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Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity in a sexually dimorphic manner
Jiahui Liu, Ali Hussainy Zaidi, Christian J. Pike. Journal of Neuroinflammation, 2025-09-26
Topic: Brain proteins, microglia and lab models
Obesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer's disease (AD) and vascular dementia. Obesity is also characterized by chronic, low-grade inflammation that is implicated in mediating negative consequences body-wide. Toll-like receptor 4 (TLR4) signaling from peripheral macrophages is implicated as an essential regulator of the systemic inflammatory effects of obesity. In the brain, obesity drives chronic neuroinflammation that involves microglial activation, however the contributions of microglia-derived TLR4 signaling to the consequences of obesity are poorly understood. To investigate this issue, we first generated mice that carry an inducible, microglia/macrophage-specific deletion of TLR4 that yields long-term TLR4 knockout only in brain indicating microglial specificity. Next, we analyzed the effects of microglia/macrophage TLR4 deletion on systemic and neural effects of a 16-week of exposure to control versus obesogenic high-fat diets. In male mice, TLR4 deletion generally yielded limited effects on diet-induced systemic metabolic dysfunction but significantly reduced neuroinflammation and impairments in neurogenesis and cognitive performance. In female mice maintained on obesogenic diet, TLR4 deletion partially protected against weight gain, adiposity, and metabolic impairments. Compared to males, females showed milder diet-induced neural consequences, against which TLR4 deletion was protective. Collectively, these findings demonstrate a central role of microglia/macrophage TLR4 signaling in mediating the neural effects of obesogenic diet and highlight sexual dimorphic responses to both diet and TLR4.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Liu, J., Zaidi, A. H., & Pike, C. J. (2025). Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity in a sexually dimorphic manner. Journal of Neuroinflammation. https://doi.org/10.1186/s12974-025-03534-z
Vancouver
Liu J, Zaidi AH, Pike CJ. Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity in a sexually dimorphic manner. Journal of Neuroinflammation. 2025. doi:10.1186/s12974-025-03534-z. PMID: 41013506.
BibTeX
@article{liu2025-41013506,
author = {Liu, Jiahui and Zaidi, Ali Hussainy and Pike, Christian J.},
title = {{Microglia/macrophage-specific deletion of TLR-4 protects against neural effects of diet-induced obesity in a sexually dimorphic manner}},
journal = {Journal of Neuroinflammation},
year = {2025},
doi = {10.1186/s12974-025-03534-z},
pmid = {41013506},
url = {https://doi.org/10.1186/s12974-025-03534-z}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
Key findings
- Obesity is associated with numerous adverse neural effects, including reduced neurogenesis, cognitive impairment, and increased risks for developing Alzheimer's disease (AD) and vascular dementia.
- Next, we analyzed the effects of microglia/macrophage TLR4 deletion on systemic and neural effects of a 16-week of exposure to control versus obesogenic high-fat diets.
- In male mice, TLR4 deletion generally yielded limited effects on diet-induced systemic metabolic dysfunction but significantly reduced neuroinflammation and impairments in neurogenesis and cognitive performance.
- Compared to males, females showed milder diet-induced neural consequences, against which TLR4 deletion was protective.
- Collectively, these findings demonstrate a central role of microglia/macrophage TLR4 signaling in mediating the neural effects of obesogenic diet and highlight sexual dimorphic responses to both diet and TLR4.
Why it matters
In mice on an obesogenic diet, deleting TLR4 in microglia/macrophages reduced neuroinflammation and cognitive problems in males, with partial protection in females. This is animal research, so it does not establish that targeting TLR4 would treat or prevent Alzheimer's disease in humans.
Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Journal of Neuroinflammation) |
| Journal's citation record | 2 / 4 | Journal of Neuroinflammation: journal h-index 216 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 4 / 5 | 2025 — within 3 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 5 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 1.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 1.5× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 1 / 4 | Cited 5 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Christian J. Pike: h-index 67 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | University of Southern California: institution h-index 1,521 (OpenAlex) |
| Multicenter collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 41013506) |
| Free to read | 2 / 2 | Free to read |
| Total | 39 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
- DOI: 10.1186/s12974-025-03534-z
- PubMed: 41013506
- Original source →
- Free full text: Journal of Neuroinflammation →
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
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