Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements

Abstract

Lakeland TV, Borg ML, Matzaris M, Abdelkader A, Evans RG, Watt MJ. Augmented expression and secretion of adipose-derived pigment epithelium-derived factor does not alter local angiogenesis or contribute to the development of systemic metabolic derangements. Am J Physiol Endocrinol Metab 306: E1367-E1377, 2014. First published April 23, 2014; doi:10.1152/ajpendo.00046.2014.-Impaired coupling of adipose tissue expansion and vascularization is proposed to lead to adipocyte hypoxia and inflammation, which in turn contributes to systemic metabolic derangements. Pigment epithelium-derived factor (PEDF) is a powerful antiangiogenic factor that is secreted by adipocytes, elevated in obesity, and implicated in the development of insulin resistance. We explored the angiogenic and metabolic role of adipose-derived PEDF through in vivo studies of mice with overexpression of PEDF in adipocytes (PEDF-aP2). PEDF expression in white adipocytes and PEDF secretion from adipose tissue was increased in transgenic mice, but circulating levels of PEDF were not increased. Overexpression of PEDF did not alter vascularization, the partial pressure of O 2, cellular hypoxia, or gene expression of inflammatory markers in adipose tissue. Energy expenditure and metabolic substrate utilization, body mass, and adiposity were not altered in PEDF-aP2 mice. Whole body glycemic control was normal as assessed by glucose and insulin tolerance tests, and adipocyte-specific glucose uptake was unaffected by PEDF overexpression. Adipocyte lipolysis was increased in PEDF-aP2 mice and associated with increased adipose triglyceride lipase and decreased perilipin 1 expression. Experiments conducted in mice rendered obese by high-fat feeding showed no differences between PEDF-aP2 and wild-type mice for body mass, adiposity, whole body energy expenditure, glucose tolerance, or adipose tissue oxygenation. Together, these data indicate that adipocyte-generated PEDF enhances lipolysis but question the role of PEDF as a major antiangiogenic or proinflammatory mediator in adipose tissue in vivo. pigment epithelium-derived factor; lipolysis; obesity; insulin sensitivity ADIPOCYTES SECRETE PROTEINS AND METABOLITES that play major roles in the regulation of metabolism, appetite, energy expenditure, and inflammation.

Cold Exposure Differentially Stimulates Angiogenesis in BAT and WAT of Mice: Implication in Adrenergic Activation

“…PAI1 and PEDF have been shown as the inhibitors of angiogenesis process [31, 32]. However, a recent report described an inexplicable finding that overexpression of PEDF did not alter angiogenesis in mice adipose tissue [33]. Moreover, PAI1 has been reported to both positively and negatively regulate angiogenesis depending on the dosages [34].…”

“…Further studies are needed to determine the concentration of PAI1 contributing to cold-induced sWAT angiogenesis. Moreover, Lakeland et al has reported that instead of altering angiogenesis, the predominant role of PEDF is to modulate lipolysis positively [33]. It is possible that the cold exposure and CL treatment in sWAT utilize this mechanism to provide a fuel substrate to meet the increased energy demands.…”

PEDF-induced alteration of metabolism leading to insulin resistance

“…Exogenous administration of recombinant PEDF to lean mice reduced insulin sensitivity during hyperinsulinemic-euglycemic clamp method which is the gold standard assessment of in vivo insulin sensitivity, whereas neutralisation of PEDF restored insulin sensitivity (Crowe et al, 2009). But on the other hand adipocyte generated PEDF enhanced lipolysis but did not contribute to the development of systemic metabolic derangements and improved metabolic derangements in obese type 2 diabetic rats (Lakeland et al, 2014;Matsui et al, 2014). The mechanism by which PEDF induces IR is not yet clear but acute administration of PEDF in rodents induces IR in vivo, and this onset of IR is accompanied by an increase in serum TNF and other cytokine levels.…”

“…Moreover, the presence of PEDF in adipocyteconditioned media caused IR in myotubes, and these effects were reverted upon addition of PEDF-neutralising antibody. PEDF gene expression and secretion increased during differentiation of human preadipocytes (Lakeland et al, 2014). PEDF exclusively targets the initial adipogenic events such as repression of adipogenic transcription factors PPARγ and C/EBP-alpha and ERK1/2 activation (Yamagishi et al, 2008).…”

Angiogenesis in diabetes and obesity

“…Adipocyte-specific PEDF transgenic mice (PEDF-aP2 mice) showed an increased adipocyte lipolysis compared with wild-type mice, confirming the effect of PEDF in regulating lipid metabolism. However, WAT-derived PEDF overexpression has no effect on the adipose vascularization, hypoxia and adipose inflammation in normal condition or after high-calorie diet [157]. There is no difference in glucose and insulin tolerance between PEDF-aP2 mice and control mice [157].…”