What makes Labradors (and their owners) obese

Meanwhile here on Earth, researchers at the University of Cambridge have discovered a new clutch of genes linked to obesity in both labradors and potentially their owners, because we carry them too. These genetic factors drive greediness by tweaking the sensitivity of the brain to hunger signals. Thankfully, the effects can be overridden with a strict diet and exercise regime. Eleanor Raffan from the University of Cambridge met Chris Smith and his labradors to tell him about it…

Chris - The last time we met, you were introducing me to dogs that eat too much because of genetics. But what really is the overriding question this time?

Eleanor - Well, I'm still interested in overweight dogs, but we are ultimately interested in how our genes can control why some people overeat and gain weight. And if we do that via the medium of dogs, then it tells us something about veterinary medicine too.

Chris - So, dogs work the same way we do?

Eleanor: Very similarly. They're another large mammal with very similar genetics, actually.

Chris: How did you approach this then?

Eleanor - Well, we've done what's called a genome-wide association study. These days, we can test markers that are anchor points all the way along the genome. And we can test at each of those points whether one or other version of the genome is associated with obesity. And when we did that, it allows us to map where on our genetic code there is something associated with a trait. And in our case, to map down to particular genes which were associated with obesity in the Labrador population that we were looking at.

Chris - So, you look at a dog and you ask: this dog's fatter, this dog's thinner. Are there any differences in these different parts of the genome? Because if there are differences, genes in that region could be responsible.

Eleanor - That's a beautiful explanation.

Chris - We've got Labradors here. They're making noise and they're definitely greedy. Does that actually help then? Is that why you went for Labradors? Because they're notorious for tending to put on weight.

Eleanor - Yeah, it certainly meant that we thought we might find something interesting because they've got this reputation for being complete chowhounds.

Chris - So, how did you do the study? I mean, was this just domestic dogs, people like me, who would say, well, come and look at mine?

Eleanor - Yeah, exactly. We've got entirely pet dogs in our discovery study and we took slobber samples from them, spongy swabs, mopping up a little bit of saliva and you can get DNA. The thing that we were studying genetically was their tendency to put on weight. So, we just saw how overweight they were. There are ways to put numbers on how fat a dog are. We use something called a body condition score. And then we put a number on how greedy they are…

Chris - How did you measure that?

Eleanor - We developed a questionnaire a few years ago and it's quite simple actually. We've got 35 statements, things like, my dog will eat anything. My dog isn't fussy about food. And so we can put a number not only on how food motivated dogs are, but also on the extent to which owners control diet and exercise. So, what we did was the mapping study to test the genes with the condition score. So, first we said, what genes make a dog more prone to being overweight? And then when we could put a number on that - and combine all of them together as a risk score for obesity - then we said, well, if you're a high risk dog, why are you high risk? And we could use our greed score and see that actually the high risk dogs were at risk because they were more foodie. They were the kind of dogs who pester you for food at the table or always snaffle a scrap when they're out and about. They're the ones who will patiently wait even for something like a carrot when you're chopping vegetables. And they're the ones who are really just forever persisting in their pursuit of food.

Chris - Knowing a shopping list of genes that might be linked to overweightness is one thing, but actually the mechanism of how those genes translate into that, that's the key thing, isn't it? Because that tells us where the interventions might be. So, can you see possible ways in which these genes that you have linked to this behaviour, being overweight, are translating into that occurring?

Eleanor - Yeah, absolutely. What we were really struck by was that our top five genes also have links to human obesity. And our very top gene was called DENND1B. And that's the one that we pursued with studies in the lab. And we found that it acts as a dimmer switch to turn up or turn down a brain pathway, which is quite well studied actually about how the body regulates body weight. And by having probably slightly more of it or slightly less of it, it slightly turns up or down your hunger signalling.

Chris - And that's true in humans as well?

Eleanor - Yeah, the effect we got in dogs was quite big. If you are a dog that carries this risk variant, then you're about 8% fatter than others that don't. The effect in humans is really minute and they could only find it in these huge populations. But the fact that there is shared biology across the species meant that it was worth pursuing.

Chris - And is it not also the point that if you have just a small imbalance in energy terms, in what you need, in terms of what you're actually eating compared to what you really need, because we live a long time, you've got plenty of time to slowly accumulate weight. So, even if it's a small and subtle effect, it's still going to translate into quite a weight gain over a lifetime.

Eleanor - Exactly that. There's an astonishing statistic that if you eat seven calories more a day, it translates to something like 10 kilos extra when you reach middle age. It's only a very subtle imbalance that's needed to end up with quite a profound and health affecting weight gain.

Chris - Implications for clinical interventions then, off the back of this?

Eleanor - Well, our particular niche bit of biology to do with DENND1B is informative because it's acting in a pathway that is already a target of anti-obesity drugs. Not the most common ones that have been in the news recently, but others. And so that's important. We need to understand the nuances of these mechanisms in order to be able to develop drugs to target them. I think the wider implications actually from our study come from the fact that dogs are such a relatable model and the fact that we had this ability to quantify, to put a number on how at risk dogs were, to show that that was acting by altering their appetite. And then we went on to look at the impact that owner management had on that.  And what we showed is that if you're a low risk dog, actually it doesn't matter that much what your owners do. You'll probably stay about a healthy weight, maybe a little bit overweight. The low risk dogs tended not to get overweight. Whereas our high genetic risk dogs were really dependent on their owners to exert lots of control over what they were eating and make sure they were really active. So, if you were a high risk dog with a completely on it owner who absolutely regulated your food and gave you lots of activity, you could be perfectly slim. The problem comes that if you're a bit relaxed about the management, those dogs will pile on the pounds.