title: Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue.
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.
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: James E N
authors.initials: JE
authors.lastname: Minchin
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden;
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlman
authors.affiliation: Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Harvey
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden;
authors.forename: Niklas
authors.initials: N
authors.lastname: Mejhert
authors.affiliation: Cell and Developmental Biology and the Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104; Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore Graduate Medical School, National Heart Center, 169857 Singapore; and.
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
authors.affiliation: Cell and Developmental Biology and the Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.affiliation: Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden;
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.affiliation: Department of Cell Biology, Helen L. and Martin S. Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of Medicine, New York, NY 10016.
authors.forename: Jesús
authors.initials: J
authors.lastname: Torres-Vázquez
authors.affiliation: Department of Molecular Genetics and Microbiology, Duke University, Durham, NC 27710; Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; john.rawls@duke.edu.
authors.forename: John F
authors.initials: JF
authors.lastname: Rawls
mesh_terms: D000818:Animals; D001823:Body Composition; D015816:Cell Adhesion Molecules, Neuronal / Q000502:physiology*; D049109:Cell Proliferation; D024062:Collagen Type V / Q000096:biosynthesis*; D042783:Endothelial Cells / Q000166:cytology; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D050152:Intra-Abdominal Fat / Q000473:pathology*; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids / Q000737:chemistry; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009765:Obesity; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction; D015027:Zebrafish
chemical_list: C530725:COL5A1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; D024062:Collagen Type V; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008562:Membrane Glycoproteins; D009419:Nerve Tissue Proteins; C493082:PLXND1 protein, human; C473552:Plxnd1 protein, mouse; D012333:RNA, Messenger
keywords: adipose development; body fat distribution; extracellular matrix; insulin resistance; zebrafish
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