Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue

• Published in: Proceedings of the National Academy of Sciences - PNAS 2015-04, Vol.112 (14), p.4363-4368
• Main Authors: Minchin, James E. N., Dahlman, Ingrid, Harvey, Christopher J., Mejhert, Niklas, Singh, Manvendra K., Epstein, Jonathan A., Arner, Peter, Torres-Vázquez, Jesús, Rawls, John F.
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Body Composition; Body fat; Cell Adhesion Molecules, Neuronal - physiology; Cell Proliferation; Collagen; Collagen Type V - biosynthesis; Endothelial Cells - cytology; Extracellular Matrix - metabolism; Female; Gene Expression Regulation; Humans; Insulin - metabolism; Intra-Abdominal Fat - pathology; Lipids - chemistry; Matrix; Medicin och hälsovetenskap; Membrane Glycoproteins - physiology; Mice; Morphology; Mutation; Nerve Tissue Proteins - physiology; Obesity; Proteins; RNA, Messenger - metabolism; Signal Transduction; Tissues; Zebrafish
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1416412112

Genome-wide association studies have implicated PLEXIN D1 ( PLXND1 ) in body fat distribution and type 2 diabetes. However, a role for PLXND1 in regional adiposity and insulin resistance is unknown. Here we use in vivo imaging and genetic analysis in zebrafish to show that Plxnd1 regulates body fat distribution and insulin sensitivity. Plxnd1 deficiency in zebrafish induced hyperplastic morphology in visceral adipose tissue (VAT) and reduced lipid storage. In contrast, subcutaneous adipose tissue (SAT) growth and morphology were unaffected, resulting in altered body fat distribution and a reduced VAT:SAT ratio in zebrafish. A VAT-specific role for Plxnd1 appeared conserved in humans, as PLXND1 mRNA was positively associated with hypertrophic morphology in VAT, but not SAT. In zebrafish plxnd1 mutants, the effect on VAT morphology and body fat distribution was dependent on induction of the extracellular matrix protein collagen type V alpha 1 ( col5a1 ). Furthermore, after high-fat feeding, zebrafish plxnd1 mutant VAT was resistant to expansion, and excess lipid was disproportionately deposited in SAT, leading to an even greater exacerbation of altered body fat distribution. Plxnd1-deficient zebrafish were protected from high-fat-diet-induced insulin resistance, and human VAT PLXND1 mRNA was positively associated with type 2 diabetes, suggesting a conserved role for PLXND1 in insulin sensitivity. Together, our findings identify Plxnd1 as a novel regulator of VAT growth, body fat distribution, and insulin sensitivity in both zebrafish and humans. Significance PLEXIN D1 ( PLXND1 ) has been implicated in body fat distribution and type 2 diabetes by genome-wide association studies, but the mechanism is unknown. We show here that Plxnd1 regulates body fat distribution in zebrafish by controlling the visceral adipose tissue (VAT) growth mechanism. Plxnd1 deficiency in zebrafish resulted in induction of a hyperplastic state and reduced lipid deposition in VAT. Regulation of VAT was dependent on the induction of the type V collagen, col5a1 , suggesting that Plxnd1 controls body fat distribution by determining the status of VAT extracellular matrix. Plxnd1-deficient zebrafish were protected from high-fat-induced insulin resistance, and human PLXND1 mRNA was positively associated with type 2 diabetes. These results suggest that the role of Plxnd1 in body fat distribution and insulin signaling is conserved from zebrafish to humans.