PUBLICATION
Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue
- Authors
- Minchin, J.E., Dahlman, I., Harvey, C.J., Mejhert, N., Singh, M.K., Epstein, J.A., Arner, P., Torres-Vazquez, J., Rawls, J.F.
- ID
- ZDB-PUB-150402-1
- Date
- 2015
- Source
- Proceedings of the National Academy of Sciences of the United States of America 112(14): 4363-8 (Journal)
- Registered Authors
- Epstein, Jonathan A., Minchin, James, Rawls, John F., Torres-Vázquez, Jesús
- Keywords
- adipose development, body fat distribution, extracellular matrix, insulin resistance, zebrafish
- MeSH Terms
-
- Collagen Type V/biosynthesis*
- Nerve Tissue Proteins/physiology*
- Female
- Lipids/chemistry
- Extracellular Matrix/metabolism
- Body Composition
- RNA, Messenger/metabolism
- Animals
- Humans
- Membrane Glycoproteins/physiology*
- Intra-Abdominal Fat/pathology*
- Gene Expression Regulation
- Cell Proliferation
- Obesity
- Zebrafish
- Endothelial Cells/cytology
- Insulin/metabolism*
- Mutation
- Signal Transduction
- Cell Adhesion Molecules, Neuronal/physiology*
- Mice
- PubMed
- 25831505 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Minchin, J.E., Dahlman, I., Harvey, C.J., Mejhert, N., Singh, M.K., Epstein, J.A., Arner, P., Torres-Vazquez, J., Rawls, J.F. (2015) Plexin D1 determines body fat distribution by regulating the type V collagen microenvironment in visceral adipose tissue. Proceedings of the National Academy of Sciences of the United States of America. 112(14):4363-8.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping