title: Adipocyte-derived factors potentiate nutrient-induced production of plasminogen activator inhibitor-1 by macrophages.
abstract: Macrophages are more abundant in adipose tissue from obese individuals than from those of normal weight and may contribute to the metabolic consequences of obesity by producing various circulating factors. One of these factors is plasminogen activator inhibitor-1 (PAI-1), which contributes to both atherosclerosis and insulin resistance. Because nutritional factors appear to regulate PAI-1 expression, we hypothesized that exposure to fatty acids and adipocyte secretory products could stimulate production of PAI-1 by adipose macrophages. Increased free fatty acid (FFA) concentrations in blood for 5 hours in nondiabetic, overweight subjects markedly suppressed insulin-stimulated glucose uptake and raised circulating PAI-1 concentrations, with a concomitant increase in the expression of the PAI-1 gene in adipose tissue. FFAs also rapidly increased PAI-1 gene expression in adipose macrophages and PAI-1 protein immunofluorescence surrounding these cells. By contrast, PAI-1 expression in circulating monocytes was very low and was not affected by raising the concentration of FFAs. Medium from cultured adipocytes stimulated PAI-1 expression in cultured macrophages and potentiated the increase in PAI-1 messenger RNA expression in response to FFAs. Together, our data suggest that adipocyte-derived factors prime adipose macrophages so that they respond to nutritional signals (FFAs) by releasing a key inflammatory adipokine, PAI-1.
authors.affiliation: Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA. preeti.kishore@einstein.yu.edu
authors.forename: Preeti
authors.initials: P
authors.lastname: Kishore
authors.forename: Weijie
authors.initials: W
authors.lastname: Li
authors.forename: Julia
authors.initials: J
authors.lastname: Tonelli
authors.forename: Do-Eun
authors.initials: DE
authors.lastname: Lee
authors.forename: Sudha
authors.initials: S
authors.lastname: Koppaka
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhang
authors.forename: Ying
authors.initials: Y
authors.lastname: Lin
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kehlenbrink
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Meredith
authors.initials: M
authors.lastname: Hawkins
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism*; D054392:Adipokines / Q000097:blood / Q000276:immunology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002096:C-Peptide / Q000097:blood; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology / Q000503:physiopathology; D005230:Fatty Acids, Nonesterified / Q000097:blood*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D009765:Obesity / Q000276:immunology / Q000503:physiopathology*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*
chemical_list: D054392:Adipokines; D001786:Blood Glucose; D002096:C-Peptide; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1