Dogs are compelling animal models of human obesity, in part because they also develop obesity due to similar environmental factors as humans. In a genome-wide association study (GWAS) of Labrador retrievers, researchers identified a gene associated with obesity: DENND1B; this gene may also contribute to obesity in humans.
These findings highlight the value of using non-traditional animal models to study complex diseases and underscore the potential of this gene as a target for future cross-species obesity research.
Obesity is a heritable, complex disease influenced by both biological and environmental factors. Although human obesity research has identified multiple genetic loci that play a role in the disease, understanding the mechanisms underlying the association between these genetic loci and obesity remains challenging. Dogs provide a valuable – albeit underutilized – model for studying obesity, including human obesity. However, despite the high prevalence of obesity in pet dogs (40-60%), the genetic basis of canine obesity remains poorly understood; only a few studies have elucidated its complex inheritance patterns.
Natalie Wallis and colleagues conducted a canine GWAS obesity study in 241 Labrador retrievers, a breed particularly susceptible to obesity. Using a cross-species approach, they identified multiple genes associated with obesity in dogs and humans. Of these, DENND1B (which plays a role in a key process in which cells regulate energy) is thought to have the strongest genetic link to canine obesity: it affects the 'body condition score' (BCS) and body weight. According to Wallis et al., DENND1B is also highly conserved among different species and has strong genetic similarity with the corresponding gene in humans.
In past human studies, researchers found a significant association between DENND1B variants and body mass index. In this study, the authors identified a rare and deleterious DENND1B mutation in a patient with severe obesity that appears to disrupt energy regulation. They also demonstrate that in dogs, the risk of obesity is partially influenced by dietary behavior, highlighting the consequences of gene-environment interactions and reinforcing the conclusions of human studies showing that stimulated appetite in a food-rich environment is associated with an increased risk of obesity.