| First Author | Douglass JD | Year | 2017 |
| Journal | Mol Metab | Volume | 6 |
| Issue | 4 | Pages | 366-373 |
| PubMed ID | 28377875 | Mgi Jnum | J:318449 |
| Mgi Id | MGI:6859712 | Doi | 10.1016/j.molmet.2017.01.010 |
| Citation | Douglass JD, et al. (2017) Astrocyte IKKbeta/NF-kappaB signaling is required for diet-induced obesity and hypothalamic inflammation. Mol Metab 6(4):366-373 |
| abstractText | 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 IKKbeta (Gfap(CreER)Ikbkb(fl/fl), IKKbeta-AKO), an essential cofactor of NF-kappaB-mediated inflammation. RESULTS: IKKbeta-AKO mice with tamoxifen-induced IKKbeta 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 IKKbeta-AKO mice from further weight gain through an immediate reduction of food intake and increase of energy expenditure. Astrocyte IKKbeta 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 IKKbeta-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. |
