Control of adipose tissue inflammation through TRB1
Oil Red O stained adipocytes
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Obesity is a pandemic disease affecting more and more people worldwide. The sedentary lifestyle and high energy intake as well as genetic factors contribute to the increase in white adipose tissue (WAT) mass and the development of overweight and obesity. The subsequently developing diseases like type 2 diabetes, atherosclerosis or cancer decrease life expectancy and life quality. Based on its role as an energy storage compartment and endocrine organ, WAT fulfils 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 previously 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 fulfils broader functions in the integration of metabolic and inflammatory pathways in various tissues.
In this study S. Herzig et al. show that the expression of TRB1 was specifically up-regulated in WAT fat pads of obese mice as well as in adipose tissue of mice, suffering from an acute systemic inflammatory response after bacterial lipopolysaccharide injection.
Further analysis showed, that the gene expression of TRB1 was regulated by factors secreted by macrophages and that the JNK pathway and the NF-êB transcription factor were involved in its transcriptional regulation.
Functional studies showed that deficiency of TRB1 impaired cytokine gene expression in primary white adipocytes as well as in WAT of LPS injected TRB1 heterozygous mice. These heterozygous mice were also protected against high-fat diet-induced obesity, they were more insulin sensitive and did not show an increase in pro-inflammatory gene expression in WAT.
Mechanistically, TRB1 was found to serve as a nuclear transcriptional co-activator for the NF-êB subunit RelA by interacting with the RelA transactivation domain, thereby promoting the induction of pro-inflammatory cytokines in adipocytes.
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 pro-inflammatory responses in WAT in these subjects.
Ostertag, A., Jones, A., Rose, A.J., Liebert, M., Kleinsorg, S., Reimann, A., Vegiopoulos, A., Berriel Diaz, M., Strzoda, D., Yamamoto, M., Satoh, T., Akira, S., and Herzig, S. 2010. Control of adipose tissue inflammation through TRB1. Diabetes, in press
doi:10.2337/db09-1537