TY - JOUR
T1 - Inflammatory pathways regulated by tumor necrosis receptor-associated factor 1 protect from metabolic consequences in diet-induced obesity short communication
AU - Michel, Nathaly Anto
AU - Colberg, Christian
AU - Buscher, Konrad
AU - Sommer, Björn
AU - Pramod, Akula Bala
AU - Ehinger, Erik
AU - Dufner, Bianca
AU - Hoppe, Natalie
AU - Pfeiffer, Katharina
AU - Marchini, Timoteo
AU - Willecke, Florian
AU - Stachon, Peter
AU - Hilgendorf, Ingo
AU - Heidt, Timo
AU - Von Zur Muhlen, Constantin
AU - Von Elverfeldt, Dominik
AU - Pfeifer, Dietmar
AU - Schüle, Roland
AU - Kintscher, Ulrich
AU - Brachs, Sebastian
AU - Ley, Klaus
AU - Bode, Christoph
AU - Zirlik, Andreas
AU - Wolf, Dennis
N1 - Funding Information:
This study was supported by the Fritz-Thyssen-Foundation to A. Zirlik and by the German Research Foundation to D. Wolf (WO1994/1-1).
Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2018/3
Y1 - 2018/3
N2 - Rationale: The coincidence of inflammation and metabolic derangements in obese adipose tissue has sparked the concept of met-inflammation. Previous observations, however, suggest that inflammatory pathways may not ultimately cause dysmetabolism. Objective: We have revisited the relationship between inflammation and metabolism by testing the role of TRAF (tumor necrosis receptor-associated factor)-1, an inhibitory adapter of inflammatory signaling of TNF (tumor necrosis factor)-a, IL (interleukin)-1ß, and TLRs (toll-like receptors). Methods and Results: Mice defcient for TRAF-1, which is expressed in obese adipocytes and adipose tissue lymphocytes, caused an expected hyperinflammatory phenotype in adipose tissue with enhanced adipokine and chemokine expression, increased leukocyte accumulation, and potentiated proinflammatory signaling in macrophages and adipocytes in a mouse model of diet-induced obesity. Unexpectedly, TRAF-1-/-mice were protected from metabolic derangements and adipocyte growth, failed to gain weight, and showed improved insulin resistance-an effect caused by increased lipid breakdown in adipocytes and UCP (uncoupling protein)-1-enabled thermogenesis. TRAF-1-dependent catabolic and proinflammatory cues were synergistically driven by ß3-adrenergic and inflammatory signaling and required the presence of both TRAF-1-defcient adipocytes and macrophages. In human obesity, TRAF-1-dependent genes were upregulated. Conclusions: Enhancing TRAF-1-dependent inflammatory pathways in a gain-of-function approach protected from metabolic derangements in diet-induced obesity. These fndings identify TRAF-1 as a regulator of dysmetabolism in mice and humans and question the pathogenic role of chronic inflammation in metabolism.
AB - Rationale: The coincidence of inflammation and metabolic derangements in obese adipose tissue has sparked the concept of met-inflammation. Previous observations, however, suggest that inflammatory pathways may not ultimately cause dysmetabolism. Objective: We have revisited the relationship between inflammation and metabolism by testing the role of TRAF (tumor necrosis receptor-associated factor)-1, an inhibitory adapter of inflammatory signaling of TNF (tumor necrosis factor)-a, IL (interleukin)-1ß, and TLRs (toll-like receptors). Methods and Results: Mice defcient for TRAF-1, which is expressed in obese adipocytes and adipose tissue lymphocytes, caused an expected hyperinflammatory phenotype in adipose tissue with enhanced adipokine and chemokine expression, increased leukocyte accumulation, and potentiated proinflammatory signaling in macrophages and adipocytes in a mouse model of diet-induced obesity. Unexpectedly, TRAF-1-/-mice were protected from metabolic derangements and adipocyte growth, failed to gain weight, and showed improved insulin resistance-an effect caused by increased lipid breakdown in adipocytes and UCP (uncoupling protein)-1-enabled thermogenesis. TRAF-1-dependent catabolic and proinflammatory cues were synergistically driven by ß3-adrenergic and inflammatory signaling and required the presence of both TRAF-1-defcient adipocytes and macrophages. In human obesity, TRAF-1-dependent genes were upregulated. Conclusions: Enhancing TRAF-1-dependent inflammatory pathways in a gain-of-function approach protected from metabolic derangements in diet-induced obesity. These fndings identify TRAF-1 as a regulator of dysmetabolism in mice and humans and question the pathogenic role of chronic inflammation in metabolism.
KW - Adipocytes
KW - Lipolysis
KW - Metabolic syndrome
KW - Mice
KW - Obesity
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U2 - 10.1161/CIRCRESAHA.117.312055
DO - 10.1161/CIRCRESAHA.117.312055
M3 - Article
C2 - 29358227
AN - SCOPUS:85047770748
SN - 0009-7330
VL - 122
SP - 693
EP - 700
JO - Circulation Research
JF - Circulation Research
IS - 5
ER -