Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue

Serum Progranulin Concentrations May Be Associated With Macrophage Infiltration Into Omental Adipose Tissue Byung-Soo Youn 1 , Sa-Ik Bang 2 , Nora Klöting 3 , Ji Woo Park 1 , Namseok Lee 1 , Ji-Eun Oh 1 , Kyung-Bae Pi 1 , Tae Hee Lee 4 , Karen Ruschke 3 , Mathias Fasshauer 3 , Michael Stumvoll 3 and Matthias Blüher 3 1 AdipoGen, College of Life Science and Biotechnology, Korea University, Seoul, Korea 2 Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Department of Medicine, University of Leipzig, Leipzig, Germany 4 Formulae Pharmacology Department, Oriental Medical School, Kyungwon University, Seong Nam City, Kyunggi-Do, Korea Corresponding authors: Matthias Blüher, bluma{at}medizin.uni-leipzig.de , and Byung-Soo Youn, bsyoun{at}adipogen.com Abstract OBJECTIVE— Progranulin is an important molecule in inflammatory response. Chronic inflammation is frequently associated with central obesity and associated disturbances; however, the role of circulating progranulin in human obesity, type 2 diabetes, and dyslipidemia is unknown. RESEARCH DESIGN AND METHODS— For the measurement of progranulin serum concentrations, we developed an enzyme-linked immunosorbent assay (ELISA). Using this ELISA, we assessed circulating progranulin in a cross-sectional study of 209 subjects with a wide range of obesity, body fat distribution, insulin sensitivity, and glucose tolerance and in 60 individuals with normal (NGT) or impaired (IGT) glucose tolerance or type 2 diabetes before and after a 4-week physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and cells of the stromal vascular fraction) from 55 lean or obese individuals. Measurement of Erk activation and chemotactic activity induced by progranulin in vitro was performed using THP-1–based cell migration assays. RESULTS— Progranulin serum concentrations were significantly higher in individuals with type 2 diabetes compared with NGT and in obese subjects with predominant visceral fat accumulation. Circulating progranulin significantly correlates with BMI, macrophage infiltration in omental adipose tissue, C-reactive protein (CRP) serum concentrations, A1C values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as the strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxi