Lipoprotein lipase maintains microglial innate immunity in obesity

Yuanqing Gao, Andrés Vidal-Itriago, Martin J. Kalsbeek, Clarita Layritz, Cristina García-Cáceres, Robby Zachariah Tom, Thomas O. Eichmann, Frédéric M. Vaz, Riekelt H. Houtkooper, Nicole van der Wel, Arthur J. Verhoeven, Jie Yan, Andries Kalsbeek, Robert H. Eckel, Susanna M. Hofmann, Chun Xia Yi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

33 Citations (Scopus)
34 Downloads (Pure)

Abstract

Consumption of a hypercaloric diet upregulates microglial innate immune reactivity along with a higher expression of lipoprotein lipase (Lpl) within the reactive microglia in the mouse brain. Here, we show that knockdown of the Lpl gene specifically in microglia resulted in deficient microglial uptake of lipid, mitochondrial fuel utilization shifting to glutamine, and significantly decreased immune reactivity. Mice with knockdown of the Lpl gene in microglia gained more body weight than control mice on a high-carbohydrate high-fat (HCHF) diet. In these mice, microglial reactivity was significantly decreased in the mediobasal hypothalamus, accompanied by downregulation of phagocytic capacity and increased mitochondrial dysmorphologies. Furthermore, HCHF-diet-induced POMC neuronal loss was accelerated. These results show that LPL-governed microglial immunometabolism is essential to maintain microglial function upon exposure to an HCHF diet. In a hypercaloric environment, lack of such an adaptive immunometabolic response has detrimental effects on CNS regulation of energy metabolism. Microglia are brain macrophages responsible for immune defense. LPL is a key enzyme gating lipid uptake by microglia. Gao et al. show that loss of Lpl in microglia results in downregulation of immune reactivity. Mice with knockdown of the Lpl gene in microglia are more vulnerable to diet-induced metabolic syndrome.

Original languageEnglish
Pages (from-to)3034-3042
Number of pages9
JournalCell Reports
Volume20
Issue number13
DOIs
Publication statusPublished - 26 Sep 2017
Externally publishedYes

Bibliographical note

Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

Keywords

  • autophagosomes
  • fuel dependency
  • glutamine
  • hypothalamus
  • mitochondria
  • NF-κB
  • phagocytosis
  • phospholipid
  • TNF-α
  • very low-density lipoprotein

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