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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 Article has an altmetric score of 100

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

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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 2

Visceral adipose NLRP3 induction impairs hippocampus-dependent memory and synaptic plasticity.

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Visceral adipose NLRP3 induction impairs hippocampus-dependent memory an...
(A) Schematic of the experiment is shown. Graph shows body weights in WT mice maintained on a HFD or a LFD for 10 weeks before sham operation (SHAM) or VAT transplantation from a WT/HFD (TRANSWT) or NLRP3-KO/HFD donor (TRANSKO) (n = 20). (B) There was no effect of VAT transplantation on glycemic control, as determined by IPGTT and analysis of the AUC (n = 8–10). (C) Hippocampal and serum IL-1β increased in HFD/SHAM and TRANSWT mice, but not TRANSKO mice (n = 6). VAT RES, resident VAT; VAT TRANS, transplanted VAT. (D) Visceral adipose NLRP3 impaired spatial memory acquisition (left) and probe trial performance (right) (n = 10–11). (E) NLRP3-mediated deficits in the Y-maze following VAT transplantation (n = 10–12). (F) NLRP3-dependent reductions in novel object preference (NOP) (n = 12). (G) TRANSWT mice recapitulated obesity-induced LTP deficits in an NLRP3-dependent manner (left), based on a comparison of fEPSP slopes 60 minutes after high-frequency stimulation (n = 9–10 slices, n = 4–5 mice). For traces (left graph, inset), scale bars: x = 1 msec, y = 1 mV. (H) Recombinant IL-1RA eliminated LTP deficits in TRANSWT mice (n = 9–10 slices, n = 4–5 mice). Data indicate the mean ± SEM. *P < 0.05, by 1-way ANOVA with Tukey’s HSD post hoc.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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