Roxanne Khamsi, give rise to new drugs


Research reveals fresh risk factors around obesity in humans

A mutation in some obesity-prone dog breeds might reveal new risk factors for obesity in humans — and perhaps, says Roxanne Khamsi, give rise to new drugs

Research reveals fresh risk factors around obesity in humans

What lengths will a dog go to for a bite of sausage?

Last November, scientists at the University of Cambridge in Britain persuaded several dozen pet owners to bring their Labrador retrievers to its veterinary school for a true test of will.

Inside a mostly empty white room, a research associate let each dog sniff a hot dog before demonstratively placing it inside a small plastic hamster cage on the floor and sealing it shut with black duct tape.

Some of the Labs showed only passing interest in the trapped sausage and spent more time exploring the rest of the room. But others stayed laser-focused on the treat. One in particular, a black Labrador named Ash, went into a tizzy, banging the cage around and not giving up until he pried the tape loose with his teeth and ate the hot dog.

As it turns out, Ash has more than just determination and a precise tooth grip. He also has a gene mutation linked to obesity. Ash is not overweight, perhaps because his owner keeps him on a rigid diet.

But Eleanor Raffan, the researcher who designed the study, suspects his underlying gene mutation and his food-induced frenzy in the experiment are linked. She hasn’t yet analysed all the data from this latest study, but it has become a mission of hers to understand what makes some canines so voracious.

Dr Raffan’s curiosity about this traces back 15 years, to when she became a veterinary surgeon and saw firsthand that certain breeds are more likely than others to put on extra weight.

Shortly afterward, when scientists published the first complete dog genome, Raffan decided she wanted to search for DNA mutations that might contribute to heaviness.

She got a doctorate in genetics and in 2013 began the GOdogs Project — short for the genetics of obesity in dogs — at Cambridge. She notes that because of the way people have bred dogs, there’s a small gene pool within each breed, making the animals simpler to study.

“The way the jiggery-pokery of genetics works means that it’s remarkably easy to get to map the sites where disease-causing genes are in dogs,” says Dr Raffan.

In one of the first GOdogs projects Dr Raffan undertook, she initially analysed the DNA of more than 300 Labradors, the breed with the most extensively documented risk of obesity, using the dogs’ saliva samples, some of which were sent by pet owners as far away as the Orkney Islands, off the northeastern coast of Scotland. Along with the saliva, she and her colleagues gathered important data about the animals’ size and behaviour.

Close examination of the DNA revealed that in some dogs, such as Ash, a chunk of a gene called pro-opiomelanocortin (POMC) is missing. The primary metabolic effect of POMC occurs within a peanut-size region deep within the brain known as the hypothalamus, which affects appetite and calorie-burning.

Only a few hundred cells within this area are under the influence of the POMC gene, but this small cluster acts like a sort of signal interchange that controls the body’s metabolism.

Dr Raffan’s findings, published last year in the journal Cell Metabolism, suggest that roughly one-fifth of labrador retrievers have the mutation she identified in their POMC gene, and that it is associated with increased appetite and obesity.

Exactly how this particular breed came to carry the mutation is somewhat of a mystery. The gene error was absent in the 78 other breeds that Dr Raffan examined in her study, with the exception of one: the flat-coated retriever, a more obscure retriever breed found predominantly in Britain.

This breed and the Labrador trace their lineage back to the St John’s water dog, now extinct, a dog with a sterling reputation for loyalty that was used in the 1800s by fishermen in Newfoundland to retrieve catch that got loose from the fishing line.

Dr Raffan’s study also looked at a group of Labradors that guide blind people and found that three-quarters possessed the POMC mutation, suggesting that their genetic predisposition to seek food rewards perhaps made them easier to train.

Ireland has one of the highest obesity rates in Europe. One in four adults are obese and one in four children are overweight.

About one in 20 adults in Ireland have an obesity-related disease such as type-2 diabetes, heart disease, sleep apnoea, or fertility issues.

Dr Raffan and others say that understanding why certain breeds of dogs are more prone to weight gain might reveal previously unknown risk factors for obesity in humans — and perhaps one day give rise to new drugs to manage our metabolic woes.

Upward of 10,000 living people worldwide are currently estimated to have mutations in POMC, although the effects of such mutations may vary. In addition, errors within a closely related gene, involved in the same brain pathway controlling metabolism, are estimated to afflict some 65,000 people in Britain, including as many as 6% of white individuals in that country who have been severely obese since childhood.

Obesity researchers say it’s particularly urgent to diagnose the most severe mutations in POMC, which are so catastrophic that they lead to fatal liver failure if undetected.

“I’m sure that in many clinics worldwide that link is not made,” says Heiko Krude, a German scientist who helped identify this type of mutation in humans.

Recent work from Prof Krude’s group hints that people with normal versions of POMC might become prone to putting on extra pounds when, for reasons yet unknown, the gene is in an inactive form.

“There’s now more and more evidence that a partial loss of POMC gene function is linked to more common forms of obesity,” he says.

Not all dogs pounce on junk food. Whippets and greyhounds will sometimes even leave their dinner unfinished. But many of the most popular breeds, including beagles, dachshunds and labradors, gravitate toward gluttony.

Dogs with severe obesity can develop health issues such as breathing problems, painful joint damage and life-threatening inflammation of the pancreas. Until these grave consequences arise, however, many pet owners remain oblivious to the fact that their dogs are overweight and keep feeding them too much.

“We kind of use food as love sometimes, which can really harm pets,” says Deborah Linder, a veterinarian who heads the Tufts Obesity Clinic for Animals in Massachusetts.

Authors of a small 1998 study of 120 dogs, published in the Journal of Nutrition, speculated that obese pets were “indulged as ‘fellow-humans’ ” and that owners of these animals were “over humanising” their pets.

The paper asserted that owners of obese dogs are often obese themselves. But veterinarians caution that this link is neither proven nor necessarily causal. In the meantime, Ernie Ward, a veterinarian who founded the Association for Pet Obesity Prevention, likens the way that overfeeding and underexercising contribute to excess weight in dogs to “the same way second- or third-hand smoke can also cause certain cancers”.

There’s a growing sentiment that investigating the health similarities and differences between dogs and humans might lead to medical breakthroughs in metabolic diseases. One question that scientists hope to eventually answer is why obesity in dogs doesn’t make them as prone to diabetes as it does in humans.

About a quarter of a million people in Ireland have diabetes. Your chances of developing Type 2 diabetes, which is the most common form of this disease and the kind linked to excess weight, increase at least fourfold when you are obese. The disease is documented to be caused by obesity in other species like cats and monkeys as well. But it’s unusual for dogs to develop obesity-related diabetes. Even a labrador in Australia named Sampson who weighed 85kg when he arrived at a rescue shelter showed no clinical signs of diabetes.

It is still unclear exactly what role genetics plays in human obesity. Studies comparing twins have suggested that a person’s individual weight is as much as 70% determined by genes. Among adults, fewer than 1% of cases are thought to be the result of errors in a single gene. But the list of such genes is growing. In March, scientists announced they’d done a survey of scientific literature and tallied up 79 obesity syndromes, 19 of which had a clear-cut genetic cause for which there is a test.

Karen Snizek has witnessed the power a single gene can have on metabolism. Ms Snizek gave birth to her son, Nate, in 2008 and gradually noticed that he was putting on an unusual amount of weight. But it wasn’t until his bottom got stuck in a walker when he was 8 months old, and she needed Nate’s father to help dislodge him, that she understood that something was seriously wrong.

“I started realizing this is not a normal child,” she says. “This is not going to be a normal childhood.” A geneticist diagnosed a mutation in Nate’s POMC gene that predisposed him to severe obesity. The gene was first linked to this disease two decades ago, when doctors in Berlin identified errors in POMC in a toddler who was putting on an unusual amount of weight. The child had been under close watch because her 7-month-old brother, who died before she was born, had succumbed to an undiagnosed hormone

deficiency, which also affected her and which scientists have since linked to her POMC mutation.

Severe obesity tied to POMC is usually associated with DNA variations that affect the gene’s ability to make a peptide called alpha-MSH. This peptide triggers a sequence of nerve signals controlling appetite and metabolism that are transmitted from the hypothalamus to areas of the brain and spinal cord. But there’s also growing evidence that mutations in a part of the gene that produces a related peptide, beta-MSH, also confer some risk of obesity. This peptide happens to be affected in Nate — and it is precisely the peptide that some labradors lack.

The research into the possible role of beta-MSH in obesity is still very much in its infancy, but some of the first evidence that it might influence weight came from a 2006 study. As part of the investigation, 26 children, six of whom had an error in the part of POMC that encodes for beta-MSH, were brought in individually and told they could eat as much as they wanted from a breakfast buffet at a clinical research facility in a wing of the hospital complex in Cambridge where Dr Raffan has her laboratory.

The children with the beta-MSH variant consumed three times as many calories for their weight as the others. The scientists found this particular POMC mutation in five of 538 research participants who had been severely obese since childhood, compared with only four out of 5,152 average-weight individuals. The investigation, led by Dr Raffan’s mentors Stephen O’Rahilly and Sadaf Farooqi, who both work at the Wellcome Trust-Medical Research Council’s Institute of Metabolic Science in Cambridge, concluded that this particular mutation increases your risk of obesity.

Beta-MSH has been proved to bind to the same cell receptor as alpha-MSH. But it has been hard to study beta-MSH because rats and mice, the laboratory animals of choice, have evolved in such a way that they don’t make any beta-MSH. That’s where Labradors might be able to help.

Not everyone is convinced that the canines or beta-MSH have a big role in cracking obesity.

“I’ve certainly been challenged at conferences by people who say, Well, why does it matter if the dogs have got a beta mutation because they’ve got alpha, surely it can compensate,” sayd Dr Raffan. “But one suspicion is that there is a subtle distinction in what alpha and beta do.”

Before anyone had thought to look for POMC mutations in dogs, drug companies were already trying, and failing, to develop compounds to treat related causes of obesity in humans. Now an experimental medication is finally making headway.

File image
File image

Bart Henderson is a founder of Rhythm, a Boston-based drug company that has an obesity drug in clinical trials. The drug caused substantial weight loss in at least two people with alpha-MSH mutations in POMC. The medication, called setmelanotide, caused one patient — the individual who received her diagnosis as a toddler in Berlin 20 years ago — to shed 51kg from her starting weight of 155kg after taking the drug for 42 weeks.

Last year, the drug received the first-ever “breakthrough therapy” designation from the FDA’s Division of Metabolism and Endocrinology Products, which means the agency will expedite its review. Earlier this month, the drug moved ahead into the final phase of clinical testing for POMC deficiency.

Mr Henderson explains that Dr Raffan’s DNA findings in dogs have made people in his company and the field more interested in the role of beta-MSH deficiencies and how that hormone might also be contributing to obesity.

“Beta-MSH just really hasn’t been the focus,” he says. “When that labrador paper came out we all said ‘whoa’.”

Labradors would be a perfect animal to test this and other obesity drugs for beta-MSH deficiencies caused by POMC, says Dr Raffan. Rhythm is focused on human studies and doesn’t have plans to test setmelanotide in dogs, but Sr Raffan says she would be curious about the effects of a drug like this on labradors.

There’s no drug on the market to treat canine obesity, but research into the underlying causes of this condition in dogs continues. In February, a group in Poland published data from a study of 272 dogs, reaffirming the connection between obesity and the same POMC gene mutation that Dr Raffan identified. Her group is now looking at additional obesity-prone breeds that don’t have the POMC mutation she found in labradors but perhaps have other genetic variants that influence obesity. Dog researchers have previously found mutations in another gene, which produces the cell receptor that binds to alpha-MSH and beta-MSH, that might be associated with heightened body weight in beagles, echoing similar results in humans. Additional studies have offered preliminary evidence that other genes might be linked in some way with body weight in dogs and humans.

As the science moves ahead, Karen hopes that increased awareness about the genetic causes of obesity in people and our pets will break down the stigma surrounding her son’s weight struggles. Even when Nate is on a strict diet, his metabolic disorder makes it hard for him to avoid putting on weight. She’s hoping a drug like setmelanotide might become available soon for him. Because he uses a wheelchair at times when he feels unwell and fatigued, she’s looking for a service dog for him and hoping to find one with the POMC mutation that Raffan has identified. That would be comforting for Nate, Karen explains. “He could say: ‘My dog has the same thing I do.’ ”

Roxanne Khamsi is the chief news editor for Nature Medicine. She last wrote for the magazine about the quest to develop a less allergenic peanut

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