Visceral adipose NLRP3 impairs cognition in obesity via IL1R1 on Cx3cr1⁺ cells

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Abstract

Induction of the inflammasome protein cryopyrin (NLRP3) in visceral adipose tissue (VAT) promotes release of the pro-inflammatory cytokine interleukin-1β (IL1β) in obesity. While this mechanism contributes to peripheral metabolic dysfunction, effects on the brain remain unexplored. These studies investigated whether visceral adipose NLRP3 impairs cognition by activating microglial interleukin-1 receptor 1 (IL1R1). After observing protection against obesity-induced neuroinflammation and cognitive impairment in NLRP3KO mice, we transplanted VAT from obese WT or NLRP3KO donors into lean recipients. Transplantation of VAT from a WT donor (TRANSWT) increased hippocampal IL1β and impaired cognition, but VAT transplants from comparably obese NLRP3KO 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 IL1-dependent. Flow cytometric and gene expression analyses revealed that VAT transplantation recapitulated the effects of obesity on microglial activation and IL1β gene expression, and visualization of hippocampal microglia revealed similar effects in vivo. Inducible ablation of IL1R1 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 IL1-mediated microglial activation, and suggest that NLRP3-IL1β 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