Pigment Epithelium-Derived Factor Contributes to Insulin Resistance in Obesity

Crowe, Seamus; Wu, Lindsay E.; Economou, Catherine; Turpin, Sarah M.; Matzaris, Maria; Hoehn, Kyle L.; Hevener, Andrea L.; James, David E.; Duh, Elia J.; Watt, Matthew J.

doi:10.1016/j.cmet.2009.06.001

Cited by 158 publications

(201 citation statements)

References 46 publications

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“…These differences likely reflect tissue-specific PEDF gene expression, whereby the liver had the highest expression levels, whereas those in the pancreas were low. 44 Other studies 7,45,46 indicate significant PEDF production by organs, such as the kidney and adipose tissue, and suggest that an increased distribution may occur under inflammatory conditions, such as obesity. Given PEDF's role in ameliorating tissue fibrosis, the contribution of other organs may be reflected in circulating systemic levels.…”

Section: Discussionmentioning

confidence: 99%

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Schmitz

Protiva

Gattu

et al. 2011

The American Journal of Pathology

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Pigment epithelium-derived factor (PEDF) is important for maintaining the normal extracellular matrix. We hypothesized that the initiation of pancreatic fibrosis is dependent on the loss of PEDF. Pancreatic PEDF expression was assessed in wild-type mice fed either a control or ethanol diet using an intragastric feeding model. Pancreatitis responses were elicited with either a single episode or a repetitive ceruleininduced (50 g/kg, 6 hourly i.p. injections) protocol in wild-type and PEDF-null mice. Quantitative realtime PCR and immunoblotting were performed to assess fibrogenic responses. In wild-type animals, PEDF expression increased with pancreatitis and was more pronounced in mice fed ethanol. Compared with wild-type mice, ␣-smooth muscle actin staining and expression levels of fibrogenic markers (eg, transforming growth factor-␤1, platelet-derived growth factor, collagen I, and thrombospondin-1) were higher in PEDF-null mice at baseline. Sirius red staining revealed more fibrosis in PEDF-null versus wildtype pancreas 1 week after pancreatitis. Differences in tissue fibrosis resolved with longer recovery periods. PEDF overexpression suppressed thrombospondin-1 levels in vitro. Ethanol feeding and experimental pancreatitis increased PEDF expression in wildtype mice. PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wildtype mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in

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Section: Discussionmentioning

confidence: 99%

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Schmitz

Protiva

Gattu

et al. 2011

The American Journal of Pathology

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“…Such regulation is unlikely to occur in other cell types that do not express perilipin A, and potential regulation by other members of the perilipin family, including PLIN2 (adipocyte differentiation-related protein), PLIN3 (tail-interacting protein of 47 kDa), PLIN4 (S3-12), and PLIN5 (LSDP5), requires more study. Finally, recent work shows that the adipokine pigment epithelium-derived factor, which is elevated in obesity (15), associates with ATGL (13) and enhances adipocyte lipolysis (15).…”

Section: Regulation Of Tg Lipasesmentioning

confidence: 99%

Triacylglycerol lipases and metabolic control: implications for health and disease

Watt

Spriet

2010

American Journal of Physiology-Endocrinology and Metabolism

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Watt MJ, Spriet LL. Triacylglycerol lipases and metabolic control: implications for health and disease. Am J Physiol Endocrinol Metab 299: E162-E168, 2010. First published January 12, 2010; doi:10.1152/ajpendo.00698.2009.-Fatty acids derived from the hydrolysis of adipose tissue and skeletal muscle triacylglycerol (TG) are an important energy substrate at rest and during physical activity. This review outlines the identification of the new TG lipase, adipose triglyceride lipase, the current understanding of how cellular TG lipases are regulated, and the implications for understanding the integrated control of TG lipolysis. Furthermore, this review outlines recent advances that propose a "revised" role for TG lipases in cellular function, metabolic homeostasis, and disease prevention. fatty acid; metabolism; adipose; skeletal muscle TRIACYLGLYCEROLS (TG) are stored within discrete cytosolic lipid droplets within most tissues. Contrary to the common misconception in the literature that the TG pool is "inert," these droplets are highly dynamic, and the TG within is highly labile. The overall TG content within these droplets is ultimately dependent on the balance between the rates of TG hydrolysis and fatty acid uptake, oxidation, and storage. The fatty acids derived from TG breakdown participate in a variety of cellular processes, including membrane biosynthesis, signal transduction, and, most critically for this review, ATP production after ␤-oxidation. From a systemic viewpoint, fatty acids can be derived from both intracellular and extracellular sources, and with the exception of adipose tissue, the latter is most prevalent due to limited intracellular stores. Under postprandial conditions, ϳ30% of total energy expenditure is reliant on fatty acids derived from adipose TG hydrolysis, and this becomes quantitatively more important with extended fasting or exercise. In cases of caloric surplus leading to obesity, elevated circulating fatty acids may contribute to the accumulation of intramyocellular and hepatic lipids, which are associated with secondary metabolic complications such as insulin resistance (77). Therefore, the liberation of fatty acids from adipocyte TG and release into the systemic circulation is under most conditions the first point of control in the regulation of fatty acid metabolism, and accordingly, tight control of adipocyte lipolysis is a critical mediator of whole body metabolic homeostasis. Similarly, an emerging body of evidence indicates that altering TG metabolism within ectopic tissues, such as liver and skeletal muscle, can influence local fatty acid metabolism with implications for obesity-related metabolic disorders.This review will first focus on the regulation of TG lipolysis and how the understanding of TG regulation has evolved since the discovery and partial characterization of adipose triglyceride lipase (ATGL) only 5 years ago. The review will then outline how changes in TG metabolism can influence adipocyte and skeletal muscle metabolism and summarize the recent evidence sug...

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“…In type 1 diabetes patients, microvascular complications, vascular stiffness, inflammation and diabetic retinopathy have been significantly correlated with increased serum levels of PEDF (28,29). Systemic PEDF administration to naïve animals induced activation of proinflammatory cytokine responses, and reduced insulin sensitivity (16,18). Inhibition or blockade of PEDF in obese, insulin-resistant mice, significantly improves whole-body insulin sensitivity, even when initial dosing of inhibitors was delayed until after the onset of frank obesity (18).…”

Section: Histologymentioning

confidence: 99%

“…Systemic PEDF administration to naïve animals induced activation of proinflammatory cytokine responses, and reduced insulin sensitivity (16,18). Inhibition or blockade of PEDF in obese, insulin-resistant mice, significantly improves whole-body insulin sensitivity, even when initial dosing of inhibitors was delayed until after the onset of frank obesity (18).…”

Section: Histologymentioning

confidence: 99%

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

Hudson

Dancho

et al. 2016

Mol Med

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Type 1 diabetes mellitus (T1D) is a chronic autoimmune disease characterized by β cell destruction, insulin deficiency and hyperglycemia. Activated macrophages and autoimmune T cells play a crucial role in the pathogenesis of hyperglycemia in NOD murine diabetes models, but the molecular mechanisms of macrophage activation are unknown. We recently identified pigment epithelium-derived factor (PEDF) as an adipocyte-derived factor that activates macrophages and mediates insulin resistance. Reasoning that PEDF might participate as a proinflammatory mediator in murine diabetes, we measured PEDF levels in NOD mice. PEDF levels are significantly elevated in pancreas, in parallel with pancreatic TNF levels in NOD mice. To identify experimental therapeutics, we screened 2,327 compounds in two chemical libraries (the NIH Clinical Collection and Pharmakon-1600) for leads that inhibit PEDF mediated TNF release in macrophage cultures. The lead molecule selected, "emetine" is a widely used emetic. It inhibited PEDF-mediated macrophage activation with an EC50 or 146 nmol/L. Administration of emetine to NOD mice and to C57Bl6 mice subjected to streptozotocin significantly attenuated hyperglycemia, reduced TNF levels in pancreas and attenuated insulitis. Together, these results suggest that targeting PEDF with emetine may attenuate TNF release and hyperglycemia in murine diabetes models. This suggests that further investigation of PEDF and emetine in the pathogenesis of human diabetes is warranted.

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Pigment Epithelium-Derived Factor Contributes to Insulin Resistance in Obesity

Cited by 158 publications

References 46 publications

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Triacylglycerol lipases and metabolic control: implications for health and disease

Emetine Di-HCl Attenuates Type 1 Diabetes Mellitus in Mice

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