DENND1B Gene Linked to Obesity in Dogs and Humans

Dogs are a compelling model of human obesity, in part because they develop obesity due to similar environmental influences as people. In a genome-wide association study (GWAS) of Labrador retrievers, researchers have identified an obesity-related gene – DENND1B – that may also influence obesity in humans.

These findings highlight the value of using non-traditional animal models to study complex diseases and highlight the gene's potential as a target for future obesity research across species. Obesity is a heritable complex condition influenced by both biological and environmental factors. While human obesity research has identified numerous genetic loci that play a role in the disease, understanding the mechanisms behind these associations remains challenging. Dogs offer a valuable model – albeit underused – for studying obesity, including in humans. However, despite the high prevalence of obesity in pet dogs (40-60%), the genetic basis of canine obesity is still poorly understood; only a few studies shed light on its complex inheritance patterns.

Natalie Wallis and colleagues performed a canine GWAS for obesity in 241 Labrador retrievers – a particularly obesity-prone breed of dogs. Using a cross-species approach, they identified multiple genes linked to obesity in dogs and humans alike. Among these, DENND1B – which plays a role in cellular processes crucial to regulating energy – emerged as the strongest genetic association with canine obesity, influencing "body condition score" (BCS), and body weight. According to Wallis et al., DENND1B is also highly conserved across species and shares strong genetic similarities to its human counterpart.

In past work in humans, researchers found significant links between DENND1B variants and body mass index. In this study, the authors identified a rare and harmful DENND1B mutation that appears to disrupt energy regulation, in a severely obese human patient. They also showed, in dogs, that risk for obesity was influenced in part by eating behavior, highlighting the role of gene-environment interactions and reinforcing human studies that show that, in environments with abundant food, heightened appetite is linked to increased obesity risk.