Dieting doesn’t work. No really, it doesn’t. Much as people like to talk about how the things they are sticking to are “lifestyle changes”, etc, a lot of them (but not all) are still diets, still ways of restricting your eating, and over 80{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} of them will fail. By fail, scientists mean that you will gain back all the weight you lost, and then some, within five years. This is not only bad because of the weight people end up gaining, but some people believe that the “yo-yo” dieting style itself can contribute to the beginning of metabolic disorders later in life.
So why DO the diets fail? Why can’t people stick to them and why can’t they keep the weight off even after they’ve lost it? While some people may just claim weak willpower, neuroscientists know that it goes a lot deeper than that. And it turns out that going on a diet may change the way that your brain reacts to stress, changing both how you express stress and whether you start eating for comfort because of it.
Pankevitch et al. “Caloric restriction experience reprograms stress and orexigenic pathways and promotes binge eating” J. Neuroscience, 2010.
It’s time to put some mice on a diet.
(Source)
In order to mimic dieting in humans, the authors of this study took a bunch of mice and restricted the amount that they could eat, to make them lose 10{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} of their body weight. That’s the equivalent of a 150 lb person losing 15 lbs, and is about what people on average lose when they go on a diet. They had another group of mice that ate whatever they liked. At the end of three weeks, the diet mice had lost 10{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} of their body weight (about 2.5 g for a mouse), while the non-dieting mice had gained weight (as mice do). They then took these two groups and looked at their stress levels.
The first thing they looked at was a response to stress.
The top figure here is a measure of corticosterone, a hormone strongly associated with stress. They took the mice here and restrained them in little tubes (not too tight, you usually just prevent them from escaping or turning around, and often people wrap them in saran wrap like little mouse burritos) for over an hour, measuring their blood levels of corticosterone. Mice don’t like being restrained, it’s stressful, and both groups had corticosterone go up. But the dieting group had a much higher response to stress than the non-dieting group.
The bottom figure shows something called the tail suspension test, which is a test usually used to detect the actions of clinically effective antidepressants. You can see that the dieting mice (shown on the right) had a higher immobility level in this test, which is sometimes associated with pro-depressive behavior. This suggests that, not only are dieting mice high stress, they may also show more depressive symptoms (in major air quotes) than non-dieting mice. But I’m not sure about that interpretation and I’ll get back to it later.
But where is this stress response coming from? The scientists looked in two areas, the first was the central amygdala, an area that has previously been shown to be involved in stress responses. They were looking for corticotropin releasing factor (CRF) a hormone that is upstream and controls corticosterone responses.
Unfortunately the Amygdala ended up looking by a big pile of nothing in terms of CRF differences. But when they looked in another area, the bed nucleus of the stria terminalis (BNST, and I have no idea why they call it the bed nucleus), they found some interesting stuff. You can see above there in B that the dieting mice (dark bar) had low levels of CRF, and those levels STAYED low even when the mice were refed on a regular diet (the grey bars).
But the question is, WHY are these levels low? To find that out, the scientists looked at DNA methylation, which is a very hot new field right now. The idea is this. You know you have DNA, and that DNA is a code which is transcribed into RNA and then translated into protein, yes? We call that the Central Dogma. Once you have a protein, you can then keep it around, break it down, etc. So when levels of a PROTEIN (like CRF) change, is that because the protein is being broken down more than before? Does it mean the protein isn’t making it as much out of the RNA stage? Or does it mean it’s never made it from the DNA stage to RNA in the first place? This last one is particularly important, because you can change whether or not DNA is available for coding by several mechanisms. Today we’re focusing on methylation. When DNA gets methylated (in this case) it gets chunked up, and is less available to be made into RNA and then into protein. So the protein levels will be lower. But the really crazy thing about this change in methylation is that it’s very long LASTING. Cells don’t methylate lightly, and once they do, the change can go on for years. In some cases, if the methylation happens to DNA in the testes, for example, that change can actually make it into your offspring!
In this case, the jury is out on the offspring, but when the scientists looked at mice that had diets compared to those that didn’t, they saw that the methylation of the CRF gene was decreased, both in dieting mice and in mice that had previous had diets but were now being refed. This suggests that the mice that had had diets retain the changes in stress hormone expression that they had during diets. The pounds may not stay off, but the methylation will stick with you.
And it turns out that these changes will affect how the mice react to stress later on. The scientists took the mice that had had diets and those that hadn’t (AFTER they had been refed so they aren’t on diets anymore), and put them in a paradigm called chronic variable stress (CVS). This is a pile of different environmental stresses that the mice are exposed to, to give them just a lot of little stressors that get to them (kind of like grad school, only for mice). So the mice might get 15 min of being wrapped up like a burrito one day, and the next day they might get a little red ball put in their cage (mice don’t like new things), and the day after that they might get a period of being left in the dark in the middle of the day, and then they might get the radio left on, etc etc. None of them cause pain or hurt the mouse, but they are all annoying, and the mouse never knows what’s coming next, leading to a stressed out mouse.
Then they gave the now stressed out mice the opportunity to eat a high fat diet, to see how much they ate. It appears in this study they used an actual high fat diet that you can buy from a company, but a lot of labs use peanut butter chips or Crisco (mice LOVE Crisco).
You can see in the two top panels that the mice who had been on diets and mice who hadn’t generally ate the same amount of high fat food when unstressed. But when they were stressed, the former diet mice ate more high fat food than the non-diet mice did. They didn’t go whole hog or anything, but I think this effect could be higher with more stressors (they only used one stress per day, but many labs use THREE). So apparently having been on a diet makes mice more likely to eat their feelings in times of stress.
They did a bunch of other stuff in this paper (it’s a very fat paper), like looking at hormone responses to high fat diets (which are higher in mice that have been on diets), and that you can stop the high fat overeating by giving mice an MCH antagonist (MCH is a melanin response hormone and is another feeding related hormone). But the take home message is this: Dieting not only causes you to lose weight, it interacts with the way your body deals with stress, and makes it more likely for you to eat more when times of stress come around again. Over the long run, this could result in…weight gain, screwing over all you worked for.
Of course this study raises more questions than it answers. Here are a few of mine:
1) What was cort like DURING the diet? Is the dieting itself stressful? It appears that it was, as the dieting mice had higher levels of CORT at baseline (before the stress test), but it’d be interesting to see if there was a stress response to the dieting during the diet itself.
2) Does this stress effect get WORSE if you diet them again? Does it get better?
3) Why MALE MICE?!?! There are far more women than men on diets, I know that male mice are “easier” (scientists often use male mice because working out the cyclings of the females and the effects of cycling is really annoying, and ovarectomizing the females doesn’t give a picture of what’s really going on), but I think female mice would be more relevant.
4) The depression test is interesting (The tail suspension I referred to up there). Other studies with MORE caloric restriction, causing mice to lose up to 30{9f43b4361d9a125bc126dd2a2d1949be02545ec69880430bc4fed2272fd72da3} of their body weight, have shown increased struggle in these tests, but that could be related to the high locomotor activity seen in models of anorexia. Regardless, is there proof that dieting makes you depressed? Has anyone looked at this in humans? There are lots of possible confounds here, mice don’t care about their self-esteem and certainly don’t base their self-esteem on fitting into their skinny mouse jeans, so could this kind of effect be counteracted in humans, who might feel good about their success as they lose weight? Edit: I realize I didn’t explain how I thought the tail suspension test might be working here. Tail suspension measures don’t always work as a measure of “prodepressive” behavior. Rather, the measures can sometimes be interpreted as a “passive” or “active” response to a stressor, which is THEN interpreted as “prodepressive” behavior. In this case, I think that perhaps the more passive response to the stressor might be a key feature. Of course, how to get at that is a big question.
5) I notice that the dieting group had cort that went up and then down, while the non-dieting went UP the whole time, is this an adaptation to stress in the dieting model? Or did they just hit a ceiling?
6) The dieted mice do get back to weight when you feed them normally. Does this mean they are eating more normal food from the get go? Because that is also really interesting.
Despite all these questions, I think this paper is very interesting. It not only shows THAT diets don’t work, it provides a lot of insight into HOW. And research in this area could help scientists study how we can change those stress reactions and stop stress responses to diets. After all, when are people today NOT stressed? And if dieters eat more when stressed, and they are ALWAYS stressed, take makes them doubly doomed to failure.
Pankevich, D., Teegarden, S., Hedin, A., Jensen, C., & Bale, T. (2010). Caloric Restriction Experience Reprograms Stress and Orexigenic Pathways and Promotes Binge Eating Journal of Neuroscience, 30 (48), 16399-16407 DOI: 10.1523/JNEUROSCI.1955-10.2010
