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“Because of the increasing rates of obesity, unhealthy eating habits, and physical inactivity, we may see the first generation that will have a shorter life expectancy than their parents.”

U.S. Surgeon General,
Richard Carmona,
March 2004

Presenters


Gene-Jack Wang, MD

2009 Summit video presentation

Chairman of the Brookhaven National Laboratory Medical
Department

BIOGRAPHY:
Dr. Gene-Jack Wang is a board certified Nuclear Medicine physician and began working at the Brookhaven National Laboratory (BNL) Medical Department in 1990. In addition to performing his own research, he is the Chairman of the BNL Medical Department and continues to hold a joint appointment as a Professor of Psychiatry at Mount Sinai School of Medicine. He also practices Nuclear Radiology at the Glen Cove Hospital. His research has focused on the application of Positron Emission Tomography (PET) and functional Magnetic Resonance Imaging (fMRI) techniques to the study of various brain disorders. He is interested in using PET to study the neuro-psychiatric mechanisms and manifestations of alcoholism, drug addiction, attention deficit/hyperactivity disorder (ADHD), obesity and eating disorder in humans and in animal models. He used PET to study the effects of drug expectation on the ability of psychostimulants to increase extracellular dopamine and the relationship to the reinforcing and addictive properties of stimulant drugs in cocaine addicted subjects. In methamphetamine abusers, he uses PET to assess the effect of long-term detoxification to the recovery of brain dopamine system. He is currently comparing the changes in brain dopamine activity in response to food stimulation for two subtypes of obese subjects, those with and those without binge eating disorders. He predicts that the two subtypes will differ in their brain dopamine activity. His other interests include the study of brain and gut interaction as well as the effect of diet control drug to brain satiety circuit using fMRI. He has published over 200 peer-reviewed papers on his imaging research. The National Institute of Health (NIMH, NIDA and NIAAA), the Department of Energy (DOE/OBER) and pharmaceutical companies fund his ongoing research.

PERSONAL STATEMENT:

My primary interest is using medical imaging techniques to study brain disorders. In the 1990s, our laboratory used positron emission tomography (PET), an imaging device that can detect brain chemistry and function to study the neuro-psychiatric mechanisms and manifestations of alcoholism and drug addiction. We found significant brain deficits in drug-addicted subjects. At the same time the prevalence of obesity in the US was rising in an alarming rate. Since overeating behavior in morbidly obese subjects is very similar to loss of control and compulsive drug using behavior observed in drug-addicted subjects, we used PET to investigate if obese subjects had similar brain deficits. We measured brain dopamine (DA) D2 receptor levels, a receptor for neurotransmitter dopamine known to play a role in motivation as well as in experiencing reward and pleasure, in subjects with BMI more than 40. We found the morbidly obese subjects had reductions in striatal DA D2 receptors, which were similar to that observed in drug-addicted subjects. We postulated that decreased levels of DA receptors predisposed subjects to search for strongly rewarding reinforcers; that is, drug-addicted subjects seek the drug whereas obese subjects seek food as a means to temporarily compensate for decreased sensitivity of their DA-regulated reward circuits. Subsequently we did several imaging studies in humans and animals to understand the involvement of brain DA pathway in overeating and obesity.

To assess if low DA D2 receptors in obesity reflected the consequences of food over-consumption as opposed to a vulnerability that preceded obesity we assessed the effect of food intake on DA D2 receptor in a genetically leptin deficient rodent model of obesity using autoradiography. Results showed that the obese rats had lower D2 receptor levels than the lean rats and that food restriction increased D2 receptors both in the lean and the obese rats indicating that low D2 reflects in part the consequences of food over-consumption. In one study of normal-body-weight fasting human subjects, the presentation of food that could not be consumed was associated with increases in striatal extracellular DA. Since the research subjects experienced no reward or pleasure from eating the food, this finding provides evidence for the involvement of DA in the non-hedonic motivational properties of food.

Our imaging studies have also shown that metabolic activity in the orbitofrontal cortex (OFC), a part of the brain that is key to controlling and planning behavior, is in part regulated by DA activity. In drug-addicted subjects, lower striatal DA D2 receptor levels were associated with lower metabolism in the OFC. Lower activity in this region could indicate a reduced ability to plan or control behavior, which has been implicated in the compulsive behavioral characteristics of drug-addictive states. Additionally, in normal-body-weight fasting subjects, food presentation increased metabolism in OFC, which was significantly associated with the perception of hunger and the desire for food. Such changes in perception and desire could explain the deleterious effects of constant exposure to food stimuli (e.g., advertisements and food displays) in overeating.

In another study in obese subjects implanted with a gastric stimulator, which induces stomach expansion via electrical stimulation of the vagus nerve, we found the gastric stimulation increased metabolism in OFC, striatum, and hippocampus. The activation in the hippocampus during gastric stimulation is associated with a sensation of fullness. These regions are involved with self-control, motivation, and memory, respectively, and were previously shown to be involved in drug craving in addicted subjects. This finding suggests that similar brain circuits underlie the enhanced motivational drive for food (and for drugs) seen in obese (and drug-addicted) subjects.

Different from drug-addicted subjects, obese subjects have increased metabolism in the somatosensory cortex when compared with control subjects, making them more sensitive to the sensory properties of food. In the case of obesity the reduction in DA D2 receptors coupled with the enhanced sensitivity to food palatability makes food their most salient reinforcer, putting them at risk for food over-consumption.

The studies from our laboratory provide evidence that multiple but similar brain circuits (reward, motivation, learning, inhibitory control) are disrupted in drug addiction and obesity. The results implicate the need for a multimodal approach in the treatment of obesity.

PUBLICATIONS:

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