Serum Progranulin Concentrations May be Associated with Macrophage Infiltration into Omental Adipose Tissue

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 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 (T2D) before and after a 4 weeks physical training program. Progranulin mRNA and protein expression was measured in paired samples of omental and subcutaneous adipose tissue (adipocytes and 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 T2D compared to NGT as well as 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, HbA_1c values, and total cholesterol. Multivariable linear regression analyses revealed CRP levels as strongest independent predictor of circulating progranulin. The extent of in vitro progranulin-mediated chemotaxis is similar to that of MCP-1, but independent of Gα. Moreover, in T2D, but not in IGT and NGT individuals, physical training for 4 weeks resulted in significantly decreased circulating progranulin levels.

Conclusions: Elevated progranulin serum concentrations are associated with visceral obesity, elevated plasma glucose, and dyslipidemia. We identified progranulin as a novel marker of chronic inflammation in obesity and type 2 diabetes which closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes.