Many people smoke to keep their weight down. The identification of the molecular target in the brain for the appetite-suppressant effects of nicotine is a first step towards finding healthy alternatives to smoking for weight management.
Anyone who has tried to stop smoking knows that quitting is frequently followed by a rapid weight gain1 of some 4 or 5 kilograms, and as much as 13 kilograms. It isn't surprising, therefore, that despite a general decrease in the rates of smoking within the past decade2, it remains prevalent in professions such as acting and modelling, in which being thin is often a job requirement. Indeed, the prospect of a gain in weight is a major deterrent to many smokers who want to quit but who see it either as a threat to their appearance or, wrongly3, as a greater threat to their health than smoking. Writing in Science, Mineur et al.4 shed light on the molecular targets of nicotine in the brain that are responsible for the compound's ability to suppress appetite. Their data may lead to alternative — healthy — ways of maintaining reduced body weight.
Over the past 15 years, our understanding of the brain circuitry that serves to control appetite and regulate body weight has grown rapidly. One of the most notable advances has been the discovery that the melanocortin (MC) system in the brain seems to be a crucial regulator of body weight5. In peripheral tissues of the body, this system regulates such features as the colour of hair and skin. However, genetic analyses in humans and animals, as well as pharmacological data, have established that activation of the MC4 receptor in the brain reduces food intake and promotes weight loss5. Manipulations that reduce the activity of this receptor are associated with increased food intake and weight gain5.
MC4-receptor activity is regulated by a complex interplay between two populations of neurons; these cells are found intermingled in a small brain region called the arcuate nucleus within the hypothalamus. One neuron population (POMC) synthesizes the precursor to several molecules that activate MC4 receptors. The other population (AgRP) synthesizes an endogenous antagonist to these receptors (Fig. 1). When individuals lose weight by restricting their calorie intake, decreased activity of the POMC neurons and increased activity of the AgRP neurons result in reduced activity of MC4 receptors, which predisposes the individuals to regain the lost weight5.
Mineur et al.4 explored the hypothesis that nicotine directly activates POMC neurons. They found that, indeed, receptors known as α3β4 nicotinic acetylcholine receptors, located on these neurons, mediate nicotine's potent appetite-suppressant effects. Specifically, nicotine-induced activation of these receptors enhances the firing of POMC neurons. The authors also show that in mice lacking these neurons, nicotine no longer suppresses appetite.
Mineur and colleagues' data are supported by another study6 which also shows that not only does nicotine lead to increased activity of POMC neurons, but it also enhances their synaptic communication with other neurons. Together, these results strongly support the idea that nicotine exerts its potent effects via the brain MC system, and that the weight gain associated with cessation of smoking is due to reduced activity of MC4 receptors.
These findings4 have two major implications. First, they further confirm the central role of the brain MC system in weight regulation through MC4 receptors. In fact, these data put nicotine in good company with several other successful ways of manipulating letters of the alphabet appetite that seem to exert their effects via the MC system. The effects on food intake of many things — from bariatric surgery to a high-fat diet to endogenous peripheral hormones such as leptin, ghrelin and PYY — are thought to be mediated by changes in this brain system.
In addition, the results indicate a potentially new way of activating the MC system to achieve weight loss. Obesity remains the largest unmet medical challenge in developed countries, and yet no new drug has been approved in the United States to treat this disorder since 1999. Obviously, smoking is far from an ideal way to avoid obesity, but targeting specific receptors on POMC neurons that mediate the appetite-suppressing effect of nicotine may be a pharmacological approach to providing obese individuals with safe and sustained weight loss. This is particularly important because, although drugs that target MC4 receptors directly are effective weight-loss agents, they are plagued by side effects, including increased heart rate and blood pressure7. Stimulating the release of endogenous activators of MC4 would provide an attractive alternative by targeting more discrete populations of these receptors.
Chiolero, A., Faeh, D., Paccaud, F. & Cornuz, J. Am. J. Clin. Nutr. 87, 801–809 (2008).
Williamson, D. F. et al. N. Engl. J. Med. 324, 739–745 (1991).
Mineur, Y. S. et al. Science 332, 1330–1332 (2011).
Schwartz, M. W. et al. Nature 404, 661–671 (2000).
Huang, H., Xu, Y. & van den Pol, A. J. Neurophysiol. doi:10.1152/jn.00740.2010 (2011).
Greenfield, J. R. et al. N. Engl. J. Med. 360, 44–52 (2009).
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