Just one more slice

Picture the scene: you’ve just finished a massive Sunday lunch and you feel like you can barely move. In fact, you’ve just slackened your belt a notch because your trousers feel uncomfortably tight. You honestly couldn’t manage another thing. But then someone says, “who would like a slice of this lovely chocolate cake?” And, miraculously, your stomach forgets how full it is and finds a convenient cake-sized corner to enable you to accommodate a generous portion, despite the fact that you definitely don’t need to eat it and just now you felt fit to burst… Speaking with Chris Smith, Saleem Nicola explains how he's uncovered the brain circuitry responsible for what we think is an evolutionary mechanism that once prevented us from starving but is rapidly becoming our downfall…

Saleem - There has been an epidemic of obesity recently, where many people in the modern world gaining much more weight than they did even 50 or 100 years ago. And of course, one reason for this is because many of us don't exercise enough. But it's also the case that we eat too much and typically we tend to eat calorie dense high fat, high sugar foods and we were interested in understanding what the mechanisms of that might be. So that's kind of the broad outline of what motivated this study.

Chris - I guess where you're coming from is you've got people who are already well-fed - clearly, in fact, overfed - yet we overeat despite being well nourished. And the question is why we would want to do that?

Saleem - That's exactly right. And so the way that we normally study animal models of eating has a couple of problems that we tried to solve. One of those problems is that what most people do, most scientists, neuroscientists do when they're trying to figure out the neural mechanisms of caloric intake is they just give the animal food and they say "well how much are you going to eat?" And they do some manipulation and maybe they change it and they say "a-ha, I figured out how this aspect of regulation of calorie intake works." And the problem is that, you know, you might tell your children it's time to eat, and they say I'm not very hungry, but you say but no you don't understand, I've got a chocolate chip cookie. And then they'll say "oh great yes, now I'm hungry," right? So the stimulus makes all the difference in the world because the stimulus predicts the positive outcome. And so we respond to those stimuli and that facilitates and increases the amount that we eat. That hasn't been studied as carefully partly because when people study those mechanisms they tend to study them in animals that are food restricted. But that's a totally different situation than most of us where we really do have enough to eat.

Chris - So how did you do the experiment, the rat equivalent of saying "I've got a cookie for you?"

Saleem - Right, of course we can't tell rats what to do but we can train them. And so we have animals, rats, in what we call an operant chamber, where we can present them with sounds, and lights, and things like that. And also a little well where we can deliver liquid reward, we used a cream reward which is high in fat. And so we had an auditory stimulus that just came on occasionally and told the animal that if it goes well there will be cream available for him. You know, within a week or two you can train animals that respond reliably to these stimuli and they'll do it even when they're not restricted. Even if you give them as much of an ordinary sort of yucky but very nutritious rat chow to eat as they want.

Chris - So you get animals here, which you're allowing them to eat as much they would want to normally, but then you can present the stimulus and they'll still go and overeat because there's a reward on tap which they love?

Saleem - That's correct. Rats, as people do love to drink cream and so they respond to the stimulus even though they're not restricted on food. So we actually had two groups of animals, we had one group of animals that was restricted and one that wasn't. And the study was to ask whether in fact the mechanisms that control responding to the stimulus that predicts cream, are different in the restricted versus non restricted group.

Chris - So how did you study the brain angle of this? What's going on in their nervous system to make them have the "I want to eat the cream, even when I'm full" behaviour?

Saleem - We focused on a part of the brain called the nucleus accumbens, because it's been shown before that a particular neurotransmitter system in the nucleus accumbens can promote animals eating particularly of calorie dense rewards, and particularly of high fat food. This system is an opioid system. there's a kind of opioid receptor called the mu opioid receptors, of which there are a lot in the nucleus accumbens. A neurotransmitter that activates these receptor peptides called opioid peptides, and there are a lot of those in the accumbens as well. And so we reason that maybe this opioid system is involved in responding to that kind of stimulus. And one of the first things we did is we blocked those opioid receptors and asked whether manipulation had different effects in the restricted versus the non restricted animals. And lo and behold we found that there was actually no effect on the restricted animals but it severely impaired responding to the cream predicted cue, in the animals that had as much chow to eat as they like.

Chris - Can I speculate then by saying that are the animals that have eaten normally, once you're sated that, sort of, sets up their system and primes it to be responsive through these mu opioid receptors to the stimulus saying well now you can find room for a bit more a few more highly palatable calories and is that why the animals are susceptible in that context?

Saleem - Right, so we don't know exactly how it works. And one idea is that maybe the opioid peptides that bind to those receptors and activate them, maybe those are released only in situations where: A) the animal or maybe even the person is relatively sated and B) when there are high calorie rewards available. But exactly how that works is really a mystery and that's partly because it's hard to study when these peptides are released because it's released in such tiny quantities that they're very very hard to measure. But what we did do, is we can figure out how these peptides work because we can block that with an antagonist, we can ask what that actually does to the neurons in the nucleus accumbens

Chris - And what are you going to do now to follow this up? What's the outstanding question and the implications of this?

Saleem - There are a couple of questions. We kind of had an idea what happens, when opioid receptors, when they're bound, and then it does this to the firing of these accumbens neurons but what controls the release of those opioid peptides that bind to the receptors. And the other question is we don't know exactly how this works, so we know that this is reduction in the firing of these accumbens neurons. We don't know why and there are a number of different possibilities that we can investigate. We know that the neurotransmitter dopamine is very important. The levels are much lower in animals that are not hungry and it could be that what's happening is that opioid peptide, by activating this receptor is somehow increasing the dopamine levels so that there is sufficient to actually drive this firing.