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

Yonah B. Esterson; Preeti Kishore; Sudha Koppaka; Weijie Li; Kehao Zhang; Julia Tonelli; Do Eun Lee; Sylvia Kehlenbrink; Stephanie Lawrence; Jill Crandall; Nir Barzilai; Meredith Hawkins

doi:10.1093/gerona/gls200

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

Yonah B. Esterson, Preeti Kishore, Sudha Koppaka, Weijie Li, Kehao Zhang, Julia Tonelli, Do Eun Lee, Sylvia Kehlenbrink, Stephanie Lawrence, Jill Crandall, Nir Barzilai, Meredith Hawkins

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1321-1328
Number of pages	8
Journal	Journals of Gerontology - Series A Biological Sciences and Medical Sciences
Volume	67
Issue number	12
DOIs	https://doi.org/10.1093/gerona/gls200
State	Published - Dec 2012
Externally published	Yes

Keywords

Free fatty acids
Insulin resistance
Plasminogen activator inhibitor-1

ASJC Scopus subject areas

Aging
Geriatrics and Gerontology

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10.1093/gerona/gls200

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Esterson, Y. B., Kishore, P., Koppaka, S., Li, W., Zhang, K., Tonelli, J., Lee, D. E., Kehlenbrink, S., Lawrence, S., Crandall, J., Barzilai, N., & Hawkins, M. (2012). Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants. Journals of Gerontology - Series A Biological Sciences and Medical Sciences, 67(12), 1321-1328. https://doi.org/10.1093/gerona/gls200

Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants. / Esterson, Yonah B.; Kishore, Preeti; Koppaka, Sudha et al.
In: Journals of Gerontology - Series A Biological Sciences and Medical Sciences, Vol. 67, No. 12, 12.2012, p. 1321-1328.

Research output: Contribution to journal › Article › peer-review

Esterson, YB, Kishore, P, Koppaka, S, Li, W, Zhang, K, Tonelli, J, Lee, DE, Kehlenbrink, S, Lawrence, S, Crandall, J, Barzilai, N & Hawkins, M 2012, 'Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants', Journals of Gerontology - Series A Biological Sciences and Medical Sciences, vol. 67, no. 12, pp. 1321-1328. https://doi.org/10.1093/gerona/gls200

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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.",

keywords = "Free fatty acids, Insulin resistance, Plasminogen activator inhibitor-1",

author = "Esterson, {Yonah B.} and Preeti Kishore and Sudha Koppaka and Weijie Li and Kehao Zhang and Julia Tonelli and Lee, {Do Eun} and Sylvia Kehlenbrink and Stephanie Lawrence and Jill Crandall and Nir Barzilai and Meredith Hawkins",

note = "Funding Information: Funding This work was supported in part the National Institutes of Health (NIH) DK048321, DK069861, AG-18728-01A1, AG024391, AG7992, K23 RR023335, DRTC RIA Core P60-DK20541, P01-AG021654, PO1 AG027734, the Einstein Nathan Shock Center of Excellence in Biology of Aging (P30), and by the CTSA Grants UL1RR025750, KL2RR025749, and TL1RR025748 from the National Center for Research Resources and NIH roadmap for Medical Research. Contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. Dr. Hawkins is a Beeson Scholar of the American Federation of Aging Research.",

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doi = "10.1093/gerona/gls200",

language = "English (US)",

volume = "67",

pages = "1321--1328",

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number = "12",

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T1 - Fatty acid-induced production of plasminogen activator inhibitor-1 by adipose macrophages is greater in middle-aged versus younger adult participants

AU - Esterson, Yonah B.

AU - Kishore, Preeti

AU - Koppaka, Sudha

AU - Li, Weijie

AU - Zhang, Kehao

AU - Tonelli, Julia

AU - Lee, Do Eun

AU - Kehlenbrink, Sylvia

AU - Lawrence, Stephanie

AU - Crandall, Jill

AU - Barzilai, Nir

AU - Hawkins, Meredith

N1 - Funding Information: Funding This work was supported in part the National Institutes of Health (NIH) DK048321, DK069861, AG-18728-01A1, AG024391, AG7992, K23 RR023335, DRTC RIA Core P60-DK20541, P01-AG021654, PO1 AG027734, the Einstein Nathan Shock Center of Excellence in Biology of Aging (P30), and by the CTSA Grants UL1RR025750, KL2RR025749, and TL1RR025748 from the National Center for Research Resources and NIH roadmap for Medical Research. Contents are solely the responsibility of the authors and do not necessarily represent the official view of the NIH. Dr. Hawkins is a Beeson Scholar of the American Federation of Aging Research.

PY - 2012/12

Y1 - 2012/12

N2 - 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.

AB - 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.

KW - Free fatty acids

KW - Insulin resistance

KW - Plasminogen activator inhibitor-1

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

Abstract

Keywords

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