Visceral adipose NLRP3 impairs cognition in obesity via IL-1R1 on CX3CR1+ cells
De-Huang Guo, … , Babak Baban, Alexis M. Stranahan
De-Huang Guo, … , Babak Baban, Alexis M. Stranahan
Published January 14, 2020
Citation Information: J Clin Invest. 2020;130(4):1961-1976. https://doi.org/10.1172/JCI126078.
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Research Article Immunology Neuroscience

Visceral adipose NLRP3 impairs cognition in obesity via IL-1R1 on CX3CR1+ cells

Abstract

Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the proinflammatory cytokine IL-1β in obesity. Although this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. We investigated whether visceral adipose NLRP3 impairs cognition by activating microglial IL-1 receptor 1 (IL-1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3-KO mice, we transplanted VAT from obese WT or NLRP3-KO donors into lean recipient mice. Transplantation of VAT from a WT donor (TRANSWT) increased hippocampal IL-1β and impaired cognition, but VAT transplants from comparably obese NLRP3-KO donors (TRANSKO) had no effect. Visceral adipose NLRP3 was required for deficits in long-term potentiation (LTP) in transplant recipients, and LTP impairment in TRANSWT mice was IL-1 dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL-1β gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL-1R1 in CX3CR1-expressing cells eliminated cognitive impairment in mice with dietary obesity and in transplant recipients and restored immunoquiescence in hippocampal microglia. These results indicate that visceral adipose NLRP3 impairs memory via IL-1–mediated microglial activation and suggest that NLRP3/IL-1β signaling may underlie correlations between visceral adiposity and cognitive impairment in humans.

Authors

De-Huang Guo, Masaki Yamamoto, Caterina M. Hernandez, Hesam Khodadadi, Babak Baban, Alexis M. Stranahan

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Figure 8

Visceral fat transplantation disrupts microglial organization at dendritic spines and impairs cognition by activating IL-1R1 on microglia and brain macrophages.

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Visceral fat transplantation disrupts microglial organization at dendrit...
(A) Cx3cr1CreERT Il1r1fl/fl–Tg mice were crossed with Thy-eGFP(S) mice for quantification of dendritic spine density and morphology. Loss of thin spines was associated with reductions in total dendritic spine density in nTg/TRANS mice (n = 6–7). (B) Analysis of IBA1+ microglial processes in different spine morphologies revealed preferential localization at mushroom spines. VAT transplantation increased the proportion of mushroom spines with microglial processes, and increases were IL-1R1 dependent. For micrographs, left panel shows a Z-projection of Thy1-GFP and IBA1 (scale bar: 20 μm); middle panels show individual Z-planes, with asterisks indicating contact between IBA1+ processes and dendritic spines (scale bar: 25 μm). Far right panels show representative Z-projection images from each condition, with arrowheads indicating spines and asterisks indicating IBA1 contact at the spine head (scale bar: 10 μm). n = 6–7. (C) Protection against VAT transplantation–induced LTP deficits in Tg/TRANS mice (left), based on comparison of fEPSP slopes 60 minutes after high-frequency stimulation (right). (D) No change in presynaptic paired-pulse plasticity was observed. ISI, interstimulus interval. n = 10 slices, n = 4–5 mice. (E) No effect of genotype or surgery on input/output ratios was observed. (F) VAT transplantation impaired water maze acquisition (left) and probe trial performance (right) in nTg/TRANS, but not Tg/TRANS, mice (n = 16). (G and H) Ablation of IL-1R1 in CX3CR1-expressing cells eliminated VAT transplantation–induced deficits in the Y-maze (G) and maintained object recognition memory (H). n = 10–12. Data indicate the mean ± SEM. *P < 0.05, by 2-way ANOVA with Tukey’s HSD post hoc.