Induction of the inflammasome protein cryopyrin (NLRP3) in visceraladipose 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 visceraladiposeNLRP3impairscognition 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. VisceraladiposeNLRP3 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 visceraladiposeNLRP3impairs 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.
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