Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation

Objective: Obesity and high fat diet (HFD) consumption in rodents is associated with hypothalamic inflammation and reactive gliosis. While neuronal inflammation promotes HFD-induced metabolic dysfunction, the role of astrocyte activation in susceptibility to hypothalamic inflammation and diet-induced obesity (DIO) remains uncertain. Methods: Metabolic phenotyping, immunohistochemical analyses, and biochemical analyses were performed on HFD-fed mice with a tamoxifen-inducible astrocyte-specific knockout of IKK beta (Gfap(CreER)Ikbkb(fl/fl), IKK beta-AKO), an essential cofactor of NF-kappa B-mediated inflammation. Results: IKK beta-AKO mice with tamoxifen-induced IKK beta deletion prior to HFD exposure showed equivalent HFD-induced weight gain and glucose intolerance as Ikbkb(fl/fl) littermate controls. In Gfap(CreER)TdTomato marker mice treated using the same protocol, minimal Cre-mediated recombination was observed in the mediobasal hypothalamus (MBH). By contrast, mice pretreated with 6 weeks of HFD exposure prior to tamoxifen administration showed substantially increased recombination throughout the MBH. Remarkably, this treatment approach protected IKK beta-AKO mice from further weight gain through an immediate reduction of food intake and increase of energy expenditure. Astrocyte IKK beta deletion after HFD exposuredbut not beforedalso reduced glucose intolerance and insulin resistance, likely as a consequence of lower adiposity. Finally, both hypothalamic inflammation and astrocytosis were reduced in HFD-fed IKK beta-AKO mice. Conclusions: These data support a requirement for astrocytic inflammatory signaling in HFD-induced hyperphagia and DIO susceptibility that may provide a novel target for obesity therapeutics. (C) 2017 The Authors. Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).