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

• Applicant: Professor Dr. Andreas L. Birkenfeld
• Subject Area: Pediatric and Adolescent Medicine ; Endocrinology, Diabetology, Metabolism
• Term: from 2012 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 101434729

• Final Report Year: 2019

Final Report Abstract

Kallistatin (KST), also known as SERPIN A4, is a circulating, broadly acting human plasma protein with anti-angiogenic and anti-inflammatory properties. Clinical studies in humans revealed increased levels of KST in poor glycemic control and microvessel disease. Whether or not KST has a direct effect on glucose homeostasis in the setting of insulin resistance and T2D is currently unknown. To address this question, transgenic mice overexpressing human KST systemically (hKST-TG) and littermate-control wildtype mice (WT) were studied under chow (ND) and high fat diet (HFD) conditions. Body weights were similar between hKST-TG and WT mice up to an age of 24 weeks on both diets. Intraperitoneal glucose tolerance tests (IPGTT) yielded similar glucose and insulin excursion curves in ND animals. In the weight matched HFD cohort, an IPGTT revealed an improvement in glucose tolerance in hKST-TG mice. Additionally, the HOMA-IR was significantly lower in hKST-TG on HFD (2.2±0.27, hKST-TG vs. 4.42±0.87, WT, p<0.05), indicating improved insulin sensitivity in hKST-TG mice. To better understand the tissue specific contribution to the protective effect of hKST, hyperinsulinemic euglycemic clamp studies with tracer labelled glucose were performed. Glucose infusion rates were higher in hKST-TG mice (31.5±3.7 mg/kg/min, hKST-TG vs. 18.1±3.5 mg/kg/min, WT, p<0.05), validating the insulin sensitizing effect of hKST in HFD fed mice. Specifically, hKST overexpression protected against HFD induced hepatic insulin resistance (clamp hepatic glucose output: 7.7±1.9 mg/kg/min, hKST-TG vs 12.1±0.8 mg/kg/min, WT, p=0.05). Insulin sensitization was associated with reduced ratio of beta-catenin/ active beta-catenin, known mediators of hepatic insulin sensitivity. These data show that human KST protects against diet induced hepatic insulin resistance in mice. We speculate that increased KST levels in the setting of poor glycemic control and microvascular complications are a protective mechanism.

Publications

• Insulin resistance is associated with elevated serum pigment epithelium-derived factor (PEDF) levels in morbidly obese patients. Acta Diabetol. 2012; 49:161-9
  Gattu AK, Birkenfeld AL, Jornayvaz F, Dziura J, Li F, Crawford SE, Chu X, Still CD, Gerhard GS, Chung C, Samuel V
  
• Pigment Epithelium-Derived Factor suppresses IL-1β-mediated c-Jun N-terminal Kinase activation to improve hepatocyte insulin signaling. Endocrinology 2014, 155:1373-85
  Gattu A, Birkenfeld AL, Iwakiri Y, Jay MS, Saltzman M, Doll J, Protiva P, Samuel VT, Crawford S, Chung C
  
• Human Kallistatin Improves Diet-induced Insulin Resistance in Mice. Diabetes 2016; 65, Supplement1, A469 ADA abstract
  Reinke J, Brachs S, Willmes DM, Tio J, Spranger J, McBride J, Ma JX, Bornstein SR, Shulman GI, Birkenfeld AL