Elucidating the role of plexin D1 in body fat distribution and susceptibility to metabolic disease using a zebrafish model system.

Non-communicable diseases (NCDs) such as cardiovascular disease, diabetes and cancer were responsible for 68% of all deaths worldwide in 2012. The regional distribution of lipid deposited within adipose tissue (AT) - so called body fat distribution (BFD) - is a strong risk factor for NCDs. BFD is highly heritable; however, the genetic basis of BFD is almost entirely unknown. Genome-wide association studies have identified several loci associated with BFD, including at Plexin D1 (PLXND1) - a gene known to modulate angiogenesis. We recently demonstrated that zebrafish homozygous for a null mutation in plxnd1 had a reduced capacity to store lipid in visceral AT (VAT) leading to altered BFD. Moreover, we found that type V collagens were upregulated in plxnd1 mutants, and mediated the inhibitory effect of Plxnd1 on VAT growth. These results strengthen evidence that Plxnd1 influences BFD in human populations, and validate zebrafish as a model to study BFD. However, many pertinent questions remain unanswered. Here we outline potential Plxnd1 mechanisms of action in AT, and describe the genetic architecture at human PLXND1 that is associated with BFD and NCD susceptibility.