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 (GfapCreERIkbkbfl/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 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.
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.
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.