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Genes Dev. 2018 Aug 1;32(15-16):1035-1044. doi: 10.1101/gad.312355.118. Epub 2018 Jul 13.

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

Author information

1
Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
2
Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Philadelphia, Pennsylvania 19104, USA.
3
Lewis-Sigler Institute for Integrative Genomics, Department of Chemistry, Princeton University, Princeton, New Jersey 08544, USA.
4
Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
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Contributed equally

Abstract

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 have been implicated in alternative activation (AA) of macrophages, and PPARγ was required for interleukin 4 (IL4)-dependent gene expression and stimulation of macrophage respiration. Indeed, unstimulated macrophages lacking PPARγ contained elevated levels of the inflammation-associated metabolite itaconate and express a proinflammatory transcriptome that, remarkably, phenocopied that of macrophages depleted of glutamine. Thus, PPARγ functions as a checkpoint, guarding against inflammation, and is permissive for AA by facilitating glutamine metabolism. However, PPARγ expression is itself markedly increased by IL4. This suggests that PPARγ functions at the center of a feed-forward loop that is central to AA of macrophages.

KEYWORDS:

PPARγ; alternative activation; glutamine; macrophage; metabolism; rosiglitazone

PMID:
30006480
PMCID:
PMC6075146
DOI:
10.1101/gad.312355.118
[Indexed for MEDLINE]
Free PMC Article

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