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

M.J. Kraakman, H.L. Kammoun, T.L. Allen, V. Deswaerte, D.C. Henstridge, E. Estevez, Vance Matthews, B. Neill, D.A. White, A.J. Murphy, L. Peijs, C. Yang, S. Risis, C.R. Bruce, X.J. Du, A. Bobik, R.S. Lee-Young, B.A. Kingwell, A. Vasanthakumar, W. Shi & 4 others A. Kallies, G.I. Lancaster, S. Rose-John, M.A. Febbraio

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Abstract

© 2015 Elsevier Inc. 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
JournalCell Metabolism
Volume21
Issue number3
DOIs
Publication statusPublished - 2015

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High Fat Diet
Insulin Resistance
Adipose Tissue
Interleukin-6
Macrophages
Interleukin-6 Receptors
Fatty Liver
Weight Gain
Homeostasis
Obesity
Insulin
Inflammation

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Kraakman, M. J., Kammoun, H. L., Allen, T. L., Deswaerte, V., Henstridge, D. C., Estevez, E., ... Febbraio, M. A. (2015). Blocking IL-6 trans-signaling prevents high-fat diet-induced adipose tissue macrophage recruitment but does not improve insulin resistance. Cell Metabolism, 21(3), 403-416. https://doi.org/10.1016/j.cmet.2015.02.006
Kraakman, M.J. ; Kammoun, H.L. ; Allen, T.L. ; Deswaerte, V. ; Henstridge, D.C. ; Estevez, E. ; Matthews, Vance ; Neill, B. ; White, D.A. ; Murphy, A.J. ; Peijs, L. ; Yang, C. ; Risis, S. ; Bruce, C.R. ; Du, X.J. ; Bobik, A. ; Lee-Young, R.S. ; Kingwell, B.A. ; Vasanthakumar, A. ; Shi, W. ; Kallies, A. ; Lancaster, G.I. ; Rose-John, S. ; Febbraio, M.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.
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Kraakman, MJ, Kammoun, HL, Allen, TL, Deswaerte, V, Henstridge, DC, Estevez, E, Matthews, V, Neill, B, White, DA, Murphy, AJ, Peijs, L, Yang, C, Risis, S, Bruce, CR, Du, XJ, 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, M.J.; Kammoun, H.L.; Allen, T.L.; Deswaerte, V.; Henstridge, D.C.; Estevez, E.; Matthews, Vance; Neill, B.; White, D.A.; Murphy, A.J.; Peijs, L.; Yang, C.; Risis, S.; Bruce, C.R.; Du, X.J.; Bobik, A.; Lee-Young, R.S.; Kingwell, B.A.; Vasanthakumar, A.; Shi, W.; Kallies, A.; Lancaster, G.I.; Rose-John, S.; Febbraio, M.A.

In: Cell Metabolism, Vol. 21, No. 3, 2015, p. 403-416.

Research output: Contribution to journalArticle

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, M.J.

AU - Kammoun, H.L.

AU - Allen, T.L.

AU - Deswaerte, V.

AU - Henstridge, D.C.

AU - Estevez, E.

AU - Matthews, Vance

AU - Neill, B.

AU - White, D.A.

AU - Murphy, A.J.

AU - Peijs, L.

AU - Yang, C.

AU - Risis, S.

AU - Bruce, C.R.

AU - Du, X.J.

AU - Bobik, A.

AU - Lee-Young, R.S.

AU - Kingwell, B.A.

AU - Vasanthakumar, A.

AU - Shi, W.

AU - Kallies, A.

AU - Lancaster, G.I.

AU - Rose-John, S.

AU - Febbraio, M.A.

PY - 2015

Y1 - 2015

N2 - © 2015 Elsevier Inc. 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 - © 2015 Elsevier Inc. 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.

U2 - 10.1016/j.cmet.2015.02.006

DO - 10.1016/j.cmet.2015.02.006

M3 - Article

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EP - 416

JO - Cell Metabolism

JF - Cell Metabolism

SN - 1550-4131

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ER -