, but they gain weight once they’ve kicked the tobacco habit, which discourages many smokers from quitting. By understanding how to control nicotine receptors in the hypothalamus, Picciotto says, researchers may be able to develop a drug that would prevent weight gain for smokers trying to quit, and would perhaps be useful for the treatment of obesity in non-smokers as well. “It is possible,” says Picciotto, “that a nicotinic medication could be one more tool to help motivate and assist those struggling with obesity to lose weight.”