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Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation
Open accessAbstract
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.
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“Reversing neuroinflammation via targeted genetic [96,97], pharmacological [98,99], or dietary [49,100] approaches that rescue behavioral anomalies offers convincing support for a causal role of neuroinflammation in obesity-induced neuropathophysiology.”
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Metadata
- Authors
- Douglass, J. D., Dorfman, M. D., Fasnacht, R., Shaffer, L. D., & Thaler, J. P.
- Affiliations
- University of Washington (US)
- Corresponding author
- Thaler, J.P.
- Venue
- Molecular Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 6
- Issue
- 4
- Pages
- 366-373
- ISSN
- 2212-8778 (ISSN-L)
- PMC
- PMC5369266
- OpenAlex
- W2581154578
- Cited by
- 248
- References
- 37
- Citations by year
- 2026: 12 · 2025: 23 · 2024: 28 · 2023: 34 · 2022: 32 · 2021: 31 · 2020: 31 · 2019: 26 · 2018: 20 · 2017: 11
- FWCI
- 14.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Molecular Metabolism (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- American Diabetes Association (1-14-ACE-51)
- NIDDK (K08 DK088872, T32 DK7247-37, F32 DK108473-01)
- NIH (DK035816)
- Diabetes Research Center (DK017047)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- diet-induced obesity, hypothalamic inflammation, astrocytes, IKKβ, NF-κB signaling, astrocyte-specific knockout, high-fat diet, impaired glucose tolerance, insulin resistance, hyperphagia, energy expenditure, reactive gliosis, astrocyte activation, mediobasal hypothalamus, obesity treatment
- MeSH terms
- Animals, Astrocytes, Cells, Cultured, Gliosis, Hypothalamus, Inflammation, Male, Mice, Inbred C57BL, Obesity, Signal Transduction, NF-kappa B, Mice, I-kappa B Kinase, Diet, High-Fat
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