Obesity-Prone Dogs and Humans Share Genetic Variants

Genetic variants associated with canine obesity, particularly DENND1B, are also associated with obesity in humans, new research revealed.

Notably, labrador retrievers carrying DENND1B had around 7% more body fat and tended to be more highly food-motivated than those without the gene. 

The findings could lead to a “big advance” in understanding how the human brain controls eating behavior and energy use, suggested the study’s principal investigator Eleanor Raffan, University of Cambridge, Cambridge, United Kingdom.

Raffan, a veterinarian and obesity genetics researcher, told Medscape Medical News, “We were expecting some overlap between canine and human obesity genes but were surprised that for every one of our top five dog obesity genes, there was also a human association with body mass index.”

Furthermore, the team found that a dog’s polygenic obesity risk was mediated by increased appetite. “Low-risk dogs tended to stay slim even if their owners had a fairly relaxed attitude to how they fed and exercised them,” she said. “This contrasted with the high-risk dogs, where relaxed owners ended up with overweight pets, but owners who were very assiduous in rationing food and providing exercise could keep even the highest risk dogs slim.”

“We know that people at high genetic obesity risk also have higher appetites, and they have to work harder to resist weight gain in our modern ‘obesogenic’ environment,” she said.

The study was published online in Science.

Labrador Retrievers ‘Obesity-Prone’

Dogs are a good model for studying human obesity because they develop obesity through similar environmental influences as humans, according to the researchers. And because dogs within any given breed have a high degree of genetic similarity, their genes can be more easily linked to disease.

The researchers performed a canine genome-wide association study for body condition score, a measure of canine obesity, in 241 labrador retrievers, a breed known to be obesity-prone and highly food-motivated, according to the authors. Only adult (mean age, 6 years) pet and working dogs were included. Participating dogs were free of known or suspected systemic illness and were not being treated with medications likely to affect obesity status.

The dog gene found to be most strongly associated with obesity in labradors was DENND1B. An additional four genes associated with canine obesity, but which exert a smaller effect than DENND1B, were also mapped directly onto human genes.

In people, DENND1B directly affects the leptin-melanocortin pathway, a brain pathway responsible for regulating energy balance in the body. Specifically, it helps regulate the melanocortin-4 receptor gene (MC4R), an important regulator of energy homeostasis, food intake, and body weight in the hypothalamus. MC4R mutations are associated with early-onset severe obesity.

DENND1B also has been implicated in the pathogenesis of childhood asthma and other immune disorders by modifying T-cell receptor function.

Because the gene is widely expressed in the body, “it isn’t an obvious focus for anti-obesity drugs, as we might expect off-target effects,” Raffan said. “Nonetheless, understanding its function in the context of melanocortin signaling is valuable since the leptin-melanocortin signaling pathway…is already the focus for some anti-obesity therapeutics (eg, setmelanotide).”

“It’s worth pointing out that the human genome-wide association study with DENND1B had a small effect size and that this is just one of thousands of genetic variants which can increase or decrease a person’s tendency to weight gain,” she added. “It is the net effect of those variants which make people prone or relatively resistant to obesity.”

The team also constructed a polygenic risk score for the dogs and found that those with higher polygenic risk were more likely to seek out food in the home, to “beg” for food, and to eat any food on offer.

Labradors with low polygenic risk tended to remain normal weight irrespective of owner control of diet and exercise, but high-risk dogs were prone to developing obesity if their activity was limited and owners were permissive with food (for instance, by offering human food or not restraining their dogs’ intake by limiting the food available).

Similarly, the authors suggested, people at high genetic risk of developing obesity are more prone to weight gain, but they won’t necessarily become obese if they follow a strict diet and exercise regime.

‘Genetic, Biological, Environmental Forces at Play’

Endocrinologist Priya Jaisinghani, MD, of New York University Grossman School of Medicine in New York City, commented on the study for Medscape Medical News. “The finding of DENND1B as a regulator of MC4R activity can further enhance our understanding of signaling in a key pathway in hypothalamic energy regulation,” she said.” However, further research is needed to determine the full impact of these genetic factors on energy balance and obesity risk in humans.”

“Obesity is a complex condition shaped by genetics, biology, environment, and social factors,” said Jaisinghani, who was not involved in the study. “Research suggests that genetics play a significant role, contributing 4src%-7src% of a person’s risk. While rare single-gene mutations, like those in the MC4R gene, can lead to severe obesity — especially in children — most cases are driven by multiple genetic variations.”

“Understanding these influences is key to providing better care,” she concluded. “By recognizing the genetic, biological, and environmental forces at play, we can move toward more personalized and effective treatment strategies.” 

Raffan has engaged in paid consultancy for Purina Ltd. Jaisinghani is a speaker for Eli Lilly and Novo Nordisk.

Marilynn Larkin, MA, is an award-winning medical writer and editor whose work has appeared in numerous publications, including Medscape Medical News and its sister publication MDedge, The Lance