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GEN News Highlights : Jun 9, 2011
Researchers Identify Brain Mechanism Involved in Nicotine-Related Appetite Suppression
Studies found specific nicotinic acetylcholine receptors activated, which triggers POMC neurons and melanocortin pathway.!--h2>
Scientists have identified a biochemical pathway in the brain that mediates the nicotine-triggered mechanism by which cigarette smoking suppresses appetite. Encouragingly, the receptors involved appear to be different than those known to trigger tobacco craving in smokers.
Researchers at Yale University and Baylor College of Medicine report their findings in Science. The paper is titled “Nicotine Decreases Food Intake Through Activation of POMC Neurons.”
Smokers have a notably lower body mass index than non-smokers, and tend to gain weight when they quit, reports the research team, led by Marina R. Picciotto, M.D., at Yale University School of Medicine’s Department of Psychiatry, and Mariella De Biasi, M.D., at Baylor College of Medicine’s Center on Addiction, Learning and Memory.
The effects on body weight have been attributed to the nicotine in tobacco, because nicotine is known to decrease feeding in animal models. However, while nicotine is known to have some effects on peripheral energy metabolism, little is known about the central nervous system pathways mediating its effects on food intake and bodyweight.
To try and identify which brain receptors and downstream pathways are involved in nicotine-induced appetite suppression, the team used a combination of pharmacological, molecular genetic, electrophysiological, and feeding studies. They first carried out studies in mice to demonstrate that activation of central α3β4 nicotinic acetylcholine receptors (nAChRs) by nicotine was essential for the associated reduction in food intake.
This involved administering experimental animals with either nicotine or a more selective α3β4 nAChR agonist, cytisine. Treated animals demonstrated up to a 50% reduction in food intake and a 15–20% reduction in body fat mass. Conversely, knocking down expression of the bβ nAChR subunit by administering a neuron-specific shRNA into the hypothalamus abolished the anorexic effects of cytisine administration.
Previous studies have shown that activation of pro-opiomelanocortin cells (POMC) in the arcuate nucleus region of the brain decreases food intake and increases energy expenditure , while loss of POMC gene function leads to obesity in humans and animals. With these findings in mind, the researchers hypothesized that activation of α3β4 nAChRs by nicotine and cytisine may also trigger POMC neurons.
They initially confirmed that the bβ nAChR was indeed present in neurons dissected from transgenic mice expressing GFP under control of the POMC promoter. Further studies then showed that chronic nicotine and cytisine treatment increased markers of POMC activation in the ARC of mice treated with nicotinic drugs by about 50% without any detectable effects on other neuronal subtypes in the region.
The greatest increases in POMC activation occurred after an acute injection of the compounds. Direct electrophysiological tests showed that application of nicotinic drugs increased the spontaneous firing of POMC neurons by up to 350% compared with baseline. In contrast, administering the nicotinic antagonist mecamylamine had no effect on the firing of POMC neurons.
When the researchers treated POMC knockout mice with different doses of nicotine or cytisine and measured food intake over 24 hours, they found the POMC knockouts demonstrated no significant change in food intake in response to nicotine or cytisine, whereas cytisine-treated wild-type animals naturally reduced their food intake at each of the cystine concentrations tested.
The team moved on to determine whether the POMC-induced release of melanocortin is involved in nicotinic-induced hypophagia by using an shRNA to silence expression of the melanocortin 4 receptor in POMC-relevant regions of the brain. As expected, knockdown of the melanocortin 4 receptor significantly blunted the nicotine-induced reduction in food intake. A similar pattern was observed in response to acute cytisine.
The combined results support the notion that nAChR subunits represent critical receptors for mediating energy expenditure and feeding patterns, the authors conclude. “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. α3β4 agonists may therefore be useful for limiting weight gain after smoking cessation, and nicotinic drugs could also be useful to control obesity and related metabolic disorders.”
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