Platelet-Activating Factor-Induced Inflammation in Obesity: A Two-Sided Coin of Protection and Risk

Abstract

Obesity, marked by excessive fat accumulation, especially abdominal, is a global health concern with significant public impact. While obesity-associated chronic unresolved inflammation contributes to metabolic dysfunctions, acute inflammation supports healthy adipose tissue remodeling and expansion. Platelet-activating factor (PAF), a "primitive" signaling molecule, is among the key mediators involved in the acute phase of inflammation and in various pathophysiological processes. This article explores the role of PAF in fat accumulation and obesity by reviewing experimental data from cell cultures, animals, and humans. It proposes an emerging biochemical mechanism in an attempt to explain its dual role in the healthy and obese adipose tissue, including also data on PAF's potential involvement in epigenetic mechanisms that may be linked to the "obesity memory". Finally, it highlights the potential of natural PAF modulators in promoting functional adipose tissue, thermogenesis, and obesity prevention through a healthy lifestyle, including a Mediterranean diet rich in PAF weak agonists/PAF receptor antagonists and regular exercise, which help maintain controlled PAF levels. Conversely, in cases of obesity-related systemic inflammation with excessive PAF levels, potent PAF inhibitors like ginkgolide B and rupatadine may help mitigate metabolic dysfunctions with PAFR antagonists potentially enhancing their effects synergistically.

Keywords: LpPLA2; Mediterranean diet; PAF metabolism; PPARγ; adipocytes; ether lipids; high-fat diet; macrophages; uncoupling protein-1.

Figure 1

A schematic presentation of PAF metabolic pathways. The red arrows and red-labeled enzymes depict the remodeling pathway, while the orange arrows and orange-labeled enzymes represent the de novo pathway. The light blue arrow and enzymes represent the PAF catabolic pathways. Blue arrows and enzymes illustrate the reactions occurring in the peroxisome. The dark green arrow signifies the non-enzymatic formation of PAF, whereas the dark blue arrows indicate potential substrates for AGMO. Lastly, the green arrow shows the conversion of dietary alkylglycerols to ALPA. AGMO: alkylglycerol monooxygenase; ALPA: alkyl-lyso-glycerophosphate; cPLA2: cytoplasmic phospholipase A2; DHAP: dihydroxyacetonephosphate; F.Ald.: fatty aldehyde; LpPLA₂: lipoprotein-associated phospholipase A₂; Lyso-PAF AT: acetyl-CoA:lyso–platelet-activating factor acetyltransferase; PAF-AHs: PAF-specific acetylhydrolases; PAF-CPT: 1-alkyl-2-acetyl-sn-glycerol cholinephosphotransferase; PC: phosphatidylcholine.

Figure 2

A simplified schematic representation of the role of PAF in adipose tissue. A healthy adipose tissue (AT) is characterized by basal and controlled PAF levels while an obese adipose tissue displays uncontrolled and significantly elevated PAF levels. ↑: refers to increase; ↓: refers to decrease.