Abstract
ObjectivePigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans.Subjects/MethodsA population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ≥0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS).ResultsAfter adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p = 0.0094) and fasting leptin concentrations (p = 0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p = 0.0182) and clamp-derived insulin sensitivity (p = 0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p = 0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p = 0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all).ConclusionIn humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.
Highlights
Pigment epithelium-derived factor (MIM ID *172860), referred to as serpin F1, belongs to the serpin family of peptidase inhibitors
In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding Pigment epithelium-derived factor (PEDF) contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels
Identified as a product of cultured human retinal pigment epithelium cells, PEDF is thought to play a central role in the development of the neural retina [3]
Summary
Pigment epithelium-derived factor (MIM ID *172860), referred to as serpin F1 (human gene symbol: SERPINF1), belongs to the serpin family of peptidase inhibitors. Even though this serpin is unique in that its C-reactive loop is inactive and noninhibitory [1], PEDF was reported to exert multiple effects in vitro and in mice in vivo including promotion of neuronal survival and differentiation and potent inhibition of angiogenesis [2]. Studies on the secretome of human adipocytes using twodimensional polyacrylamide gel electrophoresis of conditioned media followed by mass spectrometric analysis confirmed PEDF as one of the most abundant adipokines [5]. Caloric restriction of diet-induced obese mice resulted in a marked reduction in adipose tissue PEDF expression [4]
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