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Cited by 252Regulation of Appetite and ObesityAdipokines, Inflammation, and Metabolic DiseasesNeuroinflammation and Neurodegeneration Mechanisms

The DOI matches its Crossref record; 37 of the 37 references it cites were found in a registry or an index.

Astrocyte IKKβ/NF-κB signaling is required for diet-induced obesity and hypothalamic inflammation

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Douglass, J.D., Dorfman, M.D., Fasnacht, R., Shaffer, L.D., Thaler, J.P.·2017·Molecular Metabolism
DOI 10.1016/j.molmet.2017.01.010PMC PMC5369266
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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.

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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.
ORCID
Venue
Molecular Metabolism
Publisher
Elsevier BV
Published
2017-04
Volume
6
Issue
4
Pages
366-373
ISSN
2212-8778 (ISSN-L)
DOI
10.1016/j.molmet.2017.01.010
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
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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