Romina Uranga - Academia.edu (original) (raw)
Papers by Romina Uranga
10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Si... more 10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Sites Find articles, minireviews, Reflections and Classics on similar topics on the Alerts: When a correction for this article is posted • When this article is cited • to choose from all of JBC's e-mail alerts Click here http://www.jbc.org/content/288/27/19773.full.html#ref-list-1 This article cites 60 references, 15 of which can be accessed free at
Frontiers in Neuroscience, 2019
Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the ... more Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the various organ systems of the body is only beginning to be fully appreciated. Because of the myriad of direct and indirect effects of obesity causing dysfunction of multiple tissues and organs, it is likely that there will be heterogeneity in the presentation of obesity effects in any given population. Taken together, these realities make it increasingly difficult to understand the complex interplay between obesity effects on different organs, including the brain. The focus of this review is to provide a comprehensive view of metabolic disturbances present in obesity, their direct and indirect effects on the different organ systems of the body, and to discuss the interaction of these effects in the context of brain aging and the development of neurodegenerative diseases.
Current gerontology and geriatrics research, 2010
Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its num... more Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its numerous complications are believed to play a role in promoting multiple aspects of brain pathogenesis. An ever increasing number of individuals in modern Western Society are regularly consuming diets high in fat which promote the development of hypercholesterolemia. Additionally, modern societies are becoming increasingly aged, causing a collision between increased hypercholesterolemia and increased aging, which will likely lead to the development of increased pathological conditions due to hypercholesterolemia, thereby promoting deleterious neurochemical and behavioral changes in the brain. Lastly, while beneficial in controlling cholesterol levels, the long-term use of statins itself may potentially promote adverse effects on brain homeostasis, although specifics on this remain largely unknown. This review will focus on linking the current understanding of diet-induced hypercholesterolem...
Antiviral research, 2010
It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequentl... more It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function reve...
Free Radical Biology and Medicine, 2010
Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a... more Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a role for proteasome inhibition occurring during the aging of a variety of tissues, and presumably contributing to the disruption of cellular homeostasis during aging. In the present study we sought to elucidate the differences between neurons and astrocytes in regards to basal levels of protein synthesis, proteasome-mediated protein degradation, and sensitivity to cytoxicity following proteasome inhibitor treatment. In these studies we demonstrate that neurons have an increased vulnerability, as compared to astrocyte cultures, to proteasome inhibitor-induced cytotoxicity. No significant difference was observed between these two cell types in regards to the basal rates of protein synthesis, or basal rates of protein degradation, in the pool of short-lived proteins. Following proteasome inhibitor treatment neuronal crude lysates were observed to undergo greater increases in the levels of ubiquitinated and oxidized proteins, and selectively exhibited increased levels of newly synthesized proteins accumulating within the insoluble protein pool, as compared to astrocytes. Together, these data suggest a role for increased oxidized proteins and sequestration of newly synthesized proteins to the insoluble protein pool, as potential mediators of the selective neurotoxicity following proteasome inhibitor treatment. The implications for neurons exhibiting increased sensitivity to acute proteasome inhibitor exposure, and the corresponding changes in protein homeostasis observed following proteasome inhibition, are discussed in the context of both aging and age-related disorders of the nervous system.
PLoS ONE, 2011
Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the... more Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the mechanisms involved in hypothalamic glucosensing. We have postulated that hypothalamic glial cells, also known as tanycytes, produce lactate by glycolytic metabolism of glucose. Transfer of lactate to neighboring neurons stimulates ATP synthesis and thus contributes to their activation. Because destruction of third ventricle (III-V) tanycytes is sufficient to alter blood glucose levels and food intake in rats, it is hypothesized that tanycytes are involved in the hypothalamic glucose sensing mechanism. Here, we demonstrate the presence and function of monocarboxylate transporters (MCTs) in tanycytes. Specifically, MCT1 and MCT4 expression as well as their distribution were analyzed in Sprague Dawley rat brain, and we demonstrate that both transporters are expressed in tanycytes. Using primary tanycyte cultures, kinetic analyses and sensitivity to inhibitors were undertaken to confirm that MCT1 and MCT4 were functional for lactate influx. Additionally, physiological concentrations of glucose induced lactate efflux in cultured tanycytes, which was inhibited by classical MCT inhibitors. Because the expression of both MCT1 and MCT4 has been linked to lactate efflux, we propose that tanycytes participate in glucose sensing based on a metabolic interaction with neurons of the arcuate nucleus, which are stimulated by lactate released from MCT1 and MCT4-expressing tanycytes.
Scientific Reports, 2019
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Scientific reports, Jun 16, 2017
Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expresse... more Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART a...
Journal of Neuroscience Research, 2011
Amino acid analogs promote translational errors that result in aberrant protein synthesis, and ha... more Amino acid analogs promote translational errors that result in aberrant protein synthesis, and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. In this study we exposed primary rat neurons and astrocyte cultures to established amino acid analogs (Canavanine and Azetidine-2-carboxylic acid), and observed both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity as compared to astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased Heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43, in response to increased protein misfolding, as compared to astrocytes.
Journal of Neurochemistry, 2010
Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. ... more Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either "Western Diet" (WD, 41% fat), very high fat lard diet (HFL, 60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the HFL diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in Nrf2 levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.
Journal of Neurochemistry, 2010
Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable asp... more Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.
10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Si... more 10.1074/jbc.M113.457622 Access the most updated version of this article at doi: . JBC Affinity Sites Find articles, minireviews, Reflections and Classics on similar topics on the Alerts: When a correction for this article is posted • When this article is cited • to choose from all of JBC's e-mail alerts Click here http://www.jbc.org/content/288/27/19773.full.html#ref-list-1 This article cites 60 references, 15 of which can be accessed free at
Frontiers in Neuroscience, 2019
Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the ... more Obesity is increasing at unprecedented levels globally, and the overall impact of obesity on the various organ systems of the body is only beginning to be fully appreciated. Because of the myriad of direct and indirect effects of obesity causing dysfunction of multiple tissues and organs, it is likely that there will be heterogeneity in the presentation of obesity effects in any given population. Taken together, these realities make it increasingly difficult to understand the complex interplay between obesity effects on different organs, including the brain. The focus of this review is to provide a comprehensive view of metabolic disturbances present in obesity, their direct and indirect effects on the different organ systems of the body, and to discuss the interaction of these effects in the context of brain aging and the development of neurodegenerative diseases.
Current gerontology and geriatrics research, 2010
Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its num... more Cholesterol is an essential molecule for brain homeostasis; yet, hypercholesterolemia and its numerous complications are believed to play a role in promoting multiple aspects of brain pathogenesis. An ever increasing number of individuals in modern Western Society are regularly consuming diets high in fat which promote the development of hypercholesterolemia. Additionally, modern societies are becoming increasingly aged, causing a collision between increased hypercholesterolemia and increased aging, which will likely lead to the development of increased pathological conditions due to hypercholesterolemia, thereby promoting deleterious neurochemical and behavioral changes in the brain. Lastly, while beneficial in controlling cholesterol levels, the long-term use of statins itself may potentially promote adverse effects on brain homeostasis, although specifics on this remain largely unknown. This review will focus on linking the current understanding of diet-induced hypercholesterolem...
Antiviral research, 2010
It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequentl... more It is well established that HIV antiretroviral drugs, particularly protease inhibitors, frequently elicit a metabolic syndrome that may include hyperlipidemia, lipodystrophy, and insulin resistance. Metabolic dysfunction in non-HIV-infected subjects has been repeatedly associated with cognitive impairment in epidemiological and experimental studies, but it is not yet understood if antiretroviral therapy-induced metabolic syndrome might contribute to HIV-associated neurologic decline. To determine if protease inhibitor-induced metabolic dysfunction in mice is accompanied by adverse neurologic effects, C57BL/6 mice were given combined lopinavir/ritonavir (50/12.5-200/50 mg/kg) daily for 3 weeks. Data show that lopinavir/ritonavir administration caused significant metabolic derangement, including alterations in body weight and fat mass, as well as dose-dependent patterns of hyperlipidemia, hypoadiponectinemia, hypoleptinemia, and hyperinsulinemia. Evaluation of neurologic function reve...
Free Radical Biology and Medicine, 2010
Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a... more Maintaining protein homeostasis is vital to cell viability, with numerous studies demonstrating a role for proteasome inhibition occurring during the aging of a variety of tissues, and presumably contributing to the disruption of cellular homeostasis during aging. In the present study we sought to elucidate the differences between neurons and astrocytes in regards to basal levels of protein synthesis, proteasome-mediated protein degradation, and sensitivity to cytoxicity following proteasome inhibitor treatment. In these studies we demonstrate that neurons have an increased vulnerability, as compared to astrocyte cultures, to proteasome inhibitor-induced cytotoxicity. No significant difference was observed between these two cell types in regards to the basal rates of protein synthesis, or basal rates of protein degradation, in the pool of short-lived proteins. Following proteasome inhibitor treatment neuronal crude lysates were observed to undergo greater increases in the levels of ubiquitinated and oxidized proteins, and selectively exhibited increased levels of newly synthesized proteins accumulating within the insoluble protein pool, as compared to astrocytes. Together, these data suggest a role for increased oxidized proteins and sequestration of newly synthesized proteins to the insoluble protein pool, as potential mediators of the selective neurotoxicity following proteasome inhibitor treatment. The implications for neurons exhibiting increased sensitivity to acute proteasome inhibitor exposure, and the corresponding changes in protein homeostasis observed following proteasome inhibition, are discussed in the context of both aging and age-related disorders of the nervous system.
PLoS ONE, 2011
Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the... more Metabolic interaction via lactate between glial cells and neurons has been proposed as one of the mechanisms involved in hypothalamic glucosensing. We have postulated that hypothalamic glial cells, also known as tanycytes, produce lactate by glycolytic metabolism of glucose. Transfer of lactate to neighboring neurons stimulates ATP synthesis and thus contributes to their activation. Because destruction of third ventricle (III-V) tanycytes is sufficient to alter blood glucose levels and food intake in rats, it is hypothesized that tanycytes are involved in the hypothalamic glucose sensing mechanism. Here, we demonstrate the presence and function of monocarboxylate transporters (MCTs) in tanycytes. Specifically, MCT1 and MCT4 expression as well as their distribution were analyzed in Sprague Dawley rat brain, and we demonstrate that both transporters are expressed in tanycytes. Using primary tanycyte cultures, kinetic analyses and sensitivity to inhibitors were undertaken to confirm that MCT1 and MCT4 were functional for lactate influx. Additionally, physiological concentrations of glucose induced lactate efflux in cultured tanycytes, which was inhibited by classical MCT inhibitors. Because the expression of both MCT1 and MCT4 has been linked to lactate efflux, we propose that tanycytes participate in glucose sensing based on a metabolic interaction with neurons of the arcuate nucleus, which are stimulated by lactate released from MCT1 and MCT4-expressing tanycytes.
Scientific Reports, 2019
An amendment to this paper has been published and can be accessed via a link at the top of the pa... more An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Scientific reports, Jun 16, 2017
Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expresse... more Glucokinase (GK), the hexokinase involved in glucosensing in pancreatic β-cells, is also expressed in arcuate nucleus (AN) neurons and hypothalamic tanycytes, the cells that surround the basal third ventricle (3V). Several lines of evidence suggest that tanycytes may be involved in the regulation of energy homeostasis. Tanycytes have extended cell processes that contact the feeding-regulating neurons in the AN, particularly, agouti-related protein (AgRP), neuropeptide Y (NPY), cocaine- and amphetamine-regulated transcript (CART) and proopiomelanocortin (POMC) neurons. In this study, we developed an adenovirus expressing GK shRNA to inhibit GK expression in vivo. When injected into the 3V of rats, this adenovirus preferentially transduced tanycytes. qRT-PCR and Western blot assays confirmed GK mRNA and protein levels were lower in GK knockdown animals compared to the controls. In response to an intracerebroventricular glucose injection, the mRNA levels of anorexigenic POMC and CART a...
Journal of Neuroscience Research, 2011
Amino acid analogs promote translational errors that result in aberrant protein synthesis, and ha... more Amino acid analogs promote translational errors that result in aberrant protein synthesis, and have been used to understand the effects of protein misfolding in a variety of physiological and pathological settings. TDP-43 is a protein that is linked to protein aggregation and toxicity in a variety of neurodegenerative diseases. In this study we exposed primary rat neurons and astrocyte cultures to established amino acid analogs (Canavanine and Azetidine-2-carboxylic acid), and observed both cell types undergo a dose-dependent increase in toxicity, with neurons exhibiting a greater degree of toxicity as compared to astrocytes. Neurons and astrocytes exhibited similar increases in ubiquitinated and oxidized protein following analog treatment. Analog treatment increased Heat shock protein (Hsp) levels in both neurons and astrocytes. In neurons, and to a lesser extent astrocytes, the levels of TDP-43 increased in response to analog treatment. Taken together, these data indicate that neurons exhibit preferential toxicity and alterations in TDP-43, in response to increased protein misfolding, as compared to astrocytes.
Journal of Neurochemistry, 2010
Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. ... more Long term consumption of a high fat diet (HFD) contributes to increased morbidity and mortality. Yet the specific effects of HFD consumption on brain aging are poorly understood. In the present study 20-month old male C57Bl/6 mice were fed either "Western Diet" (WD, 41% fat), very high fat lard diet (HFL, 60% fat), or corresponding control diets for 16 weeks and then assessed for changes in metabolism and brain homeostasis. Although both HFDs increased adiposity and fasting blood glucose, only the HFL diet increased age-related oxidative damage (protein carbonyls) and impaired retention in the behavioral test. This selective increase in oxidative damage and cognitive decline was also associated with a decline in Nrf2 levels and Nrf2 activity, suggesting a potential role for decreased antioxidant response. Taken together, these data suggest that while adiposity and insulin resistance following HFD consumption are linked to increased morbidity, the relationship between these factors and brain homeostasis during aging is not a linear relationship. More specifically, these data implicate impaired Nrf2 signaling and increased cerebral oxidative stress as mechanisms underlying HFD-induced declines in cognitive performance in the aged brain.
Journal of Neurochemistry, 2010
Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable asp... more Deleterious neurochemical, structural, and behavioral alterations are a seemingly unavoidable aspect of brain aging. However, the basis for these alterations, as well as the basis for the tremendous variability in regards to the degree to which these aspects are altered in aging individuals, remains to be elucidated. An increasing number of individuals regularly consume a diet high in fat, with high fat diet consumption known to be sufficient to promote metabolic dysfunction, although the links between high fat diet consumption and aging are only now beginning to be elucidated. In this review we discuss the potential role for age-related metabolic disturbances serving as an important basis for deleterious perturbations in the aging brain. These data not only have important implications for understanding the basis of brain aging, but also may be important to the development of therapeutic interventions which promote successful brain aging.