<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>

Introduction: The global burden of peripheral arterial disease and related critical limb ischemia has been increasing, and with it an increased incidence of limb loss and mortality. Multidisciplinary teams appear to have a beneficial impact on managing these complex patients, but measuring success depends on the outcome chosen. Determining the risk/benefit of intervention can be difficult, and there has been increasing emphasis on using frailty measures to predict the likelihood of morbidity and mortality after vascular interventions. Methods: We performed a retrospective review of patients referred to a multidisciplinary team over a 5-year period who underwent intervention. Data included the modified Frailty Index (mFI), Society for Vascular Surgery (SVS) WIfI wound score (0-2 vs 3), and pedal acceleration time (PAT) post-procedure. Outcomes analyzed were 1-year amputation-free survival (AFS-1), independence, and major complications. Results: There were 81 patients who underwent either open or endovascular revascularization. One-year amputation-free survival was positively correlated with post-procedure PAT (AFS-1 107.3 ± 25.5 vs non-AFS-1 174 ± 93; P = .025) and inversely related to wound score (SVS 3 AFS-1 5/17 [29%] vs SVS 0-2: 46/64 [72%]; P = .025). Independence was linked to wheelchair dependence prior to intervention with 6/16 (38%) patients patients spending more than 50% of their time in a wheelchair being independent versus 56/64 (88%) who were not wheelchair-dependent being independent ( P = .005). An mFI ≥6 was associated with increased incidence of major complications at 1 year (mFI ≥6 11/31 [35%] vs mFI <6 5/50 [10%]; P = .018). Conclusion: One-year amputation-free survival was impacted by post-procedural success as measured by PAT, but negatively impacted by severity of wound at presentation. An mFI ≥6 was associated with greater incidence of complications. These findings may impact decision-making in determining the relative risk/benefit of revascularization in CLI. Vascular technologists can have an important role in development of limb salvage teams.

<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>