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

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.

RETRACTED: Glutamine Metabolism and Its Role in Immunity, a Comprehensive Review

“…For the alternative activation of macrophage (IL-4), glutamine is required [57,58]. Through glutaminolysis, the alpha-ketoglutarate is generated; thus, it endorses the differentiation of macrophages M2 [59,60] peroxisome proliferator-activated receptor (PPAR alpha) which has been reported to be needed for glutamine oxidation, gene expression (IL-4) and to stimulate the respiration of a macrophage. Therefore, the metabolism of glutamine plays an essential role as a modulator and synergetic supporter for the activation of a macrophage.…”

Patient Adipose Stem Cell-Derived Adipocytes Reveal Genetic Variation that Predicts Antidiabetic Drug Response

“…Thus, our data and methodology provide a proof of principle for a mechanistic understanding of how natural genetic variants control individual responses to antidiabetic drugs. These principles could be extended to different cell types, such as macrophages, where PPARg is relatively abundant and TZDs generally favor an anti-inflammatory alternative activation phenotype (Nelson et al, 2018).…”

New Insights on the Role of Lipid Metabolism in the Metabolic Reprogramming of Macrophages

“…PPARγ can sense fatty acids, and it has been shown to mediate the transcription of M2 signature genes upon oleic acid and IL4 stimulation (35). Interestingly, PPARγ was recently found to mediate M2 polarization by promoting the oxidation of glutamine (36), an amino acid that fuels OXPHOS (37). In spite of these advances, it is still not fully understood how FAO and OXPHOS are mechanistically linked to the anti-inflammatory phenotype of M2 macrophages.…”