Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2015 Apr 7;112(14):4363-8. doi: 10.1073/pnas.1416412112. Epub 2015 Mar 23.

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

Author information

1
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;
2
Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 14186 Stockholm, Sweden;
3
Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599;
4
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.
5
Cell and Developmental Biology and the Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104;
6
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.
7
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.

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.

KEYWORDS:

adipose development; body fat distribution; extracellular matrix; insulin resistance; zebrafish

PMID:
25831505
PMCID:
PMC4394244
DOI:
10.1073/pnas.1416412112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center