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PPAR? is a nexus controlling alternative activation of macrophages via glutamine metabolism.

ABSTRACT: The nuclear receptor peroxisome proliferator-activated receptor ? (PPAR?) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPAR? ligand, in a PPAR?-dependent manner. Moreover, PPAR? is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPAR? dramatically affects the oxidation of glutamine. Both glutamine and PPAR? have been implicated in alternative activation (AA) of macrophages, and PPAR? was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPAR? contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPAR? functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPAR? expression is itself markedly increased by IL4. This suggests that PPAR? functions at the center of a feed-forward loop that is central to AA of macrophages.

SUBMITTER: Nelson VL

PROVIDER: S-EPMC6075146 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism.

Nelson Victoria L VL Nguyen Hoang C B HCB Garcìa-Cañaveras Juan C JC Briggs Erika R ER Ho Wesley Y WY DiSpirito Joanna R JR Marinis Jill M JM Hill David A DA Lazar Mitchell A MA

Genes & development 20180713 15-16

The nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) is known to regulate lipid metabolism in many tissues, including macrophages. Here we report that peritoneal macrophage respiration is enhanced by rosiglitazone, an activating PPARγ ligand, in a PPARγ-dependent manner. Moreover, PPARγ is required for macrophage respiration even in the absence of exogenous ligand. Unexpectedly, the absence of PPARγ dramatically affects the oxidation of glutamine. Both glutamine and PPARγ ha ...[more]

PMID: 30006480

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PPAR? is a nexus controlling alternative activation of macrophages via glutamine metabolism.

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PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolism.

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