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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65 Citations (Scopus)

Abstract

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
JournalDiabetes
Volume64
Issue number6
Early online date27 Jan 2015
DOIs
Publication statusPublished - Jun 2015

Keywords

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

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    Benzler, J., Ganjam, G. K., Pretz, D., Oelkrug, R., Koch, C. E., Legler, K., Stöhr, S., Culmsee, C., Williams, L. M., & Tups, A. (2015). Central inhibition of IKKβ/NF-κB signalling attenuates high fat diet-induced obesity and glucose intolerance. Diabetes, 64(6), 2015-2027. https://doi.org/10.2337/db14-0093