title: Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Belfer 709, Bronx, NY 10461, USA.
authors.forename: Yonah B
authors.initials: YB
authors.lastname: Esterson
authors.forename: Preeti
authors.initials: P
authors.lastname: Kishore
authors.forename: Sudha
authors.initials: S
authors.lastname: Koppaka
authors.forename: Weijie
authors.initials: W
authors.lastname: Li
authors.forename: Kehao
authors.initials: K
authors.lastname: Zhang
authors.forename: Julia
authors.initials: J
authors.lastname: Tonelli
authors.forename: Do-Eun
authors.initials: DE
authors.lastname: Lee
authors.forename: Sylvia
authors.initials: S
authors.lastname: Kehlenbrink
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lawrence
authors.forename: Jill
authors.initials: J
authors.lastname: Crandall
authors.forename: Nir
authors.initials: N
authors.lastname: Barzilai
authors.forename: Meredith
authors.initials: M
authors.lastname: Hawkins
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000375:Aging / Q000502:physiology*; D005230:Fatty Acids, Nonesterified / Q000502:physiology*; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology; D008262:Macrophage Activation / Q000502:physiology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D017395:Plasminogen Activator Inhibitor 1