The effect of weight loss on hormones

Researchers investigated changes to several hormones after weight loss.

This week’s New England Journal of Medicine has a landmark paper from a group of obesity researchers in Melbourne. It shows for the first time just why losing weight is the easy bit, while maintaining weight loss can be a nightmare. Joe Proietto is Professor of Medicine at the University of Melbourne and the Austin Hospital.

Joe Proietto: I’ve been treating obesity for some 15 years and what I’ve noticed is that it is such a hard battle for people to maintain weight loss. We have a very high failure rate if you look at them a few years down the track. It never made sense to me that it was just a simple going back to old habits because these people are very motivated. No one wants to be obese, so we decided to look at the various hormones that had been discovered over the years that can control hunger because it has already been shown that following weight loss leptin levels fall and another group has shown that ghrelin levels rise. Ghrelin is the hormone that makes us hungry. It goes up after weight loss.

Norman Swan: And leptin is the satiety hormone, it makes you feel satisfied.

Joe Proietto: Yes, it’s an appetite suppressing hormone. What the science had shown was that we have something like nine different hormones in the blood that can influence hunger and out of these only ghrelin seems to be appetite stimulating. The others which include cholecystokinin from the upper gut, PYY, GLP1 or glucagon-like peptide-1, and oxyntomodulin from the lower gut, leptin from fat and then insulin, amylin and pancreatic polypeptide from the pancreas.

Norman Swan: This is like an alphabet soup of names. Essentially what you’re describing is a set of hormones that are produced in our gut from the mouth through to the large bowel and the organs that hang off that so unsurprisingly our appetite in one way or another is controlled by chemical messengers that come from our intestines.

Joe Proietto: Not surprising at all because it’s telling the brain that we’ve eaten and there’s no need to go and look for food you’ve already got some here sort of thing.

Norman Swan: So tell me what you did in this study?

Joe Proietto: Well in this study we took 50 obese volunteers and the average body mass index was 34 so these were mildly obese people and we helped them lose weight using a very low energy diet and they lost about 13 kilograms over a ten week period. Prior to weight loss, immediately after the weight loss and again a year later we did a breakfast study where we took blood to measure most of these hormones before breakfast and then every half hour for the next four hours after breakfast.

Norman Swan: What did you find?

Joe Proietto: What we found was that following weight loss ghrelin levels increased, confirming what had been shown before. The leptin decreased, again confirming what had been shown before but we also found that PYY decreased, CCK decreased, insulin decreased, amylin decreased.

Norman Swan: So this is basically, just to go back over what we said a moment ago, these are basically all the hormones that in one way or another help us to feel full and tell the brain we don’t need to eat anymore.

Joe Proietto: Correct. Except for ghrelin, which tells us to go and eat.

Norman Swan: Yes.

Joe Proietto: So the ghrelin went up but the others went down, so this is a co-ordinated change.

Norman Swan: Which is not a surprise for anybody who’s on a diet, because they feel hungry for quite some time. What happened after a year?

Joe Proietto: Well after a year these subjects had regained about 5 kilograms and the hormones were still changed essentially. The only one that seemed to be heading towards base line was the ghrelin, but the other hormones were still changed and that’s the point of the paper, that is the main point of the paper that we showed that these changes are persisting even a year later.

Norman Swan: So in a sense all credit to them for persisting with the weight loss because their biology was fighting against them?

Joe Proietto: Correct and these people struggle and struggle and most of them as I said are motivated not to regain, nobody wants to be fat and they struggled and by 5 years most people had regained all the weight. And I think the reason is because it grinds them down, eventually it gets to you.

Norman Swan: It’s almost as if the body was trying to force you back to that previous weight. What’s going on here, are we talking about years of obesity, locking in a certain chemical messenger, hormone profile in our bodies? Or this is genetic, what’s the story here?

Joe Proietto: Well my view is that what this shows is further evidence for a set point for a genetically determined set point. Now in some people this is genetics in the classical sense with mutations in genes etc. But in other people, and perhaps the majority the genetic change is actually an epigenetic change.

Norman Swan: In other words our lifestyle has changed our genes?

Joe Proietto: Correct, the expression of our genes, not the sequence of the genes.

Norman Swan: So like it’s turned up the volume switch on your television set?

Joe Proietto: Correct, it’s turned up the volume or turned down the volume depending on which hormone it is that has then reset the set point higher. And so the body then – its job is to defend that new set point.

Norman Swan: So we’ve got to a level of fat and the body wants to return to it and it may be locked in genetically in a sense.

Joe Proietto: Yes.

Norman Swan: So what insight does this give you to solving this problem? I mean the first question I’d ask is do you get a different effect in terms of weight loss? You’re saying there’s a set point. Do we know how long it takes for the set point to actually develop? I’ve been obese for a year, or I’ve been over a BMI of 30 for ten years?

Joe Proietto: Look we don’t really know. We know that the set point can be altered through life, there could be other mechanisms for resetting the set point including stress for example, including what we feed our children.

Norman Swan: And is there any evidence that eventually if you keep up your low energy diet and high exercise that you can reset your set point eventually?

Joe Proietto: That would be wonderful if we could but there is not a lot of evidence for that and let me tell you what the evidence is that you don’t. The first one is in the old days they used to do gastric stapling but eventually the staples came off, most of those people even though they kept weight off for some years regained the weight. There was a study in which they used the Fen-Phen combination which turned out to be problematic.

Norman Swan: This was the diet drug which caused heart valve problems?

Joe Proietto: Yes, but before they knew that they did a study where these people were on it for I think five years, as soon as they stopped the drug most of them regained all the weight. Now that’s with pharmacotherapy and surgery, can you reset the set point if you do 5 years of vigorous exercise, dieting etc? We don’t know the answer to that.

Norman Swan: And given that you’re describing I don’t know how many hormones there are here 7, 8, 9, 10 hormones that you measured over this period of a time, given that they’re all involved in this process it doesn’t look as if a weight loss drug is on the horizon really.

Joe Proietto: Well no, I think if we can combine two or three of them I think we would have a good chance of adequate appetite suppression and at the moment there are trials in the US of the combination of leptin and amylin and there are trials of the replacement of GLP1, glucagon-like peptide-1 for appetite suppression. So in the future I’m hopeful that two or three combinations of these hormones will control the hunger.

Norman Swan: And watch what you give your children because the set point is going to live with them for the rest of their lives.

Joe Proietto: Well, let me tell you about a model that we set up in rodents where we can induce obesity with a high energy diet that is then defended.

Norman Swan: Defended?

Joe Proietto: Defended in the sense that once the animals become obese and we then put them on a diet and get them to lose weight and then expose them just to a healthy diet they overeat the healthy diet and become fat again. So what we feed our children resetting the set point. I think what the study shows is that first of all we need to switch the emphasis in obesity management from losing the weight to maintaining the weight because losing the weight is relatively easy compared to maintaining it. And the other thing this shows because it’s the long term persistence of these changes that we published it shows that any agents that we develop have to be trialled to ensure that they are safe when used long term because they are going to have to be used long term.

Norman Swan: Joe Proietto is Professor of Medicine at the University of Melbourne and the Austin Hospital.


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