Pigment epithelium-derived factor contributes to insulin resistance in obesity.
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.
Crowe
Seamus
S
Department of Physiology, Monash University, Clayton, Victoria 3800, Australia.
Wu
Lindsay E
LE
Economou
Catherine
C
Turpin
Sarah M
SM
Matzaris
Maria
M
Hoehn
Kyle L
KL
Hevener
Andrea L
AL
James
David E
DE
Duh
Elia J
EJ
Watt
Matthew J
MJ
D000818:Animals; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005136:Eye Proteins / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008066:Lipolysis; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009414:Nerve Growth Factors / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D009765:Obesity / Q000209:etiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015843:Serpins / Q000097:blood / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D000099174:Pigment Epithelium-Derived Factor
D048049:Extracellular Signal-Regulated MAP Kinases; D005136:Eye Proteins; D007328:Insulin; D048031:JNK Mitogen-Activated Protein Kinases; D009414:Nerve Growth Factors; D017346:Protein Serine-Threonine Kinases; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor