GNPAT-driven plasmalogen biosynthesis regulates macrophage polarization and protects against obesity-induced...

Chronic inflammation in white adipose tissue (WAT) contributes to obesity-associated insulin resistance. Plasmalogens, ether phospholipids synthesized in peroxisomes, have been implicated in immune regulation. GNPAT (glyceronephosphate O-acyltransferase) is a peroxisomal enzyme that catalyzes the first and rate-limiting step of plasmalogen biosynthesis. Here, we show that dietary supplementation with alkyl glycerol (AG), a plasmalogen precursor, improves insulin sensitivity and reduces adipose inflammation in high-fat diet (HFD)-fed mice, independent of changes in body weight or invariant natural killer T cell activation. AG treatment reduced M1-like macrophage infiltration and proinflammatory gene expression in WAT without altering M2 macrophage polarization. Furthermore, AG supplementation restored levels of docosahexaenoic acid-enriched plasmalogen species that were reduced by HFD. In contrast, Gnpat⁺/^- mice displayed impaired plasmalogen biosynthesis, elevated M1 polarization, and exacerbated insulin resistance upon HFD feeding. Mechanistically, GNPAT overexpression in macrophages inhibited protein kinase C delta (PKCδ) activation and downstream signal transducer and activator of transcription 1 (STAT1) signaling, attenuating lipopolysaccharide-induced inflammation. In vivo studies showed that AG supplementation reduced diacylglycerol accumulation, suggesting that altered lipid flux contributes to the modulation of PKCδ signaling observed in macrophages. Of translational relevance, GNPAT expression was decreased in the visceral adipose tissue of humans with type 2 diabetes. These findings establish GNPAT-driven plasmalogen biosynthesis as a key modulator of adipose immune homeostasis via suppression of PKCδ-STAT1 signaling. Thus, enhancing plasmalogen levels may have therapeutic potential for obesity-related metabolic disorders.