Sci picked this paper today partially because it was handed to her on a platter by the fantastic Dr. Pal, and partially because today she is SO HUNGRY. She's had a TON of food already today, and is still entirely ravenous. Maybe it was looking at this paper too long.
As I'm sure most of y'all out there are aware, obesity is a problem in the US. No one is sure whether it's due to increased portion size, increased availability, decreased physical activity, changes in gut bacteria, issues with our behavioral approaches to food, or all of the above. But scientists have been working for a while not only to look at the effects of overeating and obesity, but also to look at what CAUSES these things in the brain and body. And today we present a paper on an interesting piece of this puzzle, one that Sci has had a good deal of interest in: the idea of overeating as an addiction-like phenomenon.
Johnson and Kenney. "Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats." Nature Neuroscience, 2010.
A lot of us get a lot of good feelings out of eating. Eating creates feelings of pleasure and reward, which is obviously a pretty evolutionarily successful strategy. Not only that, foods that are of higher "value" to the body, like fats(butter), proteins (steak!), and foods high in calories (CHOCOLATE), taste better than those that don't mean much (like celery).
Obviously, if something is going to give you feelings of pleasure and reward in the brain, it will probably use the system of pleasure and reward that you have conveniently set up for the purpose. The neurotransmitter dopamine (about which Sci does love to blog), is associated with feelings of reward, and is one of the neurotransmitters that gets highjacked by certain addictive drugs like cocaine. And so scientists have hypothesized for some time that, just as the dopamine system is dysregulated in drug addiction, perhaps it is also dysregulated in problems with other natural rewards, like food intake problems.
This isn't a far fetched thought. The symptoms of severe binge eating disorders are similar to some of the symptoms of drug addiction. People who are severe binge eaters* will continue to overeat even though they KNOW it's bad for them and even though society is not kind to those who are overweight. This is similar to drug addicts, who continue to take drug even though they get in trouble and even though they KNOW it's a terrible thing to do. In addition, severe binge eaters will often try very hard to reduce their food intake, trying lots of diets, and consistently fail, which is very similar to many drug addicts, who try desperately to stop taking the drug, quitting or attempting to quit many times, and continuing to relapse.
With all these similarities, it might be a good idea to look at how chronic binge eating disrupts the dopamine system, a system closely associated with the rewarding feelings caused by drugs and food, and see whether chronic binge eating can cause changes that are like the changes caused by chronic exposure to drugs.
And for this, you need the fat rat.
So they took some rats, and divided them into three groups. The first group (we will call them 'chow') got access only to normal boring old rat chow. The second group got limited access for 1 hour per day to a high fat diet, which is super tasty to rats (we'll call them the 'snackers'). The third group got their high fat diet cafeteria style, most of the day, every day (we will call them 'fat' because that's what they got). They then asked a whole bunch of questions using these three groups of rats.
Question 1: Do "fat" rats have reward responses that are different from other rats?
Well first, let's take a look at 'em.
Above you can see the three groups of rats. You can see that the chow rats and the snacking rats (labeled "restricted" for restricted access) gained a lot less weight over time than the rats who got all the high fat food they could eat. By then end, the "fat" group weighed twice as much as the chow group!!! They also took in a much larger number of calories than the chow and snack groups, and most of their calories were in the form of that tasty, high fat food.
The authors then decided to look at how these rats responded to reward. For this they used something called "brain stimulation reward" or BSR. Scientists have known for a long time that if you put an electrode in an area of the brain called the lateral hypothalamus and run an electric current through it, you get an intense rewarding effect in rats. It's so intense that rats will willingly press a lever for it, and will even ignore food, sex, and other nice things to press the lever.
But in this case, they found that the "fat" rats pressed MORE for BSR than the control rats did. The "fat' rats had a changed response to reward. This change continued even AFTER the rats were taken off their high fat food.
Question 2: Ok, fat rats have changed reward responses, how does this connect with dopamine?
To answer this question, the scientists looked at the dopamine D2 receptor. This is one of the two types of dopamine receptors in the brain. More importantly, several people (including the current director of NIDA, Nora Volkow) have shown that people (and animals) who are addicted to cocaine have low numbers of D2 receptors, and that people and animals WITH low D2 receptors "like" drugs more and are more likely to abuse them. So, if binge eating were like drug abuse, we might expect D2 receptors to go in the same direction.
And sure enough, this is what they saw:
Sci loves this figure in particular because you can see a lovely correlation. Ah, a picture indeed worth a thousand words. Or at least a healthy paragraph. As you can see, as weight goes up (the light, grey, and black dots), the levels of D2 receptor expression (in the gel at the bottom of the picture) go DOWN. So the far rats had changes in reward, and had LOWER D2 receptor levels!
And you might think that's enough, and that is indeed a pretty little paper. But then these guys got GOOD.
Question 3: We know that the fat rats had lower D2 and changed reward responses. If WE lower the D2, will their reward changes and food intake go along with it?
Now, you might ask, HOW do you change the receptors in a rats head?! Well, we scientists are just that cool. There is a technique called viral-mediated gene expression. Basically (very very basically), you take a harmless virus (this one was a lentivirus), which is not much more than a protein packet with some DNA inside, that is capable of getting into animal cells. You take the DNA in the virus, and you split it up, and insert your gene of choice. In this case, they took a gene that would knock DOWN, or reduce, the amount of D2 receptors. Then you slip that DNA back in your virus (usually with an extra gene to make it glow all nice), and then inject that virus into the brain area you want. And you get this:
That pretty green glow is where they injected the virus, and where the virus infected the cells. In this case, you're looking at the rat striatum, which is an area in the dopamine system where reduced D2 receptors are linked with increased propensity for drug abuse. In this case, the virus they injected made the cells glow green, and ALSO knocked down the D2 receptors in that area (and ONLY that area, which is part of what makes it awesome). So now, these rats (new rats, not the fat and chow rats), had artificially low levels of D2 receptors in the striatum.
Then the authors did the same thing that they did with the first group, they had them do BSR. And the rats that had knocked down D2 receptors showed dysregulated BSR, just like the fat rats from before! Interestingly, these rats didn't eat more, but they also had not previously been exposed to the high fat diet, and it's possible that they just couldn't handle as much food at a time.
Question 4: Do these fat rats continue to overeat even in the presence of punishment?
This is an important question to ask to make this work really relevant to the way that humans binge eat. To do this, you give a rat access to the high fat food, but you add in a painful foot shock (not one that causes damage, just short and painful). You pair the foot shock with a light. The rat will learn that the light means shock and will (presumably) stop eating. Sure enough, when the light came on, the chow rats and snack rats stopped eating. The fat rats, however, DIDN'T. Their food intake wasn't sensitive to punishment anymore, something which may indicate that they will continue to overeat even though it's bad for them. This ALSO worked when they tried it with the rats that had artificially knocked down D2 receptors, they also just kept on eating, showing that the decreased D2 receptors may have something to do with the way the rats were responding for food.
However, they couldn't get the fat rats to binge eat, when they gave them a short term access. So the model isn't perfect.
So what does all this mean?
All these data put together means that binge eating of highly tasty foods in rats causes changes in D2 receptors and reward systems which are similar to the changes seen following drugs of abuse. This could mean that binge eating in this model is similar to drug abuse in other models, and that changes in D2 receptors could be part of the similarities.
Sci likes this study for several reasons. First, it's really complete. They started with getting the rats fat, looking at differences, and then seeing if they could induce the differences, and come up with a similar behavior. It's a good study that way. It's also good because they were able to play with receptor levels without using rats that were already a binge eating model, and without working with receptor knockout animals, which could have lots of other differences. This helps make the study design very clean.
And this study could be important. It makes a link between overeating and changes in D2 receptors (something that has been seen in humans), and suggests that this link is similar to changes seen with drug addiction, showing that chronic overeating and drug addiction could have some similar mechanisms. This could be very important in how scientists move forward in trying to treat chronic overeating in humans, and in how we approach the problem, as one of addiction rather than an unwillingness to get to the gym.
But it also highlights how difficult treating chronic overeating can be. Even if overeating IS just like drug abuse (and it's probably different in several ways), it's not something that is easily cured (and we haven't cured drug addiction yet, which tells you how far we have to go!). After all, in the end, the goal for drug addicts is to QUIT, to cease drug taking entirely, or as much as possible. But you can't ever QUIT eating. Instead, it's something that needs to be moderated and controlled, which makes it almost harder to treat. But understanding some of the mechanisms behind it is one of the first steps to solving the problem.
Johnson, P., & Kenny, P. (2010). Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats Nature Neuroscience DOI: 10.1038/nn.2519
(*Keep in mind, when I'm talking about binge eating disorders, I am not talking about Sci's extra bowl of Special K or your pint of ice cream that I know you picked up at the grocery store today and ate in front of the TV. No, Sci is talking about severe binge eating, people who simply cannot stop themselves, and who end up extremely overweight as a result, with corresponding quality of life issues, who are very often extremely unhappy. So don't go taking the results of this study as proof that you're a food addict. Some of you may be, but most of you probably aren't.)