Why ex-smokers commonly complain about gaining weight when they quit, and why active smokers are usually thinner on average, has been cracked by scientists in the US.
Nicotine has always been regarded as the prime suspect, because experimental animals lose weight when given the drug, but no one has ever worked out why.
Now, writing in Science, Yale scientist Yann Mineur and his colleagues have tracked the smoking gun to a region of the brain's hypothalamus concerned with appetite.
In this area, the team have found, are nerve cells activated by nicotine that make a chemical called proopiomelanocortin (POMC). When this substance is released from these cells into an adjacent, appetite-related region of the brain known as the paraventricular nucleus, it has an anorexic effect.
The team made the discovery in experimental mice by using drugs to selectively activate or block certain subclasses of the chemical docking stations, called acetyl choline receptors, that nicotine binds to in the brain.
One drug tested, cytisine, closely mimicked nicotine's appetite-blocking action. It binds selectively to acetyl choline alpha3-beta4 receptors, so the team used a modified virus to deactivate just these receptors in the hypothalami of one group of mice.
These treated animals ceased to lose weight when the nicotine-mimicking drug was subsequently given. Using a separate batch of animals, the team then made electrical recordings from nerve cells when nicotine was added, which revealed that the drug was triggering bursts of activity in nerve cells that produce POMC, suggesting that this might be the anti-appetite signal.
Consistent with this theory, mice from which POMC has been "knocked out" genetically do not show any nicotine-induced changes in appetite. And when the team used a modified virus in another group of mice to deactivate a gene called melanocortin 4R (Mc4R), which encodes the receptor for POMC, the food intake amongst these animals was also unaffected by nicotine.
Together these findings show that nicotine triggers a specific subset of POMC-producing nerve cells in the brain's hypothalamus. Acting via the melanocortin (Mc4R) receptor in the adjacent paraventricular nucleus, this damps down sensations of hunger and contributes to reduced calorie intake.
According to Mineur and his colleagues, the molecular clockwork of this pathway could be useful in producing new drugs designed to prevent weight-gain following smoking cessation, and also to tackle obesity and its related metabolic disorders.