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. 2012 Oct 24;18(1):1161-8.
doi: 10.2119/molmed.2012.00156.

Identification of pigment epithelium-derived factor as an adipocyte-derived inflammatory factor

Sangeeta S Chavan  1 , LaQueta K Hudson, Jian Hua Li, Mahendar Ochani, Yael Harris, Nirav B Patel, David Katz, Joshua A Scheinerman, Valentin A Pavlov, Kevin J Tracey
Affiliations

Identification of pigment epithelium-derived factor as an adipocyte-derived inflammatory factor

Sangeeta S Chavan et al. Mol Med. .

Abstract

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.

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Figures

Figure 1
Figure 1
PEDF secreted by adipocytes increases macrophage TNF production. (A) Different amounts of 3T3-L1 adipocyte CM was added to RAW cells, and levels of TNF in the cell supernatant were quantitated by ELISA. (B) 3T3-L1 adipocyte CM was fractionated with cation exchange chromatography. (C) RAW cells were cultured with individual fraction, and levels of secreted TNF were quantitated with ELISA. Fold change in TNF levels was determined by calculating the increase in TNF levels in response to the individual fraction compared with medium control. Arbitary units of specific activity were determined as fold change per milligram of total protein. (D) RAW cells were cultured with recombinant PEDF, and RNA was isolated after 60 min. Real-time polymerase chain reaction analysis was carried out as described in the Methods. Data are mean ± standard error (SE), *p < 0.05 and **p < 0.005 versus medium alone control. (E) RAW cells were cultured with recombinant PEDF for 2.5 h, and TNF levels were quantitated in the supernatant by ELISA. Data are mean ± SE, *p < 0.05 and **p < 0.0005 versus medium-alone control.
Figure 2
Figure 2
PEDF induces inflammatory signaling pathways in murine macrophages. (A, B) RAW were cultured with different concentrations of recombinant PEDF. Total cell lysates were resolved by sodium dodecyl sulfate–polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotted with antibodies to phosphorylated and total ERK1/2 and p38 MAPK. Data are mean ± SE. *p < 0.05 and **p < 0.005 versus medium-alone control. (C, D) RAW cells were cultured with recombinant PEDF for 2.5 h in the presence or absence of ERK1/2 inhibitor (U0126) or p38 MAPK inhibitor (SB20358) at the indicated concentrations. TNF levels were measured in the supernatant by ELISA. Data are mean ± SE.
Figure 3
Figure 3
ATGL is required for PEDF-mediated macrophage activation. (A) RAW cells express both ATGL and LR. RAW cell lysate was resolved by SDS-PAGE and immunoblotted with antibodies to β-actin, ATGL and LR. RAW cells were cultured with recombinant PEDF for 2.5 h in the presence or absence of (B, C) ATGL inhibitors, AACOCF3 or BEL or (D, E, F) anti-LR antibody or Lam B1925–933 peptide or EGF33–42 peptide at the indicated concentrations. TNF levels were measured in the supernatant by ELISA. Data are mean ± SE, *p < 0.05 and **p < 0.01 versus medium-alone control.
Figure 4
Figure 4
PEDF administration induces TNF release and insulin resistance in rats. Recombinant PEDF (2 mg/kg) was administered to rats, and ITT was carried out 90 min after PEDF administration. KITT, the first-order rate constant for the disappearance of glucose, was calculated as described in Methods. Data are mean ± SE (vehicle group, n = 12; PEDF group n = 9, p < 0.05 versus vehicle control).
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References

    1. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. JAMA. 2012;307:491–7. - PubMed
    1. Berrington dG, et al. Body-mass index and mortality among 1.46 million white adults. N Engl J Med. 2010;363:2211–9. - PMC - PubMed
    1. Flegal KM, Graubard BI, Williamson DF, Gail MH. Cause-specific excess deaths associated with underweight, overweight, and obesity. JAMA. 2007;298:2028–37. - PubMed
    1. Zheng W, et al. Association between body-mass index and risk of death in more than 1 million Asians. N Engl J Med. 2011;364:719–29. - PMC - PubMed
    1. Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:1111–9. - PMC - PubMed

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