Cecilia Lindgren: Understanding the genetics of obesity to support healthy weight loss
Image courtesy of Cecilia Lindgren
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If you’ve been paying attention to the health news, you’ve probably spotted the headlines about the latest weight loss wonder-drugs that have got celebrities, as well as regular folk, dropping pounds with alarming speed. Weight loss is big business for drug manufacturers and the diet industry, but obesity is also a serious health issue, causing life-limiting problems, stigma and shame. And it’s a problem that’s expanding, with around two thirds of the UK population now classed as overweight or obese.
Cecilia Lindgren is Professor of Genomic Endocrinology & Metabolism at the University of Oxford, and director of the Big Data Institute, or BDI, in the city. She’s dedicated her career to understanding why and how people pile on the pounds, and what we might be able to do about it. I started by asking her what we actually mean when we talk about this all-too-common health condition.
Cecilia: Obesity is a common complex disease and by complex I mean it's a disorder that has a genetic or an inherited component and also an environmental component. In the environment are things like food intake, exercise, and also metabolism, which is how much you're body basically burns in a resting state.
Cecilia: So when your body starts to accumulate fats, you basically start to store lipids in your fat cells and then you get an increased fat mass in the body to the point where it gets damaging for the person who carries that fat. We typically measure obesity by looking at body mass index, which is basically your weight over your height squared. BMI is used as a proxy or surrogate measure of fat percentage in the body. We say that somebody's overweight if they have A BMI that is between 25 and 30. And if you have a BMI of over 30, it's called obesity.
Kat: So the more conceptual question is why do we need to study obesity at the level of the genetic, the molecular studies you do? It's a bit like, I don't know, just eat less, move more. The kind of conventional wisdom there. Why do we need to dissect it in the way that you and your team are?
Cecilia: I think that's a really good question. So almost 2 billion people globally are overweight or obese today and more than 64% of adults in the UK today are overweight or obese. It's really becoming an epidemic almost. The reason we want to study it is because very simply, if you want to lose weight, the thing you should do is eat less and exercise more. You will only really lose weight if you have a calorie deficiency. So basically eat less calories than your body's burning. So it's quite an easy question, but we know from decades of studying people now that it's not that easy.
Kat: Yeah, tell me about it.
Cecilia: Likewise. Obesity has a normal distribution in the population. People will often come with the argument saying, 50 years ago nobody was obese. We know that it's the environment that has changed and that's the problem. And I will say yes, we live in a obesogenic environment where there is a lot of food available, lots of unhealthy food options and very calorie dense food available. Nevertheless, some people are much more prone to develop obesity than others. That's why we are trying to understand the underlying mechanisms in such a way that we can help further the biological understanding of why some people are more prone to get obese than others, and also use that information to think about therapeutic interventions.
Kat: So let's dig into a bit about how do you do this? How have you been trying to understand the genetic contributions to obesity?
Cecilia: What we do is basically assay genetic variation throughout the entire genome in a large number of individuals. Each person has about 3 billion base pairs in their DNA. About every 350 base pairs you have a genetic variant that will be different between different people in the population. That gives us information about that person's genetic makeup and if we see an association, we know that variant or variants in the vicinity are associated with and potentially contribute to causing obesity.
Kat: What you're doing is basically looking across little snapshots across the whole genome and saying people who are overweight or obese, do they tend to have this particular version of their DNA compared with people who aren't? But to be clear, that's not necessarily oh, that's a gene that you found. We just know that somewhere in the vicinity of this bit of their genome, there's going to be a difference between people who are obese and people who aren't.
Cecilia: That's correct. So we know that in about 80% of associations like you just described, we're going to find them in parts of the genome that actually don't code for anything. And with anything, a protein coding gene will result into a changed protein and that then can be the thing that contributes to obesity. So the non-coding variation is really interesting because that's going to be where regulatory elements sits.
Kat: Ooh, the switches.
Cecilia: Yeah, the switches, or basically the on/offs, if you want to simplify it, of gene expression and therefore protein from the nearby genes usually, not always, it could also be genes further away, so it's quite complex. So it becomes a bit of a puzzle that we need to put together for each individual instance. Taken together though, the information we get from many variants also gives us information about which processes are underlying obesity, which cell types and tissue types they operate in, which pathways are perturbated and can give us clues into how obesity susceptibility is really orchestrated in the body.
Cecilia: So that's what we're working towards, almost building a roadmap or a puzzle instead of figuring out the sort of individual pieces in a person's makeup that puts them somewhere in the distribution of obesity or BMI.
Kat: I was fascinated when you put up the results today in your presentation and you think maybe something like obesity, it's going to be about your metabolism. It's going to be about how much fat you burn and that kind of thing, or how muscley you are, but so much of it is in the brain! That surprises me.
Cecilia: There's been decades of beautiful work from monogenic obesity, and when you know that there is one single variant that is disrupted in a pretty brutal way that is causing disease, showing that predominantly it's a neuroendocrine condition leading to changes in how we perceive hunger and satiety. There are also animal models supporting this.
Cecilia: What we see for common forms of obesity, so there are a couple of things to think about there. We similarly see a really strong brain signal, like you mentioned. So the accumulated evidence is that the brain doesn't negate the fact that there might be individual variants that operate in other parts of the body, but that's not the overall signature we see. So that's just really important to point out.
Cecilia: Obesity is quite multifaceted as well. We can also look at fat distribution now because of new scanning techniques and fantastic resources like the UK Biobank, which we're proud to host in Oxford. We have scanning data from hundreds of thousands of individuals and suddenly we can do genetic studies on a more precise phenotype. That really gives us a clue into why some people are more prone to accumulate fat in the body.
Kat: What kind of difference are we talking about? If you've got particular genetic variations that, for want of a better way of expressing it, wire your brain up to make you want to eat more, versus people who don't. What sort of difference to your weight is that going to make?
Cecilia: If you look at the individual common variants, they can vary from as little as 40 grams up to the one that I think is still called the biggest effect size, which is the gene called the FTO, where each allele carries a kilogram per allele effect for an age, sex and height standardised person. So that simply means that if you're unlucky and have two copies of that, you're going to weigh two kilograms more than somebody who doesn't have any copy at all.
Cecilia: If we look at the rarer forms of variants, they can carry as much as seven kilograms per difference per allele. Accumulated, taking all the common variants and looking at them in aggregate, it can explain 10 to 15 kilograms of difference between people. So if you're really unlucky and you accumulate an unfavourable genetic makeup, you can have somewhere in the region of 15 to 18 kilograms difference, which is of course a lot.
Cecilia: Now, I don't believe in deterministic approaches to this. So we can change it and if we have unfavourable genetics, we're going to have to work much harder and it's going to be more difficult. I think increasing awareness for many of us, just in how small differences in food behaviour can really change a lot in your body weight. For instance, if you eat somewhere in the region of 150 to 250 excess calories per day consistently, you're going to accumulate obesity. And that's not particularly much.
Cecilia: So the concept that people think that you just eat and gorge yourself I would want to challenge because I just don't think that's true for most people. There's so much shaming going on in obesity, which I think is unwarranted and not helpful.
Kat: That's also a glass of wine.
Cecilia: Yes, exactly. Or two.
Kat: There were some other interesting things that you picked up in your talk about where the field is going. You mentioned the importance of diversifying the genetic information we have. This is something we've talked about on the podcast before, is that so much of the genetic data we have is from people of European ancestry and most of the world is not people of European ancestry. What are you trying to do to change that?
Cecilia: So a few things. First of all, I think it's really important we have to do science that serves all. Because otherwise we're not going to provide betterment for all, which must be of course, the goal with our science. We're working on it in a couple of ways.
Cecilia: So the first thing is that we are actively trying to invite people from various parts of the world to participate in the projects we're doing. We don't want to become like an exclusive club and we're trying to give them a proper seat at the table, which I think is really important. There are quite few data sets from other parts of the world still. So I think that there is a funding issue, which me and many other people are trying to lobby around.
Cecilia: We have also stood up at a consortium called the International Common Disease Alliance, which has 1500 members over six continents and 43 countries, where we are trying to work to empower people and help support with fundraising in such a way that the science is done.
Cecilia: It's been incredibly rewarding, but quite labour intensive because there's so much that needs to be done. But I do think that if we want to do even basic science that serves all we have to take upon ourselves to really apply ourselves. And that's not just for genetics, that's for medical research overall, I feel.
Kat: So that's going bigger on the genetics data, bigger and more inclusive. But then there's the other end of it, which is actually zooming in because as we said at the beginning, just finding these genetic variations maybe you can pin it down to a specific gene, that's not necessarily telling us how it's working. If you want to have a treatment, you need to know how it's working, right?
Cecilia: Yes. So basically what we and others are trying to do is to build large scale systematic ways of looking at basically all the variants in the genome in a natural state and trying to, in a way, shortcut the necessity of working on one gene at a time and do large systematic screens where you can do molecular and cellular profiling of cells from biopsies from a large number of individuals, in order to increase the robustness of your data. But also to make sure that you get the full variation represented, and that becomes like enormous data sets. But it's really exciting. So you can then go from the genetic variation into the cellular function or the molecular function and then what you want to do is to close the loop and link it back to the disease. That's a non-trivial question to do, but a really exciting problem I feel.
Kat: So that then brings us onto the eventual outputs of this. We are starting to see commercial weight loss medications coming through to market. What is the idea with that? How do we need to find these kinds of treatments? How are they going to work?
Cecilia: I think it does offer opportunities for us to think that obesity is actually a disease that is worth treating, similar to that of blood pressure or high lipids in a preventative fashion. Currently, there's some amazing drugs on the market. They really do work. You can lose up to 16% of your body weight over 12 to 16 weeks. It's pretty dramatic weight loss we're talking about. For a lot of people that can really be the kickstart and the positive boost that they need to get going and together with coaching and medical supervision, because you do need to change your eating behaviours and so forth. My word of caution would be that I wouldn't do it without a healthcare professional.
Cecilia: I think that another thing that I'm interested in, I'm interested in fat distribution. So where on the body you have a preponderance for starting to aggregate fats . You can think about that as a metabolic part of obesity and there are ways that you can think about drugging that as an alternative or in combination with the others will have a positive effect on obesity as well. So that's what my team is thinking about at the moment.
Kat: There's an interesting angle to this. So every time I read an article online about weight loss, or particularly weight loss drugs or research into obesity, you always get people who seem like Victorian moralists going, "You just need to eat less and move more!" and it's basically people's fault. There seems to be a lot of moralising and you sometimes get the feeling that even if there was a drug that didn't have too many side effects, people would somehow think it's almost immoral because people should just be more disciplined.
Cecilia: I think it's problematic as we just discussed. The way to lose weight in almost any instance is to have a calorie deficit generated in your body, and you basically do that by eating less and exercising more. These drugs can accelerate that process, but you still need to apply yourself to that process.
Cecilia: We've just talked about how some people though are going to struggle much more, and I think helping those individuals is of interest to everyone in the health service and everyone in society. One thing you touch upon is the shaming of people for their body size. So we know that big proportions of healthcare service providers feel that people that are overweight and obese are less worthy of treatments, which is of course problematic because 64% of people in the UK fall into that category today. Similarly so, in teaching professionals, there is also this sort of stigmatising around obesity and in the US the problem is actually classified as serious as racism at the moment, the body is shaming.
Cecilia: I think if our goal is to have a healthy, happy nation, we should support each other to be as healthy and happy as we can be. There are no straightforward, super easy answers to this, but if people have a chronic, severe condition and are struggling, you would want them ultimately to get help and support, thinking again in combination with coaching and weight loss support.
