Prostaglandin PGE2 Receptor EP4 Regulates Microglial Phagocytosis and Increases Susceptibility to Diet-Induced Obesity

Abstract

In rodents, susceptibility to diet-induced obesity requires microglial activation, but the molecular components of this pathway remain incompletely defined. Prostaglandin E2 (PGE2) levels increase in the mediobasal hypothalamus during high fat diet (HFD) feeding, and the PGE2 receptor EP4 regulates microglial activation state and phagocytic activity, suggesting a potential role for microglial EP4 signaling in obesity pathogenesis. To test the role of microglial EP4 in energy balance regulation, we analyzed the metabolic phenotype in a cell-specific EP4 knockout mouse model. Microglial EP4 deletion markedly reduced weight gain and food intake in response to HFD feeding. In correspondence with this lean phenotype, insulin sensitivity was also improved in the HFD-fed MG-EP4 KO mice though glucose tolerance remained surprisingly unaffected. Mechanistically, EP4-deficient microglia showed an attenuated phagocytic state marked by reduced CD68 expression and fewer contacts with POMC neuron processes. These cellular changes observed in the microglial EP4 knockout mice corresponded with an increased density of POMC neurites extending into the paraventricular nucleus. These findings reveal that microglial EP4 signaling promotes body weight gain and insulin resistance during HFD feeding. Furthermore, the data suggest that curbing microglial phagocytic function may preserve POMC cytoarchitecture and PVN input to limit overconsumption during diet-induced obesity.

Lipopolysaccharide-induced immune stress negatively regulates broiler chicken growth via the COX-2-PGE2-EP4 signaling pathway

“…Analogously, other studies found that the application of COX-2 inhibitors alleviated the loss of appetite caused by LPS in poultry ( 10 ) which suggests that COX-2 may mediate the suppression of feed intake of animals under immune stress. Deletion of the gene for EP4 in microglial cells reduced microglial-POMC neuron contacts ( 60 ) and implicated PGE 2 signaling via EP4 as an important regulator of microglia-POMC neuron interactions. In addition, accumulating evidence has substantiated that IL-1 affected hypothalamic peptide release were mediated via COX stimulation of PGE synthesis.…”

Palmitic Acid Modulates Microglial Cell Response to Metabolic Endotoxemia in an In Vitro Study

“…Finally, prostaglandin PGE2 is a crucial mediator of inflammation, regulating apoptosis, angiogenesis, and cell proliferation. Under physiological conditions, PGE2 is released in the brain by tanacytes, astrocytes, and neurons, and under inflammatory stimuli, also by microglial cells and vascular endothelial cells [60]. By activating E-prostanoid receptors EP1 through EP4, PGE2 activates inflammatory signaling pathways contributing to neurotoxicity [61].…”

Emerging Roles and Therapeutic Applications of Arachidonic Acid Pathways in Cardiometabolic Diseases

“…314,315 Given the close correlation between diet-induced impairment in insulin sensitivity and body weight gain, a notable increase in PGE2 levels and activation of its receptor EP4 in the mediobasal hypothalamus during HFD feeding is evident. Niraula et al 115 demonstrated that microglia-specific EP4 knockout significantly reduces weight gain and improves insulin sensitivity in mice subjected to HFD feeding. EP4 deficiency effectively attenuates the phagocytic state of microglia, disrupts cross talk with pro-opiomelanocortin (POMC) neurons, and results in an increased density of POMC neurites extending into the paraventricular nucleus (PVN).…”