Monday, November 17, 2008

Dopamine and obesity

Dopamine is a neurotransmitter that's well-known for its involvement in several notable medical and behavioral problems, such as Parkinson's disease and drug addiction. But it is connected with many other issues of medical and psychological importance.

Perhaps the main reason that dopamine is so interesting is that it plays a big role in the brain's pleasure and reward systems. And therefore it is inevitably involved in reward-motivated behaviors of all kinds, from gambling, investing, substance abuse, and sex, to – eating. After all, isn't a high percentage of behavior motivated by rewards? There are other motivations for particular behaviors – fear and physiological needs, for example – but reward covers an awful lot of it.

Consequently, problems in the reward system can lead to excesses in some behaviors (e. g., gambling, eating), and perhaps also deficiencies in other behaviors (e. g. loss of interest in normal pleasures, as might accompany depression).

And because of the importance of dopamine in the reward system, problems with dopamine signaling can lead to problems in the reward system, with predictable consequences.

In the research we're going to look at, dopamine signaling is impaired in the presence of a particular allele associated with the D2 receptor for dopamine (known as DRD2). The conclusion is reached via the observation of decreased activity, as mesured by fMRI, in a brain region called the dorsal striatum. It is known that the variant allele causes a lower density of D2 receptors in this region.

The bottom line of the research is that individuals with this variant allele tend to have impaired ability to enjoy rewards from foods that most people like, such as chocolate. As a result, such individuals are disposed to consume more food in order to achieve an acceptable level of satiation of reward.

It might be thought, instead, that since the desirable foods produce less reward in individuals with the variant allele, they might consume less, due to reduced interest. However, that's not how the reward system seems to work. It seems to require achievement of a certain signal level in order to reach satiation and thus decrease the motivated behavior.

This is similar to the way signaling works with another hormone connected with eating, namely leptin. Normally, leptin levels rise when food is consumed. There are receptors for leptin in the ventromedial nucleus of the hypothalamus, a region that is responsible for appetite. There leptin inhibits the activity of neurons that contain neuropeptide Y (NPY).

A connection has been found between obesity and insensitivity to leptin, much as diabetes results from decreased sensitivity to the hormone insulin. Preseumably, individuals with reduced sensitivity to leptin don't know when to stop eating. Much the same state of affairs seems to exist in individuals with the allele (which is a DNA restriction enzyme called TaqIA) that affects DRD2 receptor density in the dorsal striatum.

Obesity, Abnormal 'Reward Circuitry' In Brain Linked: Gene Tied To Dopamine Signaling Also Implicated In Overeating (10/16/08)
Using brain imaging and chocolate milkshakes, scientists have found that women with weakened "reward circuitry" in their brains are at increased risk of weight gain over time and potential obesity. The risk increases even more for women who also have a gene associated with compromised dopamine signaling in the brain.

The results, drawn from two studies using functional magnetic resonance imaging (fMRI) at the University of Oregon's Lewis Center for Neuroimaging, appear in the Oct. 17 issue of the journal Science. The first-of-its-kind approach unveiled blunted activation in the brain's dorsal stratium when subjects were given milkshakes, which may reflect less-than-normal dopamine output.

Here's the research paper, with abstract:

Relation Between Obesity and Blunted Striatal Response to Food Is Moderated by TaqIA A1 Allele
The dorsal striatum plays a role in consummatory food reward, and striatal dopamine receptors are reduced in obese individuals, relative to lean individuals, which suggests that the striatum and dopaminergic signaling in the striatum may contribute to the development of obesity. Thus, we tested whether striatal activation in response to food intake is related to current and future increases in body mass and whether these relations are moderated by the presence of the A1 allele of the TaqIA restriction fragment length polymorphism, which is associated with dopamine D2 receptor (DRD2) gene binding in the striatum and compromised striatal dopamine signaling. Cross-sectional and prospective data from two functional magnetic resonance imaging studies support these hypotheses, which implies that individuals may overeat to compensate for a hypofunctioning dorsal striatum, particularly those with genetic polymorphisms thought to attenuate dopamine signaling in this region.

The idea that problems with dopamine signaling might be related to overeating and obesity isn't new. The following research announced in July involved rats rather than humans and considered other dopamine insufficiency mechanisms, but the basic conclusions are the same:

Obesity Predisposition Traced To The Brain's Reward System (7/29/08)
The tendency toward obesity is directly related to the brain system that is involved in food reward and addictive behaviors, according to a new study. Researchers at Tufts University School of Medicine (TUSM) and colleagues have demonstrated a link between a predisposition to obesity and defective dopamine signaling in the mesolimbic system in rats.

The mesolimbic system is a system of neurons in the brain that secretes dopamine, a neurotransmitter or chemical messenger, which mediates emotion and pleasure. The release of the neurotransmitter dopamine in the mesolimbic system is traditionally associated with euphoria and considered to be the major neurochemical signature of drug addiction. ...

Pothos says, "These findings have important implications in our understanding of the obesity epidemic. The notion that decreased dopamine signaling leads to increased feeding is compatible with the finding from human studies that obese individuals have reduced central dopamine receptors." He speculates that an attenuated dopamine signal may interfere with satiation, leading to overeating.

Paper abstract:

Evidence for defective mesolimbic dopamine exocytosis in obesity-prone rats
In electrophysiology studies, electrically evoked dopamine release in slice preparations was significantly attenuated in OP [obesity-prone] rats, not only in the nucleus accumbens but also in additional terminal sites of dopamine neurons such as the accumbens shell, dorsal striatum, and medial prefrontal cortex, suggesting that there may be a widespread dysfunction in mechanisms regulating dopamine release in this obesity model. Moreover, dopamine impairment in OP rats was apparent at birth and associated with changes in expression of several factors regulating dopamine synthesis and release: vesicular monoamine transporter-2, tyrosine hydroxylase, dopamine transporter, and dopamine receptor-2 short-form. Taken together, these results suggest that an attenuated central dopamine system would reduce the hedonic response associated with feeding and induce compensatory hyperphagia, leading to obesity.

News reports of the human dopamine results:
E. Stice, S. Spoor, C. Bohon, D. M. Small (2008). Relation Between Obesity and Blunted Striatal Response to Food Is Moderated by TaqIA A1 Allele Science, 322 (5900), 449-452 DOI: 10.1126/science.1161550

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Anonymous dual diagnosis said...

This is a very informative article. Dopamine has something to do with the state of euphoria when a person uses prohibited drugs. Maybe the best thing to do is to avoid drugs so that a person won't get addicted to it.

2/10/2009 11:36:00 AM  
Blogger Charles Daney said...

Dopamine has something to do with the state of euphoria when a person uses prohibited drugs. Maybe the best thing to do is to avoid drugs so that a person won't get addicted to it.

Addictive drugs are just a special case. As this article discusses, even real food can be "addictive".

Part of the function of dopamine is to motivate an organism to seek things that the organism actually needs, like food or sex. This works well enough, unless dopamine signaling is inhibited, due to problems with dopamine receptors, for instance.

Dopamine signaling is involved in how the brain responds to almost anything that can give pleasure. Sugar is another example - see this post.

Drugs are a special problem when there are unusual situations where the brain requires increasing amounts of the substance to be "satisfied". Fortunately, this doesn't happen with most ordinary food.

2/11/2009 07:43:00 PM  

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