Abstract
Background and objective:
Inflammation of adipose tissue (AT) is a central mediator of insulin resistance. However, the molecular mechanisms triggered by inflammatory cells are not fully understood. The aim of this study was to analyze the metabolic functions of lymphotoxin-β-receptor (LTβR)-mediated alternative NF-κB signaling in adipocytes and to reveal its effects on body weight and insulin sensitivity in vivo.
Methods:
RelBFatKO mice and littermate controls were treated with LTβR agonistic antibody (α-LTβR) or a LTβR antagonist (LTβR:Ig fusion protein) after feeding a high-fat diet or standard diet. Mice were analyzed by insulin tolerance and glucose tolerance tests prior to analysis by necropsy and qRT-PCR of abdominal white adipose tissue. 3T3-L1 preadipocytes and mouse embryonic fibroblasts were used for differentiation and expression analysis after treatment with α-LTβR and differentiation to adipocytes. The molecular mechanism was elucidated by chromatin immunoprecipitation and combinatorial treatment with α-LTβR and tumor necrosis factor (TNF).
Results:
RelBFatKO mice showed improved insulin sensitivity despite increased adiposity and adipocyte hypertrophy. LTβR-induced activation of p52-RelB in 3T3-L1 cells attenuated adipogenesis and modulated adipocyte functions via transcriptional downregulation of peroxisome proliferator-activated receptor γ (PPARγ). This LTβR-mediated pathway was synergistically regulated via a TNF-induced increase in p100 and RelB expression and nuclear translocation.
Conclusions:
Our data describe an anti-adipogenic action of LTβR signaling and a novel synergism of alternative and classical NF-κB signaling in the regulation of adipocytes. In conclusion, this strong synergism between the two NF-κB pathways shows a method to inhibit adipocyte differentiation and to improve insulin sensitivity and can be a potential target to treat metabolic disorders more efficiently than with other known drugs.
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Acknowledgements
We thank Jan P Tuckermann (University of Ulm) and Cornelis Calkhoven (University Medical Center Groningen) for helpful discussions as well as Elke Meier, Anne Gompf and Maik Baldauf for technical assistance. We thank Thomas Hehlgans (University of Regensburg) for kindly providing the LTβR:Ig and Ronny Haenold for constant support and supervision.
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Weidemann, A., Lovas, A., Rauch, A. et al. Classical and alternative NF-κB signaling cooperate in regulating adipocyte differentiation and function. Int J Obes 40, 452–459 (2016). https://doi.org/10.1038/ijo.2015.198
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DOI: https://doi.org/10.1038/ijo.2015.198