title: Liver, but not adipose tissue PEDF gene expression is associated with insulin resistance.
abstract: OBJECTIVE
  Recent studies linked circulating pigment epithelium-derived factor (PEDF) to obesity-associated insulin resistance, but the main source of circulating PEDF is unknown. We aimed to investigate liver and adipose tissue PEDF gene expression in association with obesity and insulin resistance.
  
  
  METHODS
  Three (two cross-sectional and one longitudinal) independent cohorts have been studied, for adipose tissue (n=80 and n=30) and liver gene expression (n=32 and n=14). Effects of high glucose and cytokines on HepG2 cell line were also investigated. PEDF gene expression and circulating PEDF were analyzed using real-time PCR and ELISA, respectively.
  
  
  RESULTS
  In a first cohort of subjects, PEDF relative gene expression was higher in subcutaneous (SC) than in omental (OM) adipose tissue (P<0.0001) being also higher in mature adipocytes compared with stromo-vascular cells (P<0.0001). However, OM PEDF relative gene expression was decreased in morbidly obese subjects (P=0.01). Both OM PEDF and OM PEDF receptor (PEDFR) correlated positively with lipogenic and lipolytic genes, and with genes implicated in the lipid vacuole formation. Circulating PEDF levels were not associated with fat PEDF gene expression. In the second cohort, SC PEDF was decreased in subjects with type 2 diabetes and did not change significantly after weight loss. We next explored circulating PEDF in association with markers of liver-related insulin resistance injury (alanine aminotransferase, r=0.59, P=0.001). Interestingly, liver PEDF gene expression increased with obesity and insulin resistance in men, being significantly associated with fasting glucose and glycated hemoglobin in two independent cohorts. In fact, high glucose led to increased PEDF in HepG2 cells, while inflammatory stimuli present in the adipose tissue environment downregulated PEDF.
  
  
  CONCLUSIONS
  Liver, but not adipose tissue, might be the source of increased circulating PEDF linked to insulin resistance.
authors: Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona, and CIBER Fisiopatologia Obesidad y Nutricion (CB06/03/010), Instituto de Salud Carlos III, Girona, Spain.
authors: J M
authors: JM
authors: Moreno-Navarrete
authors: V
authors: V
authors: Touskova
authors: M
authors: M
authors: Sabater
authors: M
authors: M
authors: Mraz
authors: J
authors: J
authors: Drapalova
authors: F
authors: F
authors: Ortega
authors: M
authors: M
authors: Serrano
authors: V
authors: V
authors: Catalán
authors: J
authors: J
authors: Gómez-Ambrosi
authors: M R
authors: MR
authors: Ortiz
authors: G
authors: G
authors: Pardo
authors: N
authors: N
authors: Pueyo
authors: W
authors: W
authors: Ricart
authors: Z
authors: Z
authors: Lacinova
authors: M
authors: M
authors: Haluzik
authors: G
authors: G
authors: Frühbeck
authors: J M
authors: JM
authors: Fernández-Real
mesh_terms: D017667:Adipocytes; D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D015992:Body Mass Index; D002454:Cell Differentiation; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009767:Obesity, Morbid / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D013030:Spain / Q000453:epidemiology; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor