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Friday, June 10, 2011

Why Smokers Are Skinny

From Science Magazine

Craving an afternoon snack? Take a drag on a cigarette, and your hunger will likely disappear. Smoking is the number one cause of preventable deaths in the Unites States and other developed countries, causing lung cancer, heart disease, and chronic bronchitis. But smokers are, on average, skinnier than nonsmokers. New research reveals how nicotine, the active ingredient in cigarettes, works in the brain to suppress smokers' appetites. The finding also pinpoints a new drug target for nicotine withdrawal—and weight loss.

The nicotine receptor in the brain has 15 subunits; they can combine in a multitude of ways to form different receptors with different jobs. Nicotine can bind to each combination and spur a cascade of distinct events; some lead to the addictive properties of cigarettes, others to an increase in blood pressure or a feeling of relaxation. It's long been known that nicotine causes a slump in appetite, and scientists suspected that this worked through receptors associated with reward and behavior reinforcement. After all, the brain considers both cigarettes and food to be rewards. But the new finding suggests that appetite has its own pathway.

Behavioral neuroscientist Marina Picciotto of Yale University set out to study whether activating one particular nicotine receptor, dubbed α3β4, had antidepressant effects on mice. But as postdoctoral researcher Yann Mineur was caring for the mice, which had received drugs engineered to stimulate only α3β4 receptors, he noticed a side effect: the mice were eating less.

"Before this study, we really didn't think that this type of receptor would have such a big role in the brain in food intake," Picciotto says. She and Mineur went on to show that nicotine does, in fact, bind to α3β4 receptors, which then send a signal throughout the rest of the brain, signaling satiety. It's indistinguishable from the signal the brain propagates after eating a large meal. Mice that received the drug binding to the α3β4 receptor ate half the amount of food as untreated mice in the 2 hours following administration of the drug. Their body fat dropped 15% to 20% over 30 days, the team reports online today in Science.

Since the weight gain that comes with stopping smoking is often one deterrent for smokers to quit, Picciotto suggests that the new pathway could be targeted by pharmaceuticals to suppress appetite during the initial stages of smoking cessation. In addition, such a drug could have wider reach as an appetite suppressant to aid in weight loss, without the health hazards tied to cigarette smoke.

Neil Grunberg, a behavioral neuroscientist at the Uniformed Services University of the Health Sciences in Bethesda, Maryland, was the first to prove, through rat studies in 1982, that nicotine causes a decrease in appetite. He says the new study is a step forward in understanding the phenomenon he first observed.

"Most people had accepted that the decrease in appetite was caused through a dopamine-reward pathway and left it at that," Grunberg says. "So I think the most important contribution of this paper is to prove that there is another whole pathway that nicotine is working through."

Grunberg notes, however, that the study looks only at male mice. In his previous work, he has found differences in the effects of nicotine on weight between males and females. Females, he says, experience larger weight loss when they start smoking and a larger weight gain if they quit. Whether this means nicotine is working through an additional, hormone-regulated pathway in the female brain is yet to be determined.

Picciotto says her group is repeating the experiments on female mice. "We're also still trying to get back to that original question we had," she says: "Does this also have antidepressant actions?"

Mineur YS, Abizaid A, Rao Y, Salas R, DiLeone RJ, Guendisch D, Diano S, De Bias M, Horvath TL, Gao X-B, Picciotto MP (2011) Nicotine Decreases Food Intake Through Activation of POMC Neurons. Science 332 (6035): 1330-1332 DOI: 10.1126/science.1201889

Smoking decreases appetite, and smokers often report that they smoke to control their weight. Understanding the neurobiological mechanisms underlying the anorexic effects of smoking would facilitate the development of novel treatments to help with smoking cessation and to prevent or treat obesity. By using a combination of pharmacological, molecular genetic, electrophysiological, and feeding studies, we found that activation of hypothalamic α3β4 nicotinic acetylcholine receptors leads to activation of pro-opiomelanocortin (POMC) neurons. POMC neurons and subsequent activation of melanocortin 4 receptors were critical for nicotinic-induced decreases in food intake in mice. This study demonstrates that nicotine decreases food intake and body weight by influencing the hypothalamic melanocortin system and identifies critical molecular and synaptic mechanisms involved in nicotine-induced decreases in appetite.

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