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 5

Ablation of IL-1R1 in CX3CR1-expressing cells confers resistance to obesity-induced neuroinflammation.

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Ablation of IL-1R1 in CX3CR1-expressing cells confers resistance to obes...
(A) Schematic shows the design for Cx3cr1CreERT2 Il1r1fl/fl–Tg mice. Weight gain (graph) was similar in Tg and nTg littermates (n = 24). TAM, tamoxifen. (B) Genotype had no effect on glycemic control (n = 11–12). (C) Adipose tissue hypertrophy was unaffected by genotype (n = 6–8). (D) Tg/HFD mice showed no increase in hippocampal IL-1β, despite comparable increases in VAT and serum IL-1β (n = 4). (E) Gating strategy for analysis of macrophage infiltration and microglial activation (text above plots indicates the parent gate). (F) Flow cytometric validation of CNS-specific reductions in cell-surface IL-1R1 expression (n = 6). (G) Tg mice were resistant to CNS infiltration of CD11b+CD45hiLy6Chi macrophages with dietary obesity (n = 7–8). Circles show data from cell-surface detection in live cells (n = 4–5), and squares represent data from fixed cells (n = 3). (H) Nonoverlapping effects of obesity and IL-1R1 deletion on intracellular IL-1β in the CD11b+CD45hiLy6Clo cell population, which included BAMs (right; gray shading shows the isotype) and in CD11b+CD45loLy6Clo microglia (left). n = 3. (I) IL-1R1 was required for obesity-induced microglial polarization, based on cell-surface detection of MHCII and TLR4 in CD11b+CD45loLy6Clo cells (n = 4–5). (J) IL-1R1–dependent anatomical simplification (left) and process retraction (right) with obesity (n = 4). Micrographs show IL-1R1–mediated accumulation of CD68 among IBA1+ microglia. Scale bar: 10 μm. Data indicate the mean ± SEM. *P < 0.05, by 2-way ANOVA with Tukey’s post hoc test.