A gene breakthrough for obesity

30 April 2019

Interview with 

Luca Lotta, University of Cambridge

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Scientists at Cambridge University have identified how a gene called MC4R affects the chance of someone becoming obese and carrying a higher risk of diabetes and heart disease. Chris Smith was joined in the studio by the study’s author, Luca Lotta explained what this gene was, and how it worked...

Luca -  Thank you for having me here. The MC4R for the Melanocortin 4a receptor is a receptor that is expressed in our brain and helps us control our appetite. The way it works is that when you have a meal there is a hormone and a response to the food intake, this response activates MC4R, and MC4R our tells our body, “hey, you have just had a meal. It's time to feel full”.

Chris - And so you stop taking on board more fuel, more calories?

Luca - Yes, exactly. And that's why we studied this gene and genetic variation in this gene, to understand the mechanisms of appetite regulation and their link to obesity.

Chris - It was already known that this gene is linked to obesity and appetite, wasn't it? Before you started looking at it?

Luca - Yes. Colleagues at the Institute of Metabolic Science in Cambridge discovered this gene in 1998, when they described mutations that disrupted this genes, they were associated with a higher risk of obesity. Our finding here is the opposite: that there are other genetic variants in the same gene that are actually associated with lower weight to lower risk of obesity, blood pressure, diabetes, and heart disease.

Chris - Now how did you find those variants and why did your colleagues back in the 1990s, why did they miss the fact that the gene seemed to work in both directions like that?

Luca - We studied 60 different genetic variants in MC4R and we studied this in a very large study of half a million people from the general population in the UK. Some of these genetic variants are rare, in particular the variants that we identified in this study require a large sample size to be able to detect certain associations.

Chris - Indeed. Where did you get data from half a million people?

Luca - There's a very large study in the UK which is called the UK bio bank which is a study of a half a million volunteers from the general population in the UK. UK Biobank makes data widely available to researchers, in particular in this area. We applied and we got the data and we studied this particular research question.

Chris - Were you asking of those people what's your form of MC4R? What's your gene look like and are you fat or thin? Is that basically what you're asking?

Luca - Yeah, it's what we've looked. Genetic data are part of the data that are available in UK bio bank and there's over 60 different genetic variants in this gene. We studied the association of these genetic variants with fatness, of thinness, and the risk of these diseases. And we also studied this genetic variance in lab experiments in cell cultures, where we found that genetic variance that are associated with a lower risk of obesity in this gene increase the activity of these receptors. The receptors are switched on and we think that this suggests that some people may find it easier to control their appetite because of their genetic makeup, because their appetite suppressing activity of MC4R stays activated for longer.

Chris - And does this mean then that we may be able to manipulate the gene in this way in order to make a person who would otherwise want to eat more, eat less? In other words feel fuller sooner?

Luca - Yes, so what we hope is that now drug developers may use what we've learned from this genetic study and try to copy the protective effect of this naturally occurring genetic variance with the medicines that suppress appetite, by activating this receptor and, in particular, a pathway that we've studied for the first time in relation to this receptor called Beta arrestin in which we strongly linked with this protective effect.

Chris - Now when you say this new way of interacting with cells is beta arrestin and how does that work then?

Luca - The way it works is that the receptor binds to beta arrestin and stays on the cell surface for longer.

Chris - So that’s how it leaves this I feel fuller for longer sensation?

Luca -  Exactly. The normal receptor that is carried by most people in the general population, once it's activated and gets recruited within the cells so it can stay on the surface after it's been activated, whereas the mutant receptor for these particularly beneficial genetic variants stays on the cell surface for longer in these experiments suggesting that these people may find it easier to control their appetite because their receptors stays switched on.

Chris - And if we look at a range of people what proportion of obesity in those people is attributable to this effect because, obviously, obesity isn't just down to this one gene is it? There's a whole range of factors that can lead to this.

Luca - Yes.

Chris - So what contribution to the overall picture of the person in front of you is this particular component.

Luca - Yes. We know from other studies that obesity is 50 percent due to the environment and 50 percent due to genetics. By genetics, I mean several different genetic variants, in different genes in the genome. The main reason, actually, why obesity is so prevalent in the population is due to the environment, the availability of calorie-rich food, trends in physical inactivity. But the reason why we study the genetic aspects of obesity is that obesity helps us gain insights into the mechanisms that lead to obesity and, therefore, ways that we can prevent or treat this condition.

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