Prostaglandin PGE2 receptor EP4 regulates microglial phagocytosis and increases susceptibility to diet-induced obesity

Abstract

<p>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.</p>

Microglia heterogeneity in health and disease

“…CD200 [82] Helps to maintain resting state CX3CR1 [85] Regulate microglia recruitment to the site of neuroinflammation CD47 [84] Neuronal protein sends "do not eat me" signals to microglia via CD172a/Sirp alpha interaction PRC2 [91] PRC2 enzyme catalyzes H3K27me3 modification TREM2 [93,94] Role in phagocytosis of debris and reducing proinflammatory cytokines CSF1 [95] Regulate the survival of myeloid lineage Runx1, ETS, PU.1, Irf8, Hoxb8 [15,22] Regulating differentiation processes during the embryonic development C-myb [97] Essential for microglia health, regulates proliferation, and survival in the CNS Ionotropic receptors [98,99] Calcium influx and the release of pro-inflammatory molecules Metabotropic receptors [98,99] Activate intracellular signaling cascades that contribute to microglial activation and inflammation Nerve Growth Factor [100] Regulate microglial activation and survival Prostaglandins E2 [101] Modulate microglial activation and pro-inflammatory responses Gamma-aminobutyric acid (GABA) [105] Modulate microglial activation and inflammatory responses Glucocorticoids [106] Suppresses microglia activation and inflammation via glucocorticoid receptor binding Estrogen [106] Modulates microglia activation, migration, and phagocytic activity Brain-derived Neurotropic factor (BDNF) [107] Modulate microglial function by influencing their activation, proliferation, and release of proinflammatory cytokines Norepinephrine [108,109] Controls the release of inflammatory factors like interleukin 6 (IL-6), interleukin 1b (IL-1b), and tumor necrosis factor a (TNF-a) Histamine and serotonin [111] Increases of calcium in the microglia microglial homeostasis. C-myb is an important regulator of cell proliferation and survival, and its function is essential for the normal functioning and maintenance of microglia in the healthy CNS [97].…”

“…Prostaglandins, including prostaglandin E2 (PGE2), can modulate microglial activation and proinflammatory responses. They are synthesized by microglia through cyclooxygenase 1 and 2 and can act in an autocrine or paracrine manner [101]. Notably, microglia are well known to express receptors for neurotransmitters [102][103][104].…”