Human genetic studies and zebrafish models identify Plxna4 as a regulator of adiposity, somatic growth, and feeding behaviours

Obesity is a major public health crisis, affecting billions worldwide and increasing the risk of metabolic and cardiovascular diseases. While lifestyle factors play a role, genetic variation is a key determinant of both obesity susceptibility and the efficacy of treatment strategies. Recent studies have implicated the Semaphorin 3 signalling pathway in obesity; however, specific roles for pathway components remain largely unexplored. Here, we focus on Class A Plexins and their potential contributions to body weight regulation. Using large-scale genetic association data, we identified that rare, predicted loss-of-function mutations in PLXNA4 were associated with body mass index (BMI) in females. Furthermore, common variant analysis revealed that genetic variation at PLXNA4 was linked to BMI, height, and various neuropsychiatric disorders. To investigate the biological role of Plxna4, we generated zebrafish plxna4 loss-of-function mutants, which exhibited an 85-92% reduction in Plxna4 protein. Despite appearing morphologically normal, mutant zebrafish at juvenile stages were shorter, had increased body fat levels relative to size-matched wild-type siblings, and displayed hypertrophic subcutaneous adipose tissue. Feeding assays revealed that plxna4 mutants consumed more food than wild-type siblings and exhibited food-stimulated hyperactivity, characterised by increased swimming speed, higher speed variability, and frequent high-speed bursts. Together, these findings demonstrate a conserved role for Plxna4 in regulating feeding behaviour and body fat levels, providing new insights into the genetic basis of obesity and warranting further studies to elucidate the molecular mechanisms underlying these effects.