Identification of pigment epithelium-derived factor as an adipocyte-derived inflammatory factor.
Obesity is a major risk factor for insulin resistance, type 2 diabetes mellitus and cardiovascular disease. The pathophysiology of obesity is associated with chronic low-grade inflammation. Adipose tissue in obesity is significantly infiltrated by macrophages that secrete cytokines. The mechanisms of interaction between macrophages and adipocytes, leading to macrophage activation and increased cytokine release, remain to be elucidated. We reasoned that an adipocyte-derived factor might stimulate activation of macrophages. We have identified pigment epithelium-derived factor (PEDF) as a mediator of inflammation that is secreted by adipocytes and mediates macrophage activation. Recombinant PEDF activates macrophages to release tumor necrosis factor (TNF) and interleukin-1 (IL-1). The PEDF receptor adipose triglyceride lipase (ATGL) is required for PEDF-mediated macrophage activation. Selective inhibition of ATGL on macrophages attenuates PEDF-induced TNF production, and PEDF enhances the phosphorylation of p38 and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinases. PEDF administration to rats results in increased serum TNF levels, and insulin resistance. Together, these findings suggest that PEDF secreted by adipocytes contributes to the onset and maintenance of chronic inflammation in obesity, and may be a therapeutic target in ameliorating insulin resistance.
Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, Manhasset, New York 11030, United States of America. schavan@nshs.edu
Sangeeta S
SS
Chavan
LaQueta K
LK
Hudson
Jian Hua
JH
Li
Mahendar
M
Ochani
Yael
Y
Harris
Nirav B
NB
Patel
David
D
Katz
Joshua A
JA
Scheinerman
Valentin A
VA
Pavlov
Kevin J
KJ
Tracey
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D005136:Eye Proteins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism*; D007333:Insulin Resistance; D008049:Lipase / Q000378:metabolism; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009414:Nerve Growth Factors / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015843:Serpins / Q000008:administration & dosage / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor; D000217:Acyltransferases
D005136:Eye Proteins; D018836:Inflammation Mediators; D008049:Lipase; D009414:Nerve Growth Factors; D015843:Serpins; D014409:Tumor Necrosis Factor-alpha; D000099174:Pigment Epithelium-Derived Factor; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases