Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance

Michael J. Kraakman, Helene L. Kammoun, Tamara L Allen, Virginie Deswaerte, Darren C. Henstridge, Emma Estevez, Vance B Matthews, Bronwyn A Neill, David A. White, Andrew J. Murphy, Lone Peijs, Christine Yang, Steve Risis, Clinton R. Bruce, Xiao-Jun Du, Alex Bobik, Robert S. Lee-Young, Bronwyn A. Kingwell, Ajithkumar Vasanthakumar, Wei Shi & 4 others Axel Kallies, Graeme I. Lancaster, Stefan Rose-John, Mark A. Febbraio

Research output: Contribution to journalArticleResearchpeer-review

92 Citations (Scopus)

Abstract

Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.

Original languageEnglish
Pages (from-to)403-416
Number of pages14
JournalCell Metabolism
Volume21
Issue number3
DOIs
Publication statusPublished - 3 Mar 2015
Externally publishedYes

Cite this

Kraakman, Michael J. ; Kammoun, Helene L. ; Allen, Tamara L ; Deswaerte, Virginie ; Henstridge, Darren C. ; Estevez, Emma ; Matthews, Vance B ; Neill, Bronwyn A ; White, David A. ; Murphy, Andrew J. ; Peijs, Lone ; Yang, Christine ; Risis, Steve ; Bruce, Clinton R. ; Du, Xiao-Jun ; Bobik, Alex ; Lee-Young, Robert S. ; Kingwell, Bronwyn A. ; Vasanthakumar, Ajithkumar ; Shi, Wei ; Kallies, Axel ; Lancaster, Graeme I. ; Rose-John, Stefan ; Febbraio, Mark A. / Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. In: Cell Metabolism. 2015 ; Vol. 21, No. 3. pp. 403-416.
@article{364fbdab05824d80b212954ca5a4e1eb,
title = "Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance",
abstract = "Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 {"}trans-signaling,{"} a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.",
author = "Kraakman, {Michael J.} and Kammoun, {Helene L.} and Allen, {Tamara L} and Virginie Deswaerte and Henstridge, {Darren C.} and Emma Estevez and Matthews, {Vance B} and Neill, {Bronwyn A} and White, {David A.} and Murphy, {Andrew J.} and Lone Peijs and Christine Yang and Steve Risis and Bruce, {Clinton R.} and Xiao-Jun Du and Alex Bobik and Lee-Young, {Robert S.} and Kingwell, {Bronwyn A.} and Ajithkumar Vasanthakumar and Wei Shi and Axel Kallies and Lancaster, {Graeme I.} and Stefan Rose-John and Febbraio, {Mark A.}",
year = "2015",
month = "3",
day = "3",
doi = "10.1016/j.cmet.2015.02.006",
language = "English",
volume = "21",
pages = "403--416",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Elsevier",
number = "3",

}

Kraakman, MJ, Kammoun, HL, Allen, TL, Deswaerte, V, Henstridge, DC, Estevez, E, Matthews, VB, Neill, BA, White, DA, Murphy, AJ, Peijs, L, Yang, C, Risis, S, Bruce, CR, Du, X-J, Bobik, A, Lee-Young, RS, Kingwell, BA, Vasanthakumar, A, Shi, W, Kallies, A, Lancaster, GI, Rose-John, S & Febbraio, MA 2015, 'Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance', Cell Metabolism, vol. 21, no. 3, pp. 403-416. https://doi.org/10.1016/j.cmet.2015.02.006

Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. / Kraakman, Michael J.; Kammoun, Helene L.; Allen, Tamara L; Deswaerte, Virginie; Henstridge, Darren C.; Estevez, Emma; Matthews, Vance B; Neill, Bronwyn A; White, David A.; Murphy, Andrew J.; Peijs, Lone; Yang, Christine; Risis, Steve; Bruce, Clinton R.; Du, Xiao-Jun; Bobik, Alex; Lee-Young, Robert S.; Kingwell, Bronwyn A.; Vasanthakumar, Ajithkumar; Shi, Wei; Kallies, Axel; Lancaster, Graeme I.; Rose-John, Stefan; Febbraio, Mark A.

In: Cell Metabolism, Vol. 21, No. 3, 03.03.2015, p. 403-416.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance

AU - Kraakman, Michael J.

AU - Kammoun, Helene L.

AU - Allen, Tamara L

AU - Deswaerte, Virginie

AU - Henstridge, Darren C.

AU - Estevez, Emma

AU - Matthews, Vance B

AU - Neill, Bronwyn A

AU - White, David A.

AU - Murphy, Andrew J.

AU - Peijs, Lone

AU - Yang, Christine

AU - Risis, Steve

AU - Bruce, Clinton R.

AU - Du, Xiao-Jun

AU - Bobik, Alex

AU - Lee-Young, Robert S.

AU - Kingwell, Bronwyn A.

AU - Vasanthakumar, Ajithkumar

AU - Shi, Wei

AU - Kallies, Axel

AU - Lancaster, Graeme I.

AU - Rose-John, Stefan

AU - Febbraio, Mark A.

PY - 2015/3/3

Y1 - 2015/3/3

N2 - Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.

AB - Interleukin-6 (IL-6) plays a paradoxical role in inflammation and metabolism. The pro-inflammatory effects of IL-6 are mediated via IL-6 "trans-signaling," a process where the soluble form of the IL-6 receptor (sIL-6R) binds IL-6 and activates signaling in inflammatory cells that express the gp130 but not the IL-6 receptor. Here we show that trans-signaling recruits macrophages into adipose tissue (ATM). Moreover, blocking trans-signaling with soluble gp130Fc protein prevents high-fat diet (HFD)-induced ATM accumulation, but does not improve insulin action. Importantly, however, blockade of IL-6 trans-signaling, unlike complete ablation of IL-6 signaling, does not exacerbate obesity-induced weight gain, liver steatosis, or insulin resistance. Our data identify the sIL-6R as a critical chemotactic signal for ATM recruitment and suggest that selectively blocking IL-6 trans-signaling may be a more favorable treatment option for inflammatory diseases, compared with current treatments that completely block the action of IL-6 and negatively impact upon metabolic homeostasis.

UR - http://www.scopus.com/inward/record.url?scp=84924415012&partnerID=8YFLogxK

U2 - 10.1016/j.cmet.2015.02.006

DO - 10.1016/j.cmet.2015.02.006

M3 - Article

VL - 21

SP - 403

EP - 416

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

IS - 3

ER -