Metabolic inflammation in the central nervous system might be causative for the development of overnutrition-induced metabolic syndrome and related disorders such as obesity, leptin- and insulin-resistance and type II diabetes. 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 and intracerebroventricular administration of this flavonoid acutely 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, the 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 without altering food intake and reduced arcuate SOCS3 expression, suggesting enhanced leptin signalling. These results reinforce a specific role of pro-inflammatory IKKβ/NF-κB signalling in the development of DIO-induced co-morbidities.