While resident innate immune cells of the central nervous system, the microglia, represent a cell population unique in origin, microenvironment, and longevity, they assume many properties displayed by peripheral macro...While resident innate immune cells of the central nervous system, the microglia, represent a cell population unique in origin, microenvironment, and longevity, they assume many properties displayed by peripheral macrophages. One prominent shared property is the ability to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS) upon activation by the pro-inflammatory stimuli lipopolysaccharide. This shift serves to meet specific cellular demands and allows for cell survival, similar to the Warburg effect demonstrated in cancer cells. In contrast, normal surveillance phenotype or stimulation to a non-proinflammatory phenotype relies primarily on OXPHOS and fatty acid oxidation. Thus, mitochondria appear to function as a pivotal signaling platform linking energy metabolism and macrophage polarization upon activation. These unique shifts in cell bioenergetics in response to different stimuli are essential for proper effector responses at sites of infection, inflammation, or injury. Here, we present a summary of recent developments as to how these dynamics characterized in peripheral macrophages are displayed in microglia. The new insights provided by an increased understanding of metabolic reprogramming in macrophages may allow for translation to the central nervous system and a better understanding of microglia heterogeneity, regulation, and function.展开更多
Background:Perfluorooctanoic acid(PFOA)is an environmental contaminant associated with adverse metabolic outcomes in developmentally exposed human populations and mouse models.Hexafluoropropylene oxide-dimer acid(HFPO...Background:Perfluorooctanoic acid(PFOA)is an environmental contaminant associated with adverse metabolic outcomes in developmentally exposed human populations and mouse models.Hexafluoropropylene oxide-dimer acid(HFPO-DA,commonly called GenX)has replaced PFOA in many industrial applications in the U.S.and Europe and has been measured in global water systems from<1 to 9350 ng/L HFPO-DA.Health effects data for GenX are lacking.Objective:Determine the effects of gestational exposure to GenX on offspring weight gain trajectory,adult metabolic health,liver pathology and key adipose gene pathways in male and female CD-1 mice.Methods:Daily oral doses of GenX(0.2,1.0,2.0 mg/kg),PFOA(0.1,1.0 mg/kg),or vehicle control were administered to pregnant mice(gestation days 1.5-17.5).Offspring were fed a high-or low-fat diet(HFD or LFD)at weaning until necropsy at 6 or 18 weeks,and metabolic endpoints were measured over time.PFOA and GenX serum and urine concentrations,weight gain,serum lipid parameters,body mass composition,glucose tolerance,white adipose tissue gene expression,and liver histopathology were evaluated.Results:Prenatal exposure to GenX led to its accumulation in the serum and urine of 5-day old pups(P=0.007,P<0.001),which was undetectable by weaning.By 18 weeks of age,male mice fed LFD in the 2.0 mg/kg GenX group displayed increased weight gain(P<0.05),fat mass(P=0.016),hepatocellular microvesicular fatty change(P=0.015),and insulin sensitivity(P=0.014)in comparison to control males fed LFD.Female mice fed HFD had a significant increase in hepatocyte single cell necrosis in 1.0 mg/kg GenX group(P=0.022)and 1.0 mg/kg PFOA group(P=0.003)compared to control HFD females.Both sexes were affected by gestational GenX exposure;however,the observed phenotype varied between sex with males displaying more characteristics of metabolic disease and females exhibiting liver damage in response to the gestational exposure.Conclusions:Prenatal exposure to 1 mg/kg GenX and 1 mg/kg PFOA induces adverse metabolic outcomes in adult mice that are diet-and sex-dependent.GenX also accumulated in pup serum,suggesting that placental and potentially lactational transfer are important exposure routes for GenX.展开更多
基金The research was supported by NIH intramural research funding ES021164
文摘While resident innate immune cells of the central nervous system, the microglia, represent a cell population unique in origin, microenvironment, and longevity, they assume many properties displayed by peripheral macrophages. One prominent shared property is the ability to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation (OXPHOS) upon activation by the pro-inflammatory stimuli lipopolysaccharide. This shift serves to meet specific cellular demands and allows for cell survival, similar to the Warburg effect demonstrated in cancer cells. In contrast, normal surveillance phenotype or stimulation to a non-proinflammatory phenotype relies primarily on OXPHOS and fatty acid oxidation. Thus, mitochondria appear to function as a pivotal signaling platform linking energy metabolism and macrophage polarization upon activation. These unique shifts in cell bioenergetics in response to different stimuli are essential for proper effector responses at sites of infection, inflammation, or injury. Here, we present a summary of recent developments as to how these dynamics characterized in peripheral macrophages are displayed in microglia. The new insights provided by an increased understanding of metabolic reprogramming in macrophages may allow for translation to the central nervous system and a better understanding of microglia heterogeneity, regulation, and function.
文摘Background:Perfluorooctanoic acid(PFOA)is an environmental contaminant associated with adverse metabolic outcomes in developmentally exposed human populations and mouse models.Hexafluoropropylene oxide-dimer acid(HFPO-DA,commonly called GenX)has replaced PFOA in many industrial applications in the U.S.and Europe and has been measured in global water systems from<1 to 9350 ng/L HFPO-DA.Health effects data for GenX are lacking.Objective:Determine the effects of gestational exposure to GenX on offspring weight gain trajectory,adult metabolic health,liver pathology and key adipose gene pathways in male and female CD-1 mice.Methods:Daily oral doses of GenX(0.2,1.0,2.0 mg/kg),PFOA(0.1,1.0 mg/kg),or vehicle control were administered to pregnant mice(gestation days 1.5-17.5).Offspring were fed a high-or low-fat diet(HFD or LFD)at weaning until necropsy at 6 or 18 weeks,and metabolic endpoints were measured over time.PFOA and GenX serum and urine concentrations,weight gain,serum lipid parameters,body mass composition,glucose tolerance,white adipose tissue gene expression,and liver histopathology were evaluated.Results:Prenatal exposure to GenX led to its accumulation in the serum and urine of 5-day old pups(P=0.007,P<0.001),which was undetectable by weaning.By 18 weeks of age,male mice fed LFD in the 2.0 mg/kg GenX group displayed increased weight gain(P<0.05),fat mass(P=0.016),hepatocellular microvesicular fatty change(P=0.015),and insulin sensitivity(P=0.014)in comparison to control males fed LFD.Female mice fed HFD had a significant increase in hepatocyte single cell necrosis in 1.0 mg/kg GenX group(P=0.022)and 1.0 mg/kg PFOA group(P=0.003)compared to control HFD females.Both sexes were affected by gestational GenX exposure;however,the observed phenotype varied between sex with males displaying more characteristics of metabolic disease and females exhibiting liver damage in response to the gestational exposure.Conclusions:Prenatal exposure to 1 mg/kg GenX and 1 mg/kg PFOA induces adverse metabolic outcomes in adult mice that are diet-and sex-dependent.GenX also accumulated in pup serum,suggesting that placental and potentially lactational transfer are important exposure routes for GenX.