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

Research output: Contribution to journalArticle

52 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

Fingerprint

Glucose Intolerance
High Fat Diet
Leptin
Obesity
Flavonoids
Glucose
Homeostasis
Arcuate Nucleus of Hypothalamus
Type 2 Diabetes Mellitus
Energy Metabolism
Weight Gain
Insulin Resistance
Adipose Tissue
Central Nervous System
Body Weight
Insulin
Inflammation
Morbidity
Neurons
Therapeutics

Keywords

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

Cite this

Benzler, J., Ganjam, G. K., Pretz, D., Oelkrug, R., Koch, C. E., Legler, K., ... 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

Central inhibition of IKKβ/NF-κB signalling attenuates high fat diet-induced obesity and glucose intolerance. / Benzler, Jonas; Ganjam, Goutham K; Pretz, Dominik; Oelkrug, Rebecca; Koch, Christiane E; Legler, Karen; Stöhr, Sigrid; Culmsee, Carsten; Williams, Lynda M; Tups, Alexander.

In: Diabetes, Vol. 64, No. 6, 06.2015, p. 2015-2027.

Research output: Contribution to journalArticle

Benzler, J, Ganjam, GK, Pretz, D, Oelkrug, R, Koch, CE, Legler, K, Stöhr, S, Culmsee, C, Williams, LM & Tups, A 2015, 'Central inhibition of IKKβ/NF-κB signalling attenuates high fat diet-induced obesity and glucose intolerance', Diabetes, vol. 64, no. 6, pp. 2015-2027. https://doi.org/10.2337/db14-0093
Benzler, Jonas ; Ganjam, Goutham K ; Pretz, Dominik ; Oelkrug, Rebecca ; Koch, Christiane E ; Legler, Karen ; Stöhr, Sigrid ; Culmsee, Carsten ; Williams, Lynda M ; Tups, Alexander. / Central inhibition of IKKβ/NF-κB signalling attenuates high fat diet-induced obesity and glucose intolerance. In: Diabetes. 2015 ; Vol. 64, No. 6. pp. 2015-2027.
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