Control of adipose tissue inflammation through TRB1.
OBJECTIVE
Based on its role as an energy storage compartment and endocrine organ, white adipose tissue (WAT) fulfills a critical function in the maintenance of whole-body energy homeostasis. Indeed, WAT dysfunction is connected to obesity-related type 2 diabetes triggered at least partly by an inflammatory response in adipocytes. The pseudokinase tribbles (TRB) 3 has been identified by us and others as a critical regulator of hepatic glucose homeostasis in type 2 diabetes and WAT lipid homeostasis. Therefore, this study aimed to test the hypothesis that the TRB gene family fulfills broader functions in the integration of metabolic and inflammatory pathways in various tissues.


METHODS
To determine the role of TRB family members for WAT function, we profiled the expression patterns of TRB13 under healthy and metabolic stress conditions. The differentially expressed TRB1 was functionally characterized in loss-of-function animal and primary adipocyte models.


RESULTS
Here, we show that the expression of TRB1 was specifically upregulated during acute and chronic inflammation in WAT of mice. Deficiency of TRB1 was found to impair cytokine gene expression in white adipocytes and to protect against high-fat diet-induced obesity. In adipocytes, TRB1 served as a nuclear transcriptional coactivator for the nuclear factor kappaB subunit RelA, thereby promoting the induction of proinflammatory cytokines in these cells.


CONCLUSIONS
As inflammation is typically seen in sepsis, insulin resistance, and obesity-related type 2 diabetes, the dual role of TRB1 as both a target and a (co) activator of inflammatory signaling might provide a molecular rationale for the amplification of proinflammatory responses in WAT in these subjects.
Ostertag
Anke
A
1Emmy Noether and Marie Curie Research Group, Molecular Metabolic Control, DKFZ-ZMBH Alliance, German Cancer Research Center Heidelberg, Heidelberg, Germany.
Jones
Allan
A
Rose
Adam J
AJ
Liebert
Maria
M
Kleinsorg
Stefan
S
Reimann
Anja
A
Vegiopoulos
Alexandros
A
Berriel Diaz
Mauricio
M
Strzoda
Daniela
D
Yamamoto
Masahiro
M
Satoh
Takashi
T
Akira
Shizuo
S
Herzig
Stephan
S
D017667:Adipocytes / Q000502:physiology; D000273:Adipose Tissue / Q000503:physiopathology*; D000818:Animals; D002460:Cell Line; D002843:Chromatin / Q000502:physiology; D017931:DNA Primers; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D007668:Kidney / Q000196:embryology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000037:antagonists & inhibitors; D012313:RNA / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection
D002843:Chromatin; D017931:DNA Primers; D012333:RNA, Messenger; C523519:Trb1 protein, mouse; D012313:RNA; D017346:Protein Serine-Threonine Kinases