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

Research output: Contribution to journalArticle

  • James E N Minchin
  • Ingrid Dahlman
  • Christopher J. Harvey
  • Niklas Mejhert
  • Manvendra K. Singh
  • Jonathan A. Epstein
  • Peter Arner
  • Jesús Torres-Vázquez
  • John F. Rawls
  • Roger D. Cone (Editor)

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)4363-4368
Number of pages6
JournalProceedings of the National Academy of Sciences
Volume112
Issue number14
Early online date23 Mar 2015
DOIs
Publication statusPublished - 7 Apr 2015

Abstract

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.

    Research areas

  • Adipose development, Body fat distribution, Extracellular matrix, Insulin resistance, Zebrafish

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