Role of pigment epithelium derived factor (PEDF) in the regulation of body weight

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Peripheral molecular signals of body weight and fat mass are key mechanisms for body weight maintenance. Besides leptin a couple of new proteins have been described including Pigment epithelium derived factor (PEDF), which is a secreted pleiotropic glycoprotein with neuroprotective, anti-angiogenic and anti-cancerogenic properties. The protein is predominantly synthesized in adipose tissue and the liver, and its transcription and secretion seems to be regulated by the nutritional state via insulin and glucose. Systemic PEDF levels positively correlate with fat mass, the degree of obesity, and insulin resistance in animal models and humans. We therefore hypothesize that PEDF itself is an important regulator of body weight, lipid and glucose metabolism. In support of this hypothesis, our preliminary data show that loss of PEDF in PEDF- knock out (KO) mice leads to an increase in whole body fat mass and body weight and reduced energy expenditure. Moreover, 8 months old PEDF-KO mice were severely insulin resistant compared to control mice, as assessed with an IPGTT. This proposal is aimed at determining the mechanisms through which PEDF mediates its effects on energy partitioning and energy homeostasis. We will also investigate whether chronic over-expression of PEDF in lean and obese mice mirrors the effects of PEDF deficiency in mice. Finally, in a translational approach, we will test if changes in PEDF concentrations in obese humans after weight loss are predictive of successful body weight maintenance over time. Our findings might identify new PEDF based concepts in the regulation of energy metabolism and pinpoint novel pharmacological approaches for the treatment of obesity and insulin resistance.