Central inhibition of IKKβ/NF-κB signalling attenuates high fat diet-induced obesity and glucose intolerance

Jonas Benzler, Goutham K Ganjam, Dominik Pretz, Rebecca Oelkrug, Christiane E Koch, Karen Legler, Sigrid Stöhr, Carsten Culmsee, Lynda M Williams, Alexander Tups

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100 Citations (Scopus)


Metabolic inflammation in the central nervous system might be causative for the development of over nutrition-induced metabolic syndrome and related disorders such as obesity, leptin- and insulin-resistance and type II diabetes. Here we investigated whether nutritive and genetic inhibition of the central IKKβ/NF-κB pathway in DIO- and leptin-deficient mice improves these metabolic impairments. A known prominent inhibitor of IKKβ/NF-κB signalling is the dietary flavonoid butein. We initially determined that oral, intraperitoneal and intracerebroventricular administration of this flavonoid improved glucose tolerance and hypothalamic insulin signalling. The dose-dependent glucose lowering capacity was profound regardless of whether obesity was caused by leptin deficiency or high fat diet. To confirm the apparent central role of IKKβ/NF-κB signalling in the control of glucose- and energy homeostasis we genetically inhibited this pathway in neurons of the arcuate nucleus, one key centre for control of energy homeostasis, via specific AAV2-mediated over-expression of IκBα, which inhibits NF-κB nuclear translocation. This treatment attenuated high fat diet-induced body weight gain, body fat mass accumulation, increased energy expenditure and reduced arcuate SOCS-3 expression, indicative for enhanced leptin signalling. These results reinforce a specific role of central pro-inflammatory IKKβ/NF-κB signalling in the development and potential treatment of DIO-induced co-morbidities.

Original languageEnglish
Pages (from-to)2015-2027
Number of pages13
Issue number6
Early online date27 Jan 2015
Publication statusPublished - Jun 2015

Bibliographical note

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Acknowledgments. The authors thank William C. Hahn (Dana-Farber Cancer Institute, Boston, MA) for providing the pBabe-GFP-IκB-α-mut (super repressor) vector and David R. Grattan (University of Otago) for editorial suggestions.

Funding. This study was funded by the German Ministry of Education and Research (ref. no. 0315087) and the German Research Foundation (ref. no. 0315087 and 243471766 to A.T.). L.M.W. was funded by the Scottish Government’s Rural and Environment Science and Analytical Services Division.


  • Central Inhibition
  • High Fat Diet Induced
  • Glucose Intolerance
  • Diet induced obesity
  • Obesity
  • Metabolism


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