Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation
Year: 2017
Type: article
Abstract: 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 IKKβ ( Gfap CreER Ikbkb fl/fl , IKKβ-AKO), an essential cofactor of NF-κB-mediated inflammation. Results IKKβ-AKO mice with tamoxifen-induced IKKβ 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 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. 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.
Source: Molecular Metabolism
Institution: University of Washington
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,270
Awards: G1228426491, G1452187186, G1948980911, The role of glial cells in hypothalamic inflammation and diet-induced obesity, G234089594, G2878974388, Modulating glial-neuronal interactions to treat obesity and diabetes, Cellular Mechanisms of Hypothalamic Inflammation in High Fat Diet-Induced Obesity, Glial-neuronal metabolic coupling in obesity, G7388217856, G8622162125, G882153477, G9000024636, Nutrition Obesity Research Center, Diabetes Research Center
OpenAlex ID: W2581154578