Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue

David A Hill; Hee-Woong Lim; Yong Hoon Kim; Wesley Y Ho; Yee Hoon Foong; Victoria L Nelson; Hoang C B Nguyen; Kavya Chegireddy; Jihoon Kim; Andreas Habertheuer; Prashanth Vallabhajosyula; Taku Kambayashi; Kyoung-Jae Won; Mitchell A Lazar

doi:10.1073/pnas.1802611115

Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue

David A Hill, Hee-Woong Lim, Yong Hoon Kim, Wesley Y Ho, Yee Hoon Foong, Victoria L Nelson, Hoang C B Nguyen, Kavya Chegireddy, Jihoon Kim, Andreas Habertheuer, Prashanth Vallabhajosyula, Taku Kambayashi, Kyoung-Jae Won, Mitchell A Lazar

83 Citations (Scopus)

Abstract

Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela.

Original language	English
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	115
Issue number	22
Pages (from-to)	E5096-E5105
ISSN	0027-8424
DOIs	https://doi.org/10.1073/pnas.1802611115
Publication status	Published - 29 May 2018
Externally published	Yes

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Hill, D. A., Lim, H-W., Kim, Y. H., Ho, W. Y., Foong, Y. H., Nelson, V. L., Nguyen, H. C. B., Chegireddy, K., Kim, J., Habertheuer, A., Vallabhajosyula, P., Kambayashi, T., Won, K-J., & Lazar, M. A. (2018). Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proceedings of the National Academy of Sciences of the United States of America, 115(22), E5096-E5105. https://doi.org/10.1073/pnas.1802611115

Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. / Hill, David A; Lim, Hee-Woong; Kim, Yong Hoon et al.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 22, 29.05.2018, p. E5096-E5105.

Research output: Contribution to journal › Journal article › Research › peer-review

Hill, DA, Lim, H-W, Kim, YH, Ho, WY, Foong, YH, Nelson, VL, Nguyen, HCB, Chegireddy, K, Kim, J, Habertheuer, A, Vallabhajosyula, P, Kambayashi, T, Won, K-J & Lazar, MA 2018, 'Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 22, pp. E5096-E5105. https://doi.org/10.1073/pnas.1802611115

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AU - Nelson, Victoria L

AU - Nguyen, Hoang C B

AU - Chegireddy, Kavya

AU - Kim, Jihoon

AU - Habertheuer, Andreas

AU - Vallabhajosyula, Prashanth

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AU - Won, Kyoung-Jae

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AB - Obesity is characterized by an accumulation of macrophages in adipose, some of which form distinct crown-like structures (CLS) around fat cells. While multiple discrete adipose tissue macrophage (ATM) subsets are thought to exist, their respective effects on adipose tissue, and the transcriptional mechanisms that underlie the functional differences between ATM subsets, are not well understood. We report that obese fat tissue of mice and humans contain multiple distinct populations of ATMs with unique tissue distributions, transcriptomes, chromatin landscapes, and functions. Mouse Ly6c ATMs reside outside of CLS and are adipogenic, while CD9 ATMs reside within CLS, are lipid-laden, and are proinflammatory. Adoptive transfer of Ly6c ATMs into lean mice activates gene programs typical of normal adipocyte physiology. By contrast, adoptive transfer of CD9 ATMs drives gene expression that is characteristic of obesity. Importantly, human adipose tissue contains similar ATM populations, including lipid-laden CD9 ATMs that increase with body mass. These results provide a higher resolution of the cellular and functional heterogeneity within ATMs and provide a framework within which to develop new immune-directed therapies for the treatment of obesity and related sequela.

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Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue

Abstract

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