title: Differential transendothelial transport of adiponectin complexes.
abstract: BACKGROUND
  Adiponectin's effects on systemic physiology and cell-specific responses are well-defined, but little is known about how this insulin-sensitizing and anti-inflammatory adipokine reaches its target cells. All molecules face active and passive transport limitations, but adiponectin is particularly noteworthy due to the diverse size range and high molecular weights of its oligomers. Additionally, its metabolic target organs possess a range of endothelial permeability.
  
  
  METHODS
  Full-length recombinant murine adiponectin was produced and oligomer fractions isolated by gel filtration. Adiponectin complex sizes were measured by dynamic light scattering to determine Stokes radii. Transendothelial transport of purified oligomers was quantitatively assessed under a number of different conditions in vitro using murine endothelial cells and in vivo using several mouse models of altered endothelial function.
  
  
  RESULTS
  Adiponectin oligomers exhibit large transport radii that limit transendothelial transport. Oligomerization is a significant determinant of flux across endothelial monolayers in vitro; low molecular weight adiponectin is preferentially transported. In vivo sampled sera from the heart, liver, and tail vein demonstrated significantly different complex distribution of lower molecular weight oligomers. Pharmacological interventions, such as PPARγ agonist treatment, differentially affect adiponectin plasma clearance and tissue uptake. Exercise induces enhanced adiponectin uptake to oxidative skeletal muscles, wherein adiponectin potently lowers ceramide levels. In total, endothelial barriers control adiponectin transport in a cell- and tissue-specific manner.
  
  
  CONCLUSIONS
  Adiponectin oligomer efficacy in a given tissue may therefore be endothelial transport mediated. Targeting endothelial dysfunction in the metabolic syndrome through exercise and pharmaceuticals may afford an effective approach to increasing adiponectin's beneficial effects.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Rutkowski
authors.forename: Nils
authors.initials: N
authors.lastname: Halberg
authors.forename: Qiong A
authors.initials: QA
authors.lastname: Wang
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.forename: Jonathan Y
authors.initials: JY
authors.lastname: Xia
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA. philipp.scherer@utsouthwestern.edu.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D052242:Adiponectin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D021381:Protein Transport / Q000502:physiology
chemical_list: D052242:Adiponectin; C499919:Adipoq protein, mouse