Smoking has been associated with weight loss for centuries. In the modern world, advertisements and other aspects of popular culture often link slimness with cigarettes. Scientific research generally supports this link as well; researchers have found that smokers have a lower body mass index than nonsmokers, and they have discovered that nicotine decreases the amount of food animals will eat.
While nicotine is considered to be an appetite suppressant, little is known about its actual mechanism of action in the brain. Lead author Yann Mineur from the Yale University School of Medicine and his colleagues have shed some light on this problem. They have found a pathway that governs how nicotine decreases food intake. Their discovery, which appears in a recent issue of Science, could potentially help people stop smoking and lead to new ways of treating obesity.
Mineur found that nicotine and a drug called cytisine both decrease the food intake of mice by up to 50 percent and lower the body fat mass by roughly 15 to 20 percent. Nicotine binds to the nicotinic acetylcholine receptors in the central and peripheral nervous systems, and cytisine binds to those nicotinic receptors even more selectively. When a chemical is added that blocks the binding of cytisine to the nicotinic receptors, the mice exhibited less anorexic behavior. This led Mineur and his colleagues to conclude that activation of the nicotinic acetylcholine receptors are essential for decreasing appetite.
Upon further experimentation, Mineur and his team found that a particular subunit (the β4 subunit) in nicotinic acetylcholine receptors is directly involved in producing anorexic effects. When the researchers knocked down the expression of this subunit, a nicotinic drug like cytosine had no anorexic effect on mice. This subunit is expressed in a bundle of neurons (the arcuate nucleus) in the mediobasal hypothalamus, suggesting that nicotine acts specifically on these cells.
The knockdown results led the researchers to explore the functions of different neurons in the mediobasal hypothalamus. The β4 subunit in its nicotinic acetylcholine receptors is expressed by one type of neuron, the pro-opiomelanocortin (POMC) cells. The researchers found that nicotinic drugs bind to nicotinic acetylcholine receptors on POMC neurons and cause these neurons to fire.
When the researchers applied nicotine to POMC neurons for one to two minutes, the POMC neurons fired more frequently. The effect depends on how much nicotine is present. A small dose of 0.5 µM causes an increase of about 173 percent, while a larger dose of 50 µM increases firing by about 456 percent. Activating POMC neurons is known to cause loss of appetite and increase in energy expenditure. Specifically, Mineur and his team found that a type of hormone produced by POMC neurons called melanocortin is critical for nicotine to have an anorexic effect.
To sum up the process, Mineur discovered that nicotine and other nicotinic drugs have an anorexic effect by first interacting with the β4 subunit of nicotinic acetylcholine receptors that are expressed by POMC neurons. This activates the POMC neurons, causing the release of the hormone melanocortin. The authors note that the β4 subunit may not be the only one involved. Further research could reveal that other subunits of the nicotinic acetylcholine receptors play important roles as well.
By providing a mechanism that governs how nicotine suppresses appetite, Mineur and his colleagues have opened up the possibility of tailoring different therapies to help people lose weight without the negative effects of using tobacco products. For example, it might be possible to synthesize drugs that are less toxic or addictive than nicotine, but have a similar mechanism of action in the brain. Such drugs could help people battle obesity.
Science, 2011. DOI: 10.1126/science.1201889 (About DOIs)