Modified Signaling of Membrane Formyl Peptide Receptors in NADPH-Oxidase Regulation in Obesity-Resistant Mice

Abstract

The signaling of membrane receptors is modified in obesity characterized by low-grade inflammation. The obesity-resistant state of organisms is poorly understood. We analyzed the generation of reactive oxygen species (ROS) initiated though membrane formyl peptide receptors (Fpr1, Fpr2) in bone-marrow granulocytes of obesity-resistant mice (ORM). A chemiluminescence assay was used to assess NADPH-oxidase-related intensity of ROS generation. ORM were chosen from animals that received high-fat diets and had metric body parameters as controls (standard diet). High spontaneous ROS production was observed in ORM cells. The EC50 for responses to bacterial or mitochondrial peptide N-formyl-MLF was higher in ORM with and without inflammation vs. the same control groups, indicating an insignificant role of high-affinity Fpr1. Increased responses to synthetic peptide WKYMVM (Fpr2 agonist) were observed in controls with acute inflammation, but they were similar in other groups. Fpr2 was possibly partially inactivated in ORM owing to the inflammatory state. Weakened Fpr1 and Fpr2 signaling via MAPKs was revealed in ORM using specific inhibitors for p38, ERK1/2, and JNK. P38 signaling via Fpr2 was lower in ORM with inflammation. Thus, a high-fat diet modified FPRs’ role and suppressed MAPK signaling in NADPH-oxidase regulation in ORM. This result can be useful to understand the immunological features of obesity resistance.