Pigment Epithelium-Derived Factor Contributes to Insulin Resistance in Obesity

Cell Metab. 2009 Jul;10(1):40-7. doi: 10.1016/j.cmet.2009.06.001.

Abstract

Obesity is a major risk factor for insulin resistance; however, the factors linking these disorders are not well defined. Herein, we show that the noninhibitory serine protease inhibitor, pigment epithelium-derived factor (PEDF), plays a causal role in insulin resistance. Adipocyte PEDF expression and serum levels are elevated in several rodent models of obesity and reduced upon weight loss and insulin sensitization. Lean mice injected with recombinant PEDF exhibited reduced insulin sensitivity during hyperinsulinemic-euglycemic clamps. Acute PEDF administration activated the proinflammatory serine/threonine kinases c-Jun terminal kinase and extracellular regulated kinase in both muscle and liver, which corresponded with reduced insulin signal transduction. Prolonged PEDF administration stimulated adipose tissue lipolysis, resulted in ectopic lipid deposition, and reduced insulin sensitivity, while neutralizing PEDF in obese mice enhanced insulin sensitivity. Overall, these results identify a causal role for PEDF in obesity-induced insulin resistance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Eye Proteins / blood
  • Eye Proteins / metabolism*
  • Eye Proteins / pharmacology
  • Glucose Clamp Technique
  • Humans
  • Insulin / metabolism
  • Insulin Resistance*
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Lipolysis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Obese
  • Nerve Growth Factors / blood
  • Nerve Growth Factors / metabolism*
  • Nerve Growth Factors / pharmacology
  • Obesity / etiology*
  • Protein-Serine-Threonine Kinases / metabolism
  • Serpins / blood
  • Serpins / metabolism*
  • Serpins / pharmacology
  • Signal Transduction

Substances

  • Eye Proteins
  • Insulin
  • Nerve Growth Factors
  • Serpins
  • pigment epithelium-derived factor
  • Protein-Serine-Threonine Kinases
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases