Fatty Acid-Induced Production of Plasminogen Activator Inhibitor-1 by Adipose Macrophages Is Greater in Middle-Aged Versus Younger Adult Participants

Abstract

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.