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 1

Protection against obesity-induced hippocampal dysfunction in mice lacking the inflammasome protein NLRP3.

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Protection against obesity-induced hippocampal dysfunction in mice lacki...
(A) Male WT and NLRP3-KO mice gained similar amounts of weight over time (n = 20). (B) Adipose tissue hypertrophy was comparable in WT/HFD and KO/HFD mice (n = 6). BAT, brown adipose tissue. (C) KO/HFD mice were protected against increases in IL-1β in VAT, hippocampus (Hippo), and serum (n = 4). (D) NLRP3-dependent reductions in microglial process complexity and total length with dietary obesity (n = 4). Micrographs show increased CD68 immunoreactivity in WT but not KO/HFD mice (see also Supplemental Figure 1). Scale bar: 10 μm. (E) NLRP3 was required for obesity-induced memory impairment in the water maze during acquisition training and the probe test (n = 16). (F) Dentate gyrus LTP was significantly reduced in an NLRP3-dependent manner with dietary obesity (n = 10–12 slices, n = 4–6 mice). For traces (inset, left), scale bars: x = 1 msec, y = 1 mV. Data indicate the mean ± SEM. *P < 0.05, by 2-way repeated-measures ANOVA (A) or 2-way ANOVA (B–F) with Tukey’s HSD post hoc test.