title: Pigment epithelium-derived factor regulates lipid metabolism via adipose triglyceride lipase.
abstract: OBJECTIVE
  Pigment epithelium-derived factor (PEDF) is an adipocyte-secreted factor involved in the development of insulin resistance in obesity. Previous studies have identified PEDF as a regulator of triacylglycerol metabolism in the liver that may act through adipose triglyceride lipase (ATGL). We used ATGL(-/-) mice to determine the role of PEDF in regulating lipid and glucose metabolism.
  
  
  METHODS
  Recombinant PEDF was administered to ATGL(-/-) and wild-type mice, and whole-body energy metabolism was studied by indirect calorimetry. Adipose tissue lipolysis and skeletal muscle fatty acid metabolism was determined in isolated tissue preparations. Muscle lipids were assessed by electrospray ionization-tandem mass spectrometry. Whole-body insulin sensitivity and skeletal muscle glucose uptake were assessed.
  
  
  RESULTS
  PEDF impaired the capacity to adjust substrate selection, resulting in a delayed diurnal decline in the respiratory exchange ratio, and suppressed daily fatty acid oxidation. PEDF enhanced adipocyte lipolysis and triacylglycerol lipase activity in skeletal muscle. Muscle fatty acid uptake and storage were unaffected, whereas fatty acid oxidation was impaired. These changes in lipid metabolism were abrogated in ATGL(-/-) mice and were not attributable to hypothalamic actions. ATGL(-/-) mice were also refractory to PEDF-mediated insulin resistance, but this was not related to changes in lipid species in skeletal muscle.
  
  
  CONCLUSIONS
  The results are the first direct demonstration that 1) PEDF influences systemic fatty acid metabolism by promoting lipolysis in an ATGL-dependent manner and reducing fatty acid oxidation and 2) ATGL is required for the negative effects of PEDF on insulin action.
authors.affiliation: Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, Clayton, Victoria, Australia.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Borg
authors.forename: Zane B
authors.initials: ZB
authors.lastname: Andrews
authors.forename: Elia J
authors.initials: EJ
authors.lastname: Duh
authors.forename: Rudolf
authors.initials: R
authors.lastname: Zechner
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
mesh_terms: D041721:3T3-L1 Cells; D000273:Adipose Tissue / Q000201:enzymology* / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005136:Eye Proteins / Q000494:pharmacology*; D005227:Fatty Acids / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D005947:Glucose / Q000378:metabolism; D015151:Immunoblotting; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D009414:Nerve Growth Factors / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D005227:Fatty Acids; D005947:Glucose; D008049:Lipase; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor