title: Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation.
abstract: 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.
  
  
  
  Metabolic 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.
  
  
  
  IKKβ-AKO mice with tamoxifen-induced IKKβ deletion prior to HFD exposure showed equivalent HFD-induced weight gain and glucose intolerance asIkbkbfl/fllittermate controls. InGfapCreERTdTomato 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.
  
  
  
  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.
authors.affiliation: Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Douglass
authors.affiliation: Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: M D
authors.initials: MD
authors.lastname: Dorfman
authors.affiliation: Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: R
authors.initials: R
authors.lastname: Fasnacht
authors.affiliation: Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA 98109, USA.
authors.forename: L D
authors.initials: LD
authors.lastname: Shaffer
authors.affiliation: Division of Metabolism, Endocrinology & Nutrition, Department of Medicine, University of Washington, Seattle, WA 98109, USA. Electronic address: jpthaler@uw.edu.
authors.forename: J P
authors.initials: JP
authors.lastname: Thaler
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D002478:Cells, Cultured; D059305:Diet, High-Fat / Q000009:adverse effects; D005911:Gliosis; D007031:Hypothalamus / Q000378:metabolism* / Q000473:pathology; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009765:Obesity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse
keywords: ARC, arcuate nucleus; Agrp, Agouti-related peptide; Astrocytes; Bdnf, brain-derived neurotrophic factor; Cart, cocaine- and amphetamine-regulated transcript; Ccl2, C–C motif chemokine ligand 2; DIO, diet-induced obesity; DMH, dorsomedial hypothalamus; Energy homeostasis; GFAP, glial fibrillary acidic protein; GSIS, glucose-stimulated insulin secretion; GTT, glucose tolerance test; HFD, high-fat diet; Hypothalamus; IHC, immunohistochemistry; IKKβ, inhibitor of kappa B kinase beta; ITT, insulin tolerance test; Iba1, ionized calcium binding adaptor molecule 1; Il, interleukin; Inflammation; LPS, lipopolysaccharide; MBH, mediobasal hypothalamus; Metabolism; NF-κB, nuclear factor kappa B; Npy, neuropeptide Y; Obesity; Pomc, proopiomelanocortin; RER, respiratory exchange ratio; TMX, tamoxifen; Tnfa, tumor necrosis factor α; VMN, ventromedial nucleus; ir, immunoreactivity