RESUMEN
Glaucoma is a leading cause of blindness. Current glaucoma medications work by lowering intraocular pressure (IOP), a risk factor for glaucoma, but most treatments do not directly target the pathological changes leading to increased IOP, which can manifest as medication resistance as disease progresses. To identify physiological modulators of IOP, we performed genome- and exome-wide association analysis in >129,000 individuals with IOP measurements and extended these findings to an analysis of glaucoma risk. We report the identification and functional characterization of rare coding variants (including loss-of-function variants) in ANGPTL7 associated with reduction in IOP and glaucoma protection. We validated the human genetics findings in mice by establishing that Angptl7 knockout mice have lower (~2 mmHg) basal IOP compared to wild-type, with a trend towards lower IOP also in heterozygotes. Conversely, increasing murine Angptl7 levels via injection into mouse eyes increases the IOP. We also show that acute Angptl7 silencing in adult mice lowers the IOP (~2-4 mmHg), reproducing the observations in knockout mice. Collectively, our data suggest that ANGPTL7 is important for IOP homeostasis and is amenable to therapeutic modulation to help maintain a healthy IOP that can prevent onset or slow the progression of glaucoma.
Asunto(s)
Glaucoma , Presión Intraocular , Adulto , Proteína 7 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina/genética , Animales , Ceguera , Glaucoma/tratamiento farmacológico , Glaucoma/genética , Humanos , Ratones , Ratones NoqueadosRESUMEN
Previously, organophosphate flame retardants (OPFRs) were found to produce intersecting disruptions of energy homeostasis using an adult mouse model of diet-induced obesity. Using the same mixture consisting of 1 mg/kg/day of each triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate, the current study aimed to identify the role of estrogen receptor alpha (ERα) in OPFR-induced disruption, utilizing ERα knockout (ERαKO) mice fed either a low-fat diet (LFD) or high-fat diet (HFD). Body weight and composition, food intake patterns, glucose and insulin tolerance, circulating peptide hormones, and expression of hypothalamic genes associated with energy homeostasis were measured. When fed HFD, no marked direct effects of OPFR were observed in mice lacking ERα, suggesting a role for ERα in generating previously reported wildtype (WT) findings. Male ERαKO mice fed LFD experienced decreased feeding efficiency and altered insulin tolerance, whereas their female counterparts displayed less fat mass and circulating ghrelin when exposed to OPFRs. These effects were not noted in the previous WT study, indicating that loss of ERα may sensitize animals fed LFD to alternate pathways of endocrine disruption by OFPRs. Collectively, these data demonstrate both direct and indirect actions of OPFRs on ERα-mediated pathways governing energy homeostasis and support a growing body of evidence urging concern for risk of human exposure.
Asunto(s)
Retardadores de Llama , Animales , Dieta Alta en Grasa/efectos adversos , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Retardadores de Llama/toxicidad , Insulina , Masculino , Ratones , Obesidad/inducido químicamente , Obesidad/metabolismo , OrganofosfatosRESUMEN
Previously, organophosphate flame retardants (OPFRs) were demonstrated to dysregulate homeostatic parameters of energy regulation within an adult mouse model of diet-induced obesity. Using the same OPFR mixture consisting of 1 mg/kg/day of each triphenyl phosphate, tricresyl phosphate, and tris(1,3-dichloro-2-propyl)phosphate, the current study examined the role of peroxisome proliferator-activated receptor gamma (PPARγ) in OPFR-induced disruption by utilizing mice with brain-specific deletion of PPARγ (PPARγKO) fed either a low-fat diet (LFD) or high-fat diet (HFD). Body weight and composition, feeding behavior, glucose and insulin tolerance, circulating peptide hormones, and expression of hypothalamic genes associated with energy homeostasis were recorded. When fed HFD, the effects of OPFR on body weight and feeding behavior observed in the previous wild-type (WT) study were absent in mice lacking neuronal PPARγ. This posits PPARγ as an important target for eliciting OPFR disruption in a diet-induced obesity model. Interestingly, female PPARγKO mice, but not males, experienced many novel OPFR effects not noted in WT mice, including decreased fat mass, altered feeding behavior and efficiency, improved insulin sensitivity, elevated plasma ghrelin and hypothalamic expression of its receptor. Taken together, these data suggest both direct roles for PPARγ in OPFR disruption of obese mice and indirect sensitization of pathways alternative to PPARγ when neuronal expression is deleted.
Asunto(s)
Dieta Alta en Grasa , PPAR gamma , Animales , Dieta Alta en Grasa/efectos adversos , Femenino , Retardadores de Llama , Ratones , Obesidad/inducido químicamente , Obesidad/metabolismo , Organofosfatos , PPAR gamma/genéticaRESUMEN
Persistent organic pollutants such as organophosphate flame retardants (OPFRs) can accumulate in the body and interact with nuclear receptors that control energy homeostasis. One sensitive window of exposure is during development, either in utero or neonatal. Therefore, we investigated if maternal exposure to a mixture of OPFRs alters metabolism on a low-fat diet (LFD) or a high-fat diet (HFD) in both male and female offspring. Wild-type C57Bl/6J dams were orally dosed with vehicle (sesame oil) or an OPFR mixture (1 mg/kg each of tris(1,3-dichloro-2-propyl)phosphate, triphenyl phosphate, and tricresyl phosphate) from gestation day 7 to postnatal day 14. After weaning, pups were fed LFD or HFD. To assess metabolism, we measured body weight and food intake weekly and determined body composition, metabolism, activity, and glucose homeostasis at 6 months of age. Although maternal OPFR exposure did not alter body weight or adiposity, OPFR exposure altered substrate utilization and energy expenditure depending on diet in both sexes. Systolic and diastolic blood pressure was increased by OPFR in male offspring. OPFR exposure interacted with HFD to increase fasting glucose in females and alter glucose and insulin tolerance in male offspring. Plasma leptin was reduced in male and female offspring when fed HFD, whereas liver expression of Pepck was increased in females and Esr1 (estrogen receptor α) was increased in both sex. The physiological implications indicate maternal exposure to OPFRs programs peripheral organs including the liver and adipose tissue, in a sex-dependent manner, thus changing the response to an obesogenic diet and altering adult offspring energy homeostasis.
Asunto(s)
Metabolismo Energético/efectos de los fármacos , Retardadores de Llama/toxicidad , Homeostasis/efectos de los fármacos , Metabolismo de los Lípidos/efectos de los fármacos , Exposición Materna/efectos adversos , Intercambio Materno-Fetal/efectos de los fármacos , Animales , Animales Recién Nacidos , Modelos Animales de Enfermedad , Metabolismo Energético/genética , Femenino , Homeostasis/genética , Humanos , Metabolismo de los Lípidos/genética , Intercambio Materno-Fetal/genética , Ratones , Ratones Endogámicos C57BL , EmbarazoRESUMEN
Increased usage of organophosphate flame retardants (OPFRs) has led to detectable levels in pregnant women and neonates, which is associated with negative neurological outcomes. Therefore, we investigated if maternal OPFR exposure altered adult offspring feeding, locomotor, and anxiety-like behaviors on a low-fat (LFD) or high-fat diet (HFD). Wild-type C57Bl/6J dams were orally dosed with vehicle (sesame oil) or an OPFR mixture (1 mg/kg combination each of tris(1,3-dichloro-2-propyl)phosphate, triphenyl phosphate and tricresyl phosphate) from gestation day 7 to postnatal day 14. After weaning, pups were fed either a LFD or HFD until 19 weeks of age. Locomotor and anxiety-like behaviors were evaluated with the open field test, elevated plus maze, and metabolic cages. Feeding behaviors and meal patterns were analyzed by a Biological Data Acquisition System. Anogenital distance was reduced in OPFR-exposed male pups, but no effect was detected on adult body weight. We observed interactions of OPFR exposure and HFD consumption on locomotor and anxiety-like behavior in males, suggesting an anxiogenic effect while reducing overall nighttime activity. We also observed an interaction of OPFR exposure and HFD on weekly food intake and feeding behaviors. OPFR-exposed males consumed more total HFD than oil-exposed males during the 72-hour trial. However, when arcuate gene expression was analyzed, OPFR exposure induced Agrp expression in females, which would suggest greater orexigenic tone. Collectively, the implications of our study are that the behavioral effects of OPFR exposure are modulated by adult HFD consumption, which may influence the metabolic and neurological consequences of maternal OPFR exposure.
Asunto(s)
Conducta Exploratoria/efectos de los fármacos , Conducta Alimentaria/efectos de los fármacos , Retardadores de Llama/toxicidad , Locomoción/efectos de los fármacos , Exposición Materna/efectos adversos , Organofosfatos/toxicidad , Animales , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Embarazo , Caracteres SexualesRESUMEN
Previously, sex-dependent alterations in energy homeostasis were reported in adult mice fed a standard chow attributed to exposure to a mixture of organophosphate flame retardants (OPFRs) via estrogen receptors (ERα). In this study, adult male and female mice (C57BL/6J; Taconic) were treated with the same mixture of OPFRs (1 mg/kg each of tricresyl phosphate (TCP), triphenyl phosphate (TPP), and tris(1-3-dichloro-2propyl)phosphate (TDCPP)) for 7 weeks on a low-fat diet (LFD, 10% kcal fat) or a high fat (HFD, 45% kcal fat) in a diet-induced obesity model. Consistent with our previous observations, OPFRs altered weight gain in males, differentially with diet, while females remained unaffected. OPFR treatment also revealed sex-dependent perturbations in metabolic activity. During the night (approximately 0100-0400 hr), males exhibited elevated activity and oxygen consumption, while in females these parameters were decreased, irrespective of diet. OPFR disrupted feeding behavior and abolished diurnal water intake patterns in females while increasing nighttime fluid consumption in males. Despite no marked effect of OPFRs on glucose or insulin tolerance, OPFR treatment altered circulating insulin and leptin in females and ghrelin in males. Data indicate that adult OPFR exposure might influence, and perhaps exacerbate, the effects of diet-induced obesity in adult mice by altering activity, ingestive behavior, and metabolism.
Asunto(s)
Exposición Dietética/efectos adversos , Metabolismo Energético/efectos de los fármacos , Retardadores de Llama/toxicidad , Obesidad/etiología , Organofosfatos/toxicidad , Animales , Conducta Alimentaria/efectos de los fármacos , Femenino , Homeostasis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Obesidad/metabolismo , Hormonas Peptídicas/sangre , Factores Sexuales , Aumento de Peso/efectos de los fármacosRESUMEN
Endocrine disrupting compounds (EDC) are ubiquitous environmental contaminants that can interact with steroid and nuclear receptors or alter hormone production. Many studies have reported that perinatal exposure to EDC including bisphenol A, PCB, dioxins, and DDT disrupt energy balance, body weight, adiposity, or glucose homeostasis in rodent offspring. However, little information exists on the effects of perinatal EDC exposure on the control of feeding behaviors and meal pattern (size, frequency, duration), which may contribute to their obesogenic properties. Feeding behaviors are controlled centrally through communication between the hindbrain and hypothalamus with inputs from the emotion and reward centers of the brain and modulated by peripheral hormones like ghrelin and leptin. Discrete hypothalamic nuclei (arcuate nucleus, paraventricular nucleus, lateral and dorsomedial hypothalamus, and ventromedial nucleus) project numerous reciprocal neural connections between each other and to other brain regions including the hindbrain (nucleus tractus solitarius and parabrachial nucleus). Most studies on the effects of perinatal EDC exposure examine simple crude food intake over the course of the experiment or for a short period in adult models. In addition, these studies do not examine EDC's impacts on the feeding neurocircuitry of the hypothalamus-hindbrain, the response to peripheral hormones (leptin, ghrelin, cholecystokinin, etc.) after refeeding, or other feeding behavior paradigms. The purpose of this review is to discuss those few studies that report crude food or energy intake after perinatal EDC exposure and to explore the need for deeper investigations in the hypothalamic-hindbrain neurocircuitry and discrete feeding behaviors.