The brain is the central regulator of appetite and body fatness, and genetic variation that affects body fatness tends to act in the brain. One important site of variation is the POMC gene, which codes for a signaling molecule that suppresses food intake. A new study shows that Labrador retrievers often carry an inactive version of the POMC gene, causing them to be highly food motivated, obesity-prone-- and perhaps more easily trainable.
Introduction: Brain regulation of body fatness
In mammals, body fatness is regulated by the brain, primarily in response to the hormone leptin. Fat tissue produces leptin in proportion to its size, and this informs the brain of how much fat a person carries. Regulation of body fatness happens principally via the (direct and indirect) actions of leptin on specific neurons in the brain, the most important of which are POMC neurons and AgRP neurons (1).
POMC and AgRP neurons are the yin and yang of body fatness. When POMC neuron activity goes up, appetite and body fatness go down. When AgRP activity goes up, appetite and body fatness go up. Leptin affects these populations reciprocally: it activates POMC neurons and shuts down AgRP neurons, explaining much of its effect on food intake and body weight. These neuron populations are both located in the hypothalamus, and more specifically in a tiny region called the arcuate nucleus (1).
POMC neurons exert their effects on appetite and body fatness in large part using a signaling protein called-- you guessed it-- POMC. This signal instructs downstream brain regions to engage the behaviors and physiology that cause us to eat less and lose fat. When the POMC signal goes away, appetite and body fatness increase (2).
Each of us carries a complement of genes that varies in small but important ways, and this accounts for much of why individuals are different from one another. Not surprisingly, this genetic variance affects eating behavior and body fatness: up to 70 percent of individual difference in body fatness is explained by genetic differences (3).
Many researchers have studied the genetic variation that impacts body fatness, and they have come to a consistent conclusion: genes that affect brain structure and function are heavily overrepresented among those that affect fatness (4, 5, 6). This is particularly true of genes in the brain pathways that transmit the leptin signal. This gives us a high degree of confidence that the leptin-brain axis really is the primary regulator of body fatness.
One of the sites of genetic variation that has repeatedly popped up is the POMC gene. Stephen O'Rahilly and Sadaf Farooqi have shown that mutations that inactivate the POMC gene are the most common (known) cause of single-gene obesity in humans, accounting for up to 6 percent of cases of severe childhood obesity (7). Other researchers have demonstrated that similar mutations cause obesity in mice (8). A new study by O'Rahilly's group shows that the same principle operates in dogs as well, and that it may explain the behavior and body shape of your favorite pooch.
The researchers began by comparing a small sample of lean and obese Labrador retrievers, looking for mutations in genes known to influence body weight (9). Among the obese dogs, 10 out of 15 carried a mutation in the POMC gene that is predicted to inactivate its protein product. Only 2 out of 18 lean dogs carried the mutation.
They went on to look for associations between the mutation and obesity in a larger group of 310 Labs, and found that each copy of the mutation was associated with an extra 4.2 lbs (1.9 kg) body weight. Dogs with two copies of the mutation weighed 8.4 lbs (3.8 kg) more than dogs with two functional copies of POMC.
Not only were Labs with the POMC mutation heavier, they were also more motivated by food. This was determined by administering a questionnaire to the owners that measured the dogs' behavior around food.
Interestingly, they found that Labs with the POMC mutation were much more likely to be service dogs. We don't know exactly why that is, but the most likely explanation is that highly food-motivated dogs are easier to train. By selecting for trainability in dogs, we may have inadvertently also selected for mutations that predispose to excessive food motivation and obesity.
Genetic variation can impact food motivation and the susceptibility to obesity. In mice and humans, the genes in question tend to be components of the brain pathways that regulate appetite and body fatness. This new study shows that the same is true in dogs, further supporting the fundamental importance of these pathways across diverse species. It also suggests that we may have inadvertently selected for an obesity gene in Labrador retrievers.
Some dogs-- and humans-- are simply born hungry, and this study adds to our understanding of why this happens.