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

- The first direct evidence that astrocyte inflammatory activation promotes obesity.
- GfapCreER mice given tamoxifen show minimal recombination in MBH astrocytes.
- GfapCreER mice given tamoxifen after 6 wks of HFD have recombination in the MBH.
- Astrocyte IKKβ deletion with tamoxifen before HFD has no effect on energy balance.
- Astrocyte IKKβ deletion with tamoxifen given after HFD reduces DIO susceptibility.

ObjectiveObesity 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.MethodsMetabolic phenotyping, immunohistochemical analyses, and biochemical analyses were performed on HFD-fed mice with a tamoxifen-inducible astrocyte-specific knockout of IKKβ (GfapCreERIkbkbfl/fl, IKKβ-AKO), an essential cofactor of NF-κB-mediated inflammation.ResultsIKKβ-AKO mice with tamoxifen-induced IKKβ deletion prior to HFD exposure showed equivalent HFD-induced weight gain and glucose intolerance as Ikbkbfl/fl littermate controls. In GfapCreERTdTomato 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 IKKβ-AKO mice from further weight gain through an immediate reduction of food intake and increase of energy expenditure. Astrocyte IKKβ deletion after HFD exposure-but not before-also reduced glucose intolerance and insulin resistance, likely as a consequence of lower adiposity. Finally, both hypothalamic inflammation and astrocytosis were reduced in HFD-fed IKKβ-AKO mice.ConclusionsThese data support a requirement for astrocytic inflammatory signaling in HFD-induced hyperphagia and DIO susceptibility that may provide a novel target for obesity therapeutics.

240Overview of astrocyte IKKβ inactivation in chronic HFD-fed mice. Rodents exposed to HFD have increased hypothalamic inflammation and accumulation of reactive astrocytes in the mediobasal hypothalamus. Conditional deletion of IKKβ/NFκB in astrocytes of HFD-fed mice results in obesity resistance, improved glucose homeostasis, and decreased hypothalamic inflammation. 3V = third ventricle