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

Abstract

BackgroundIn 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.MethodMetabolic phenotyping, as assessed by body weight, energy expenditure, glucose, and insulin tolerance, was performed in microglia-specific EP4 knockout (MG-EP4 KO) mice and littermate controls on HFD. Morphological and gene expression analysis of microglia, and a histological survey of microglia-neuron interactions in the arcuate nucleus was performed. Phagocytosis was assessed using in vivo and in vitro pharmacological techniques.ResultsMicroglial 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 soma and processes. These cellular changes observed in the microglial EP4 knockout mice corresponded with an increased density of POMC neurites extending into the paraventricular nucleus.ConclusionThese 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.

Microglial inflammatory activation paradoxically improves glucose tolerance during diet-induced obesity

“…In DIO, for example, HFD induction of NF-κB-mediated signaling in microglia promotes food intake, fat accumulation, and central resistance to satiety signals such as leptin (Valdearcos et al, 2014, 2017). These data together with more recent analyses of microglial mitochondrial (UCP2) (Kim et al, 2019), lipid (LPL) (Gao et al, 2017), circadian (Bmal1) (Wang et al, 2020), chemokine (CX3CR1) (Dorfman et al, 2017), and prostaglandin (Niraula et al, 2021) signaling support a primary role for microglial activation in obesity pathogenesis.…”

“…We previously demonstrated that microglial activation induced by HFD feeding increases food intake and weight gain in mice (Dorfman et al, 2017; Niraula et al, 2021; Valdearcos et al, 2014, 2017), but the impact on glucose homeostasis was not explored. To examine the impact of microglial inflammatory signaling on glycemia in established obesity, we returned to our previously published Cx3cr1 CreER/+ :: Ikbkb fl/fl mouse model (IKKβ-MGKO) (Valdearcos et al, 2017).…”

“…Therefore, the studies of microglial alterations to body weight showed the expected parallel effects on glycemic parameters (Dorfman et al, 2017;Gao et al, 2017;Kim et al, 2019;Niraula et al, 2021;Wang et al, 2020). However, CNS regulation of energy balance and systemic glycemia occurs via distinct pathways (Myers et al, 2021), raising the untested possibility of direct body weight-independent effects of microglial activation on glucose homeostasis.…”

“…These observations led to the hypothesis that activated microglia promote the progression of diet-induced obesity (DIO) and insulin resistance (Ávalos et al, 2018; Berkseth et al, 2014; Douglass et al, 2017a; Schur et al, 2015; Thaler et al, 2012; Valdearcos et al, 2015, 2019). Indeed, there is now substantial evidence that microglia increase DIO susceptibility (Dorfman et al, 2017; Gao et al, 2017; Kim et al, 2019; Niraula et al, 2021; Valdearcos et al, 2014, 2017; Wang et al, 2020), but a weight-independent role for microglia in glucose homeostasis has not been established.…”