Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Antonios Chatzigeorgioua; Tom Seijkens; Barbara Zarzycka; David Engel; Marjorie Poggi; Susan van den Berg; Sjoerd van den Berg; Oliver Soehnlein; Holger Winkels; Linda Beckers; Dirk Lievens; Ann Driessen; Pascal Kusters; Erik Biessen; Ruben Garcia-Martin; Anne Klotzsche-von Ameln; Marion Gijbels; Randolph Noelle; Louis Boon; Tilman Hackeng; Klaus Schulte; Aimin Xu; Gert Vriend; Sander Nabuurs; Kyoung-Jin Chung; Ko Willems van Dijk; Patrick C. N. Rensen; Norbert Gerdes; Menno de Winther; Norman L. Block; Andrew V. Schally; Christian Weber; Stefan R. Bornstein; Gerry Nicolaes; Triantafyllos Chavakis; Esther Lutgens

doi:10.1073/pnas.1400419111

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Antonios Chatzigeorgioua
, Tom Seijkens
, Barbara Zarzycka
, David Engel
, Marjorie Poggi
, Susan van den Berg
, Sjoerd van den Berg
, Oliver Soehnlein
, Holger Winkels
, Linda Beckers
, Dirk Lievens
, Ann Driessen
, Pascal Kusters
, Erik Biessen
, Ruben Garcia-Martin
, Anne Klotzsche-von Ameln
, Marion Gijbels
, Randolph Noelle
, Louis Boon
, Tilman Hackeng

Klaus Schulte, Aimin Xu, Gert Vriend, Sander Nabuurs, Kyoung-Jin Chung, Ko Willems van Dijk, Patrick C. N. Rensen, Norbert Gerdes, Menno de Winther, Norman L. Block, Andrew V. Schally^*, Christian Weber, Stefan R. Bornstein, Gerry Nicolaes, Triantafyllos Chavakis, Esther Lutgens

^*Corresponding author for this work

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

Abstract

The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8(+) T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII+ cells exhibited a similar phenotype in DIO as CD40(-/-) mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII+ cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII+ cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII+ cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.

Original language	English
Pages (from-to)	2686-2691
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	111
Issue number	7
DOIs	https://doi.org/10.1073/pnas.1400419111
Publication status	Published - 18 Feb 2014

Keywords

metabolism
type 2 diabetes
immunity

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10.1073/pnas.1400419111

https://europepmc.org/articles/pmc3932883?pdf=renderLicence: Other

1 Erratum / corrigendum

Correction for Chatzigeorgiou et al., Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance (vol 111, pg 2686, 2014)
Chatzigeorgiou, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., van den Berg, S., van den Berg, S., Soehnlein, O., Winkels, H., Beckers, L., Lievens, D., Driessen, A., Kusters, P., Biessen, E., Garcia-Martin, R., Klotzsche-von Ameln, A., Gijbels, M., Noelle, R., Boon, L. & Hackeng, T. & 16 others, Schulte, K.-M., Xu, A., Vriend, G., Nabuurs, S., Chung, K.-J., van Dijk, K. W., Rensen, P. C. N., Gerdes, N., de Winther, M., Block, N. L., Schally, A. V., Weber, C., Bornstein, S. R., Nicolaes, G., Chavakis, T. & Lutgens, E., 25 Mar 2014, In: Proceedings of the National Academy of Sciences of the United States of America. 111, 12, p. 4644-4644 1 p.
Research output: Contribution to journal › Erratum / corrigendum › Academic

Cite this

Chatzigeorgioua, A., Seijkens, T., Zarzycka, B., Engel, D., Poggi, M., van den Berg, S., van den Berg, S., Soehnlein, O., Winkels, H., Beckers, L., Lievens, D., Driessen, A., Kusters, P., Biessen, E., Garcia-Martin, R., Ameln, A. K., Gijbels, M., Noelle, R., Boon, L., ... Lutgens, E. (2014). Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. Proceedings of the National Academy of Sciences of the United States of America, 111(7), 2686-2691. https://doi.org/10.1073/pnas.1400419111

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title = "Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance",

abstract = "The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8(+) T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII+ cells exhibited a similar phenotype in DIO as CD40(-/-) mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII+ cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII+ cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII+ cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.",

keywords = "metabolism, type 2 diabetes, immunity",

author = "Antonios Chatzigeorgioua and Tom Seijkens and Barbara Zarzycka and David Engel and Marjorie Poggi and \{van den Berg\}, Susan and \{van den Berg\}, Sjoerd and Oliver Soehnlein and Holger Winkels and Linda Beckers and Dirk Lievens and Ann Driessen and Pascal Kusters and Erik Biessen and Ruben Garcia-Martin and Ameln, \{Anne Klotzsche-von\} and Marion Gijbels and Randolph Noelle and Louis Boon and Tilman Hackeng and Klaus Schulte and Aimin Xu and Gert Vriend and Sander Nabuurs and Kyoung-Jin Chung and \{van Dijk\}, \{Ko Willems\} and Rensen, \{Patrick C. N.\} and Norbert Gerdes and \{de Winther\}, Menno and Block, \{Norman L.\} and Schally, \{Andrew V.\} and Christian Weber and Bornstein, \{Stefan R.\} and Gerry Nicolaes and Triantafyllos Chavakis and Esther Lutgens",

year = "2014",

month = feb,

day = "18",

doi = "10.1073/pnas.1400419111",

language = "English",

volume = "111",

pages = "2686--2691",

journal = "Proceedings of the National Academy of Sciences of the United States of America",

issn = "0027-8424",

publisher = "National Academy of Sciences",

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}

Chatzigeorgioua, A, Seijkens, T, Zarzycka, B, Engel, D, Poggi, M, van den Berg, S, van den Berg, S, Soehnlein, O, Winkels, H, Beckers, L, Lievens, D, Driessen, A, Kusters, P, Biessen, E, Garcia-Martin, R, Ameln, AK, Gijbels, M, Noelle, R, Boon, L , Hackeng, T, Schulte, K, Xu, A, Vriend, G, Nabuurs, S, Chung, K-J, van Dijk, KW, Rensen, PCN, Gerdes, N, de Winther, M, Block, NL, Schally, AV, Weber, C, Bornstein, SR, Nicolaes, G, Chavakis, T & Lutgens, E 2014, 'Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 7, pp. 2686-2691. https://doi.org/10.1073/pnas.1400419111

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. / Chatzigeorgioua, Antonios; Seijkens, Tom; Zarzycka, Barbara et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 7, 18.02.2014, p. 2686-2691.

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

TY - JOUR

T1 - Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

AU - Chatzigeorgioua, Antonios

AU - Seijkens, Tom

AU - Zarzycka, Barbara

AU - Engel, David

AU - Poggi, Marjorie

AU - van den Berg, Susan

AU - van den Berg, Sjoerd

AU - Soehnlein, Oliver

AU - Winkels, Holger

AU - Beckers, Linda

AU - Lievens, Dirk

AU - Driessen, Ann

AU - Kusters, Pascal

AU - Biessen, Erik

AU - Garcia-Martin, Ruben

AU - Ameln, Anne Klotzsche-von

AU - Gijbels, Marion

AU - Noelle, Randolph

AU - Boon, Louis

AU - Hackeng, Tilman

AU - Schulte, Klaus

AU - Xu, Aimin

AU - Vriend, Gert

AU - Nabuurs, Sander

AU - Chung, Kyoung-Jin

AU - van Dijk, Ko Willems

AU - Rensen, Patrick C. N.

AU - Gerdes, Norbert

AU - de Winther, Menno

AU - Block, Norman L.

AU - Schally, Andrew V.

AU - Weber, Christian

AU - Bornstein, Stefan R.

AU - Nicolaes, Gerry

AU - Chavakis, Triantafyllos

AU - Lutgens, Esther

PY - 2014/2/18

Y1 - 2014/2/18

N2 - The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8(+) T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII+ cells exhibited a similar phenotype in DIO as CD40(-/-) mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII+ cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII+ cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII+ cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.

AB - The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8(+) T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII+ cells exhibited a similar phenotype in DIO as CD40(-/-) mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII+ cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40-TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII+ cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII+ cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance.

KW - metabolism

KW - type 2 diabetes

KW - immunity

U2 - 10.1073/pnas.1400419111

DO - 10.1073/pnas.1400419111

M3 - Article

C2 - 24492375

SN - 0027-8424

VL - 111

SP - 2686

EP - 2691

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 7

ER -

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

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Correction for Chatzigeorgiou et al., Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance (vol 111, pg 2686, 2014)

Cite this