Pippa flops by the Aga oven chewing on a stick. At just 12 weeks old, this labrador retriever puppy looks cute but clueless. But when she hears the word “biscuit”, her entire demeanour changes. Ears pricked, she’s immediately at her owner’s feet, gazing adoringly, sitting, even woofing on command.
We led a study to find out how genes have such a significant influence on why humans (and dogs) become overweight. It was their reputation for greediness that led us to focus on labrador retrievers. Genes are responsible for 40%-70% of human obesity – the rest is related to life experience.
We extracted DNA from samples of saliva sent in by interested pet owners. More than ten years after the first dog slobber arrived in the post, the results of our study are striking: dogs don’t just share a home with their human owners, they share obesity genes too.
Each of the top five genes that increased the risk of weight gain in labradors were also implicated in human obesity.
Such crossover is not astonishing; both dogs and humans evolved to deal with cycles of food glut and famine. Both have brain mechanisms that drive hunger and satiety to ensure food intake meets our daily energy requirements.
And although we often think of fat as a problem, it does make sense to have some – it is an energy reserve to draw upon in times when food is scarce. Genes influence those mechanisms, but how? The answer lies in the highly selective nature of dog breeding. A side effect of dog breeding is that it is remarkably straightforward to identify the genes which cause traits – even those like obesity, which come from the net effect of lots of changes along our DNA.
As a vet, I know obesity is a real problem for many of my patients, so we study dogs both for their own sake and as a “model” of human disease.
The genes we found were most important in determining obesity in labradors were not frontrunners in genetic studies of obesity in people. Rather, they were also-rans, with a minor impact on human weight gain.
Normally they wouldn’t interest us, but the dog results told us they can have a big effect on body weight and made them worth investigating. That was true of our top labrador obesity gene, DENND1B. Dogs who carried the problem version of this gene had around 8% more body fat, but the effect in humans is only subtle.
It turns out that DENND1B has a previously unrecognised role in the brain’s regulation of body weight, for dogs and humans. Leptin is a hormone produced from fat cells in the body. More fat, more leptin.
It acts in the brain by activating “melanocortin receptors” to reduce hunger and increase energy use. The system drives food intake in times of starvation and reduces it when the body has good energy reserves.
We showed DENND1B is produced alongside melanocortin receptors in the brain and alters signalling by them.
There is a lot we still need to learn about DENND1B, but this was a great start, especially since it is notoriously difficult to go from finding a genetic association to providing a molecular link to how the gene is acting in the body. Although not the target of the latest wave of anti-obesity drugs, there are obesity medicines which target melanocortin receptors, so there is real value in understanding the nuances of that brain pathway.
Genes make staying slim harder
Low-risk dogs in our study were all slim or only marginally overweight. But their owners don’t get the credit – this group tended to stay at a healthy weight even if owners didn’t pay much attention to how they regulated their dogs’ diet and exercise.
High-risk dogs can be kept slim, but it is much harder work. These owners need to be vigilant at all times to ensure their chow-hounds don’t get opportunities to snack and must steel themselves to resist the “big, brown eye treatment” that is such an effective way to beg for food. (The Conversation)
