Alcoholism
and Obesity: Overlapping Brain Pathways?
“That’s easy,” you may say. If you said “Obesity,” you would be correct. However, if you said “Alcoholism,” you would also be correct. Both obesity and alcoholism are prevalent and preventable causes of death that result from excessive consumption of caloric substances. Like obesity, alcoholism was once ascribed to a weak will but is now understood to be environmentally and biologically determined. Todd Thiele, who is an Assistant Professor in the University of North Carolina’s Department of Psychology and the Bowles Center for Alcohol Studies, heads research efforts devoted to exploring the physiologic basis of the striking parallels between obesity and alcoholism. Thiele hypothesizes that some of the brain signaling proteins that mediate excessive eating and weight gain also mediate uncontrolled alcohol drinking. By understanding the physiologic commonalities between excessive alcohol drinking and excessive eating, Thiele hopes to shed light on intervention strategies, such as pharmaceutical compounds, that can help those who suffer from obesity and/or alcoholism. “We are particularly interested in identifying physiologic substrates that underlie food intake and body weight as well as alcohol intake,” says Thiele. “The idea is that alcohol is a caloric compound, and alcohol intake and food intake are both reinforcing consummatory behaviors. It is therefore possible that overlapping pathways are involved in uncontrolled eating and excessive ethanol drinking.”
Thiele and his laboratory have recently explored the role of a group of signaling proteins, the melanocortins, in alcohol consumption. Melanocortin agonists are known to inhibit food intake and cause significant reduction of body weight in animal models. Are the melanocortins also involved in alcohol consumption? Thiele approached this question by infusing the drug MTII, which mimics the effects of melanocortins at specific cellular receptors (the melanocortin-3 and melanocortin-4 receptors), into the brains of mice that habitually drink large amounts of alcohol. MTII reduced both voluntary alcohol drinking and food intake in these animals. Pretreatment of mice with a drug that blocks melanocortin-3 and -4 receptors prevented the MTII-associated reduction of alcohol drinking. These findings support a key role of melanocortins in alcohol intake and suggest that the effects of melanocortins on alcohol intake are mediated by the actions of melanocortins at the melanocortin-3 and -4 receptors. These results are also consistent with Thiele’s hypothesis of a shared physiologic substrate of alcohol intake and food intake. Next, Thiele and his colleagues will extend this series of experiments by examining alcohol and food intake in mice bred to lack the melanocortin-3 receptor. Much of Thiele’s recent work focuses on a signaling protein known as neuropeptide Y. Previous research suggests that neuropeptide Y, which is found throughout the brain, is a key mediator of functions ranging from food intake to emotional responses. For example, in animal models, infusion of neuropeptide Y into the brain dramatically increases food intake. Other experiments show that infusions of neuropeptide Y can alleviate anxiety in animal models. Thiele has found that neuropeptide Y also appears to be an important regulator of alcohol intake. Neuropeptide Y becomes physiologically active by attaching to one of several receptor subtypes found on brain cell surfaces. Thiele found that mice lacking one of these receptor subtypes—the Y1 receptor—drank significantly more alcohol than normal mice (Figure 1). Given the diverse role of NPY, it will be important to determine how Y1 receptors modulate alcohol consumption, which may include NPY pathways involved with feeding, integration of emotional behavior, and/or other neurobiological functions. Thiele and his laboratory, including graduate students Jon Fee and Dennis Sparta and laboratory technician Alex Mason, have recently extended this investigation of neuropeptide Y to assess its involvement in the alcohol withdrawal syndrome, which occurs when alcohol is withheld from an animal or human addicted to it. The alcohol withdrawal syndrome, which can be life-threatening, is manifested by neurologic symptoms such as difficulty concentrating, anxiety, and hallucinations and by motor symptoms ranging from muscle tremors to convulsions. For the alcoholic, prevention or alleviation of these symptoms constitutes a powerful motivator to continue drinking. Thiele, knowing that neuropeptide Y is involved in alcohol drinking as well as emotional responses such as anxiety, wondered whether neuropeptide Y might mediate the anxiety that occurs during the alcohol withdrawal syndrome. Working with Bowles Center collaborators Drs. George Breese, Darin Knapp, and David Overstreet, Thiele found that mice deficient in neuropeptide Y (because they lack a gene necessary to produce the neuropeptide) show heightened withdrawal-associated anxiety as measured by established laboratory tests of emotionality. These data suggest that neuropeptide Y may modulate alcohol withdrawal-associated anxiety. When signaling proteins such as neuropeptide Y and the melanocortins attach to receptors on brain cells, they initiate a cascade of events that alter cellular function and, ultimately, determine how these cells will affect behavior. One of the key steps in this cascade of events is alteration of the activity of an intracellular enzyme called protein kinase A. Alterations in protein kinase A activity depend on the activity of proteins such as neuropeptide Y and the melanocortins, which Thiele showed are important in alcohol consumption. Therefore, it is possible that the protein kinase A signaling pathway constitutes a shared substrate by which any of several proteins affect consumption of alcohol. In support of this possibility, Thiele found that mutant mice bred to lack a structural component of protein kinase A (i.e., the regulatory IIß subunit) drank significantly more alcohol than normal mice (Figure 2). The increased consumption in the mutant mice was specific to alcohol as these mice showed normal consumption of sweet solutions containing sucrose or bitter solutions containing quinine. Those mutant mice were also less sensitive to the sedative effects of alcohol than normal mice and had high levels of baseline anxiety. Thiele suggests that the heightened anxiety in these mice may contribute to their excessive alcohol consumption, which alleviates anxiety.
Thiele speaks enthusiastically about the implications of this research: “Every day, we are learning more about how eating and drinking are inextricably linked at the physiologic level. These physiologic commonalities help to explain why the behaviors of excessive food intake and excessive alcohol consumption share so many similarities. Together, our data suggest that compounds directed at neuropeptide Y and/or melanocortin receptors, both of which modulate the activity of protein kinase A, may be promising candidates for treating alcohol abuse and alcoholism as well as obesity. Several compounds affecting these signaling proteins are already in development for obesity. Our research suggests that they should also be explored for alcoholism.”
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Bowles
Center for Alcohol StudiesUniversity of North Carolina at Chapel Hill CB#7178, Thurston Bowles Building Chapel Hill, NC 27599-7178 Tel: (919) 966-5678 • Fax: (919) 966-5679 |
Updated
03/24/2003
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