Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants

• Published in: The journals of gerontology. Series A, Biological sciences and medical sciences Biological sciences and medical sciences, 2012-12, Vol.67 (12), p.1321-1328
• Main Authors: Esterson, Yonah B, Kishore, Preeti, Koppaka, Sudha, Li, Weijie, Zhang, Kehao, Tonelli, Julia, Lee, Do-Eun, Kehlenbrink, Sylvia, Lawrence, Stephanie, Crandall, Jill, Barzilai, Nir, Hawkins, Meredith
• Format: Article
• Language: English
• Subjects: Adipose Tissue - metabolism; Adult; Aged; Aging; Aging - physiology; Diabetes; Fatty acids; Fatty Acids, Nonesterified - physiology; Female; Gerontology; Glucose Clamp Technique; Humans; Insulin; Insulin - blood; Insulin resistance; Insulin Resistance - physiology; Macrophage Activation - physiology; Macrophages - metabolism; Male; Middle Aged; Pathogenesis; Plasminogen Activator Inhibitor 1 - metabolism; Real-Time Polymerase Chain Reaction; Young Adult
• ISSN: 1079-5006; 1758-535X
• DOI: 10.1093/gerona/gls200

Human aging is associated with heightened risk of diabetes and cardiovascular disease. Increased fat mass may contribute to age-related diseases by harboring inflammatory macrophages that produce metabolically important proteins such as plasminogen activator inhibitor-1 (PAI-1). Elevated PAI-1 concentrations have been implicated in the pathogenesis of such aging-related conditions as insulin resistance, obesity, and atherosclerosis. We have previously reported that increased plasma free fatty acid (FFA) concentrations augment both circulating PAI-1 concentrations and PAI-1 production by adipose tissue macrophages (ATMs). Because increasing age is associated with increased infiltration and reactivity of adipose macrophages, we performed euglycemic-hyperinsulinemic clamp studies and adipose tissue biopsies with and without elevated FFA concentrations in 31 nondiabetic participants stratified by age, to determine whether middle-aged individuals manifest heightened insulin resistance and PAI-1 production by ATMs in response to elevated nutrient signals relative to their young adult peers. We observed that elevating FFA concentrations under euglycemic-hyperinsulinemic clamp conditions induced the same degree of insulin resistance in both middle-aged and younger body mass index-matched adults, whereas systemic PAI-1 concentrations were significantly increased in the middle-aged group. Likewise, elevated FFA and insulin concentrations induced larger increases in PAI-1 gene expression in the whole fat and ATMs of middle-aged compared with younger adult participants. These studies reveal a heightened adipose inflammatory response to increased FFA and insulin availability in middle-aged individuals relative to younger adults, suggesting that increased susceptibility to the effects of fatty acid excess may contribute to the pathogenesis of age-related diseases.