Serum progranulin concentrations may be associated with macrophage infiltration into omental adipose tissue.
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.


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 chemotaxis is similar to that of monocyte chemoattractant protein-1 but independent of Galpha. Moreover, in type 2 diabetes, 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 that closely reflects omental adipose tissue macrophage infiltration. Physical training significantly reduces elevated circulating progranulin in patients with type 2 diabetes.
Youn
Byung-Soo
BS
AdipoGen, College of Life Science and Biotechnology, Korea University, Seoul, Korea. bsyoun@adipogen.com
Bang
Sa-Ik
SI
Klöting
Nora
N
Park
Ji Woo
JW
Lee
Namseok
N
Oh
Ji-Eun
JE
Pi
Kyung-Bae
KB
Lee
Tae Hee
TH
Ruschke
Karen
K
Fasshauer
Mathias
M
Stumvoll
Michael
M
Blüher
Matthias
M
D052242:Adiponectin / Q000097:blood; D000273:Adipose Tissue / Q000503:physiopathology*; D000328:Adult; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D018149:Glucose Intolerance / Q000097:blood* / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000235:genetics / Q000503:physiopathology; D009852:Omentum / Q000502:physiology*; D000077153:Progranulins; D012333:RNA, Messenger / Q000235:genetics; D012016:Reference Values
D052242:Adiponectin; D005230:Fatty Acids, Nonesterified; C492314:GRN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D008055:Lipids; D000077153:Progranulins; D012333:RNA, Messenger