Obesity and Eating Disorder Research


Obesity is a major public health problem affecting and increasingly large numbers of people worldwide. Though it reflects an imbalance between energy intake and expenditure, the core pathophysiological mechanisms responsible for maintaining this balance are not well understood. It is of particular relevance that the maintenance of normal weight requires the coordination of peripheral signals of hunger and satiety and brain responses to either procure and consume food or to stop eating after a meal.

Involvement of dopamine pathways in eating behavior:
Food ingestion is not only to meet nutritional needs (energy homeostasis), it can be modulated by pleasure and responses to stress. Eating is a highly reinforcing behavior. In fact, some ingredients in palatable food (i.e. sugar) are compulsively consumed, and this loss of control over food intake is similar to what is observed with compulsive consumption of substances of abuse. Ingestion of sugar induces brain release of opioids and dopamine, which are neurotransmitters traditionally associated with the rewarding effects of drugs of abuse. In certain conditions, animal can display behavioral and neurochemical changes that resemble those observed in animal models of drug dependence.

Brain imaging of eating behaviour:
Our studies using PET implicate the involvement of brain dopamine in food intake in humans. The presentation of food that could not be consumed in normal-body-weight fasting subjects was associated with increases in striatal extracellular dopamine, a neurotransmitter known to play a role in motivation as well as in experiencing reward and pleasure. Since the research subjects experienced no reward or pleasure from eating the food, this finding provides evidence for the involvement of dopamine in the non-hedonic motivational properties of food.

Additional PET findings may help to explain certain similarities between overeating in obese individuals and the loss of control and compulsive drug-taking behaviour observed in drug-addicted subjects. For example, in pathologically obese subjects, we found reductions in striatal dopamine D2 receptors similar to that observed in drug-addicted subjects. We postulated that decreased levels of dopamine 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 dopamine -regulated reward circuits.

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 behaviour, is in part regulated by dopaminergic activity. In drug-addicted subjects, lower striatal dopamine D2 receptor levels were associated with lower metabolism in the orbitofrontal cortex. Lower activity in this region could indicate a reduced ability to plan or control behaviour, which has been implicated in the compulsive behavioural characteristics of drug-addictive states. Additionally, in non-obese fasting subjects, food presentation increased metabolism in orbitofrontal cortex, which was significantly associated with the perception of hunger and the desire for food. However, food presentation produced lesser activation in caudate and orbitofrontal cortex in obese subjects and the activation for food presentation in caudate was negatively associated with BMI.

Sensory experience of eating behaviour:
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 dopamine D2 receptors coupled with the enhanced sensitivity to food palatability makes food their most salient reinforcer, putting them at risk for food over-consumption.

Brain imaging of inhibition control:
Impaired inhibitory control may contribute to behavioral disorders such as pathological overeating. We evaluated the responses of the brain when subjects were exposed to appealing food either with or without a prior directive to suppress the desire for food (cognitive inhibition). Our imaging study with cognitive inhibition as compared with no inhibition male subjects (but not females) showed significant decreases in anterior cingulate gyrus, orbitofrontal cortex, amygdala and striatum. These regions, which decreased metabolism, had been shown by prior studies to be activated by food stimuli when presented via pictures, smells, taste, recall or a combination of these. The suppressed activation of the orbitofrontal cortex with inhibition in non-obese subject was also associated with decreases in self-reports of hunger (not in obese subjects), which corroborates the involvement of this region in processing the conscious awareness of the drive to eat. This finding suggests a mechanism by which cognitive inhibition decreases the desire for food, which is consistent with greater vulnerability of obese subjects to uncontrolled eating when food is readily available.

Imaging of brain and gut connection:
We measured regional brain activation during dynamic gastric balloon distention in health subjects using functional magnetic resonance imaging and the blood oxygenation level dependent (BOLD) responses. We found widespread activation induced by gastric distention corroborates the influence of vagal afferents on cortical and subcortical brain activity. The response in the left amygdala and insula were negatively associated with changes in self-reports of fullness whereas those in the right amygdala and insula were negatively associated with the subjectís body mass index. These findings provide evidence that the left amygdala and insula process interoceptive signals of fullness produced by gastric distention involved in the controls of food intake. 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 orbitofrontal cortex, 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.

Summary:
Brain imaging studies have the potential to facilitate understanding the mechanisms underlying obesity as well as development of novel pharmacological approaches. A key limitation to progress in this area is that a core pathophysiological abnormality that underlies overeating behaviors has yet to be identified. However, overeating behaviors and obesity are likely heterogeneous disorders. Our imaging studies provide evidence that multiple brain circuits (reward, motivation, learning, inhibitory control) are disrupted in overeating behaviour and obesity. Therefore, future brain imaging studies might be applied to investigate the interaction between peripheral signals and hedonic pathways as well as to assess the efficacy of drug treatments, surgical therapy and life style changes (i.e. diet control and aerobic exercise). Because of the complexity and multi-factorial nature of obesity and eating disorders, future progress will be facilitated by a transdisciplinary approach which integrates modern imaging tools with new knowledge on behavior and genetics to guide the development of effective preventive and therapeutic approaches.

 

PUBLICATIONS:

  • Volkow N.D., Wang G.J., Tomasi D., and Baler R.D.
    Obesity and addiction: neurobiological overlaps.
    Obes. Rev., doi: 10.1111/j.1467-789X.2012.01031.x. [Epub ahead of print] (2012 Sep 27).  PubMed
  • Volkow N.D., Wang G.J., Telang F., Fowler J.S., Goldstein R.Z., Alia-Klein N., Logan J., Wong C., Thanos P.K., Ma Y., and Pradhan K.
    Inverse Association Between BMI and Prefrontal Metabolic Activity in Healthy Adults.
    Obesity (Silver Spring), 17(1):60-65 (2009).  PubMed  PDF File
  • Wang G.J., Volkow N.D., Thanos P.K., and Fowler J.S.
    Imaging of Brain Dopamine Pathways - Implications for Understanding Obesity.
    J. Addict. Med., 3(1):8-18 (2009). PDF File
  • Wang G.J., Volkow N.D., Telang F., Jayne M., Ma Y., Pradhan K., Zhu W., Wong C.T., Thanos P.K., Geliebter A., Biegon A., and Fowler J.S.
    Evidence of gender differences in the ability to inhibit brain activation elicited by food stimulation.
    Proc Natl Acad Sci U S A., 106(4):1249-1254 (2009).  PubMed  PDF File
  • Thanos P.K., Michaelides M., Gispert J.D., Pascau J., Soto-Montenegro M.L., Desco M., Wang R., Wang G.J., and Volkow N.D.
    Differences in response to food stimuli in a rat model of obesity: in-vivo assessment of brain glucose metabolism.
    Int. J. Obes. (Lond), 32(7):1171-1179 (2008).  PubMed
  • Thanos P.K., Michaelides M., Ho C.W., Wang G.-J., Newman A.H., Heidbreder C.A., Ashby C.R., Jr., Gardner E.L., and Volkow N.D.
    The Effects of Two Highly Selective Dopamine D3 Receptor Antagonists (SB-277011A and NGB-2904) on food self-administration in a rodent model of obesity.
    Pharmacology Biochemistry Behavior, 89(4):499-507 (2008).  PubMed
  • Thanos P.K., Michaelides M., Piyis Y.K., Wang G.J. and Volkow N.D.
    Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in-vivo μPET imaging ([11C] raclopride) and in-vitro ([3H] spiperone) autoradiography.
    Synapse, 62(1):50-61 (2008).  Pubmed
  • Thanos P.K., Ramalhete R.C., Michaelides M., Piyis Y.K., Wang G.J., and Volkow N.D.
    Leptin receptor deficiency is associated with upregulation of cannabinoid 1 receptors in limbic brain regions.
    Synapse, 62(9):637-642 (2008).  PubMed
  • Volkow N.D., Wang G.J., Fowler J.S., and Telang F.
    Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology.
    Philos Trans R Soc Lond B Biol Sci., 363(1507):3191-3200 (2008).  PubMed  PDF File
  • Volkow N.D., Wang G.J., Telang F., Fowler J.S., Thanos P.K., Logan J., Alexoff D., Ding Y.S., Wong C., Ma Y., and Pradhan K.
    Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors.
    Neuroimage, 42(4):1537-1543 (2008).  PubMed   PDF File
  • Wang G.J., Tomasi D., Backus W., Wang R., Telang F., Geliebter A., Korner J., Bauman A., Fowler J.S., Thanos P.K., and Volkow N.D.
    Gastric distention activates satiety circuitry in the human brain.
    Neuroimage, 39(4):1824-1831 (2008).  PubMed   PDF File
  • Wang G.-J., Yang J., Volkow N.D., Telang F., Ma Y., Zhu W., Wong C., Tomasi D., Thanos P.K., and Fowler J.S.
    Gastric stimulation in obese subjects activates the hippocampus and other regions involved in brain reward circuitry.
    PNAS, 103(42):15641-15645 (2006).  PubMed  PDF file
  • Wang G.J., Volkow N.D., Thanos P.K., and Fowler J.S.
    Similarity between obesity and drug addiction as assessed by neurofunctional imaging: a concept review.
    J. Addict. Dis., 23(3): 39-53 (2004).  Pubmed
  • Wang G.J., Volkow N.D., Telang F., Jayne M., Ma J., Rao M., Zhu W., Wong C.T., Pappas N.R., Geliebter A., and Fowler J.S.
    Exposure to appetitive food stimuli markedly activates the human brain.
    NeuroImage, 21(4):1790-1797 (2004).  Pubmed
  • Volkow N.D., Wang G.J., Maynard L., Jayne M., Fowler J.S., Zhu W., Logan J., Gatley S.J., Ding Y.S., Wong C., and Pappas N.
    Brain dopamine is associated with eating behaviors in humans.
    Int. J. Obes. (Lond), 33(2):136-142 (2003).  Pubmed
  • Wang G.J., Volkow N.D., Fowler J.S., Felder C., Levy A.V., Pappas N.R., Wong C.T., Zhu W., and Netusil N.
    Enhanced metabolism in oral regions of somatosensory cortex in obese individuals.
    NeuroReport, 13(9):1151-1155 (2002). Pubmed
  • Volkow N.D., Wang G.J., Fowler J.S., Logan J., Jayne M., Franceschi D., Wong C., Gatley S.J., Gifford A.N., Ding Y.S., and Pappas N.
    Nonhedonic food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect.
    Synapse, 44(3):175-180 (2002).  Pubmed
  • Wang G.J., Volkow N.D., Logan J., Pappas N.R., Wong C.T., Zhu W., Netusil N., and Fowler J.S.
    Brain dopamine and obesity.
    Lancet, 357(9253):354-357 (2001).  Pubmed

 

 

Last Modified: November 1, 2012
Please forward all questions about this site to: Kathy Folkers