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Across two studies, we explored whether framing an assignment as involving either multitasking or single-tasking (Srna et al. Psychol Sci 29(12):1942-1955, 2018) leads to differences in both subjective ratings of attentional engagement (i.e., depth of concentration and attentional control) and performance during the assignment. In Experiment 1, we manipulated task framing in the context of an assignment in which participants (Ncollected = 238) simultaneously completed a word-search and an anagram task (Srna et al. Psychol Sci 29(12):1942-1955, 2018). While we replicated prior findings that participants who receive multitasking instructions perform better than those who receive single-tasking instructions, we did not find any influence of task framing on participants' subjective evaluations of their attentional engagement. Exploratory analyses, however, revealed that regardless of group assignment, those who believed they were multitasking reported greater levels of attentional engagement than those who believed they were single-tasking. In Experiment 2 (Ncollected = 238), task framing was varied in the context of the 2-back task (Kirchner J Exp Psychol 55(4): 352, 1958). Unexpectedly, we found that, relative to participants who received single-tasking instructions, those who received multitasking instructions reported exerting less attentional control over their thoughts and showed a greater number of incorrect responses to non-target trials on the 2-back. Taken together, the results do not support a straightforward conclusion regarding the influence of task framing on either subjective reports of attentional engagement or task performance. Nevertheless, they provide insight into our understanding of the role of task framing in contexts ranging from commonly performed real-world tasks to typical laboratory tasks.
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Atención , ARN Pequeño no Traducido , Humanos , Atención/fisiología , Análisis y Desempeño de TareasRESUMEN
BACKGROUND/OBJECTIVES: Alteration of the perinatal nutritional environment is an important risk factor for the development of metabolic diseases in later life. The hormone leptin plays a critical role in growth and development. Previous studies reported that postnatal overnutrition increases leptin secretion during the pre-weaning period. However, a direct link between leptin, neonatal overnutrition, and lifelong metabolic regulation has not been investigated. METHODS: We used the small litter mouse model combined with neonatal leptin antagonist injections to examine whether attenuating leptin during early life improves lifelong metabolic regulation in postnatally overnourished mice. RESULTS: Postnatally overnourished mice displayed rapid weight gain during lactation and remained overweight as adults. These mice also showed increased adiposity and perturbations in glucose homeostasis in adulthood. Neonatal administration of a leptin antagonist normalized fat mass and insulin sensitivity in postnatally overnourished mice. These metabolic improvements were associated with enhanced sensitivity of hypothalamic neurons to leptin. CONCLUSIONS: Early postnatal overnutrition causes metabolic alterations that can be permanently attenuated with the administration of a leptin antagonist during a restricted developmental window.
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Leptina , Hipernutrición , Animales , Femenino , Hipotálamo/metabolismo , Leptina/metabolismo , Ratones , Obesidad/metabolismo , Hipernutrición/metabolismo , Embarazo , Aumento de PesoRESUMEN
Rosenbaum, Mama, and Algom (2017) reported that participants who completed the Stroop task (i.e., name the hue of a color word when the hue and word meaning are congruent or incongruent) showed a smaller Stroop effect (i.e., the difference in response times between congruent and incongruent trials) when they performed the task standing than when sitting. We report five attempted replications (analyzed sample sizes: N = 108, N = 108, N = 98, N = 78, and N = 51, respectively) of Rosenbaum et al.'s findings, which were conducted in two institutions. All experiments yielded the standard Stroop effect, but we failed to detect any consistent effect of posture (sitting vs. standing) on the magnitude of the Stroop effect. Taken together, the results suggest that posture does not influence the magnitude of the Stroop effect to the extent that was previously suggested.
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Percepción de Color , Postura , Humanos , Tiempo de Reacción , Test de StroopRESUMEN
Accumulation of hyper-phosphorylated and aggregated Tau proteins is a neuropathological hallmark of Alzheimer's Disease (AD) and Tauopathies. AD patient brains also exhibit insulin resistance. Whereas, under normal physiological conditions insulin signaling in the brain mediates plasticity and memory formation, it can also regulate peripheral energy homeostasis. Thus, in AD, brain insulin resistance affects both cognitive and metabolic changes described in these patients. While a role of Aß oligomers and APOE4 towards the development of brain insulin resistance emerged, contribution of Tau pathology has been largely overlooked. Our recent data demonstrated that one of the physiological function of Tau is to sustain brain insulin signaling. We postulated that under pathological conditions, hyper-phosphorylated/aggregated Tau is likely to lose this function and to favor the development of brain insulin resistance. This hypothesis was substantiated by observations from patient brains with pure Tauopathies. To address the potential link between Tau pathology and brain insulin resistance, we have evaluated the brain response to insulin in a transgenic mouse model of AD-like Tau pathology (THY-Tau22). Using electrophysiological and biochemical evaluations, we surprisingly observed that, at a time when Tau pathology and cognitive deficits are overt and obvious, the hippocampus of THY-Tau22 mice exhibits enhanced response to insulin. In addition, we demonstrated that the ability of i.c.v. insulin to promote body weight loss is enhanced in THY-Tau22 mice. In line with this, THY-Tau22 mice exhibited a lower body weight gain, hypoleptinemia and hypoinsulinemia and finally a metabolic resistance to high-fat diet. The present data highlight that the brain of transgenic Tau mice exhibit enhanced brain response to insulin. Whether these observations are ascribed to the development of Tau pathology, and therefore relevant to human Tauopathies, or unexpectedly results from the Tau transgene overexpression is debatable and discussed.
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Encéfalo/metabolismo , Insulina/metabolismo , Tauopatías/metabolismo , Proteínas tau/metabolismo , Animales , Resistencia a la Insulina/fisiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas tau/genéticaRESUMEN
In restrictive-type anorexia nervosa (AN) patients, physical activity is usually associated with food restriction, but its physiological consequences remain poorly characterized. In female mice, we evaluated the impact of voluntary physical activity with/without chronic food restriction on metabolic and endocrine parameters that might contribute to AN. In this protocol, FRW mice (i.e., food restriction with running wheel) reached a crucial point of body weight loss (especially fat mass) faster than FR mice (i.e., food restriction only). However, in contrast to FR mice, their body weight stabilized, demonstrating a protective effect of a moderate, regular physical activity. Exercise delayed meal initiation and duration. FRW mice displayed food anticipatory activity compared with FR mice, which was strongly diminished with the prolongation of the protocol. The long-term nature of the protocol enabled assessment of bone parameters similar to those observed in AN patients. Both restricted groups adapted their energy metabolism differentially in the short and long term, with less fat oxidation in FRW mice and a preferential use of glucose to compensate for the chronic energy imbalance. Finally, like restrictive AN patients, FRW mice exhibited low leptin levels, high plasma concentrations of corticosterone and ghrelin, and a disruption of the estrous cycle. In conclusion, our model suggests that physical activity has beneficial effects on the adaptation to the severe condition of food restriction despite the absence of any protective effect on lean and bone mass.
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Adaptación Fisiológica/fisiología , Anorexia Nerviosa/fisiopatología , Privación de Alimentos/fisiología , Actividad Motora/fisiología , Animales , Metabolismo Energético/fisiología , Femenino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Condicionamiento Físico Animal/fisiología , Reproducción/fisiología , Carrera/fisiología , Factores de Tiempo , Pérdida de PesoRESUMEN
Pseudomonas aeruginosa is an opportunistic Gram-negative bacterium that causes pneumonia in immunocompromised humans and severe pulmonary damage in patients with cystic fibrosis. Imbalanced fatty acid incorporation in membranes, including increased arachidonic acid and decreased DHA concentrations, is known to play a critical role in chronic inflammation associated with bacterial infection. Other lipids, such as EPA and alkylglycerols, are also known to play a role in inflammation, particularly by stimulating the immune system, decreasing inflammation and inhibiting bacterial growth. In this context, the goal of the present study was to assess the effect of dietary DHA/EPA, in a 2:1 ratio, and alkylglycerols, as natural compounds extracted from oils of rays and chimeras, respectively, on the inflammatory reaction induced by P. aeruginosa pulmonary infection in mice. To this end, mice were fed with a control diet or isolipidic, isoenergetic diets prepared with oils enriched in DHA/EPA (2:1) or alkylglycerols for 5 weeks before the induction of acute P. aeruginosa lung infection by endotracheal instillation. In our model, DHA/EPA (2:1) significantly improved the survival of mice after infection, which was associated with the acceleration of bacterial clearance and the resolution of inflammation leading to the improvement of pulmonary injuries. By contrast, alkylglycerols did not affect the outcomes of P. aeruginosa infection. Our findings suggest that supplementation with ray oil enriched in DHA/EPA (2:1) can be considered as a preventive treatment for patients at risk for P. aeruginosa infection.
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Suplementos Dietéticos , Aceites de Pescado/uso terapéutico , Peces , Hígado/química , Neumonía Bacteriana/inmunología , Infecciones por Pseudomonas/inmunología , Pseudomonas aeruginosa/inmunología , Animales , Carga Bacteriana , Citocinas/metabolismo , Ácidos Grasos Omega-3/uso terapéutico , Inmunidad Innata , Inmunidad Mucosa , Factores Inmunológicos/uso terapéutico , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/microbiología , Masculino , Ratones Endogámicos C57BL , Infiltración Neutrófila/inmunología , Permeabilidad , Neumonía Bacteriana/dietoterapia , Neumonía Bacteriana/microbiología , Neumonía Bacteriana/prevención & control , Infecciones por Pseudomonas/dietoterapia , Infecciones por Pseudomonas/microbiología , Infecciones por Pseudomonas/prevención & control , Pseudomonas aeruginosa/aislamiento & purificación , Distribución Aleatoria , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/metabolismo , Mucosa Respiratoria/microbiología , Análisis de SupervivenciaRESUMEN
OBJECTIVES: In Western society, high-caloric diets rich in fats and sugars have fueled the obesity epidemic and its related disorders. Disruption of the body-brain communication, crucial for maintaining glucose and energy homeostasis, arises from both obesogenic and genetic factors, leading to metabolic disorders. Here, we investigate the role of hypothalamic tanycyte shuttles between the pituitary portal blood and the third ventricle cerebrospinal fluid in regulating energy balance. METHODS: We inhibited vesicle-associated membrane proteins (VAMP1-3)-mediated release in tanycytes by expressing the botulinum neurotoxin type B light chain (BoNT/B) in a Cre-dependent manner in tanycytes. This was achieved by injecting either TAT-Cre in the third ventricle or an AAV1/2 expressing Cre under the control of the tanycyte-specific promoter iodothyronine deiodinase 2 into the lateral ventricle of adult male mice. RESULTS: In male mice fed a standard diet, targeted expression of BoNT/B in adult tanycytes blocks leptin transport into the mediobasal hypothalamus and results in normal-weight central obesity, including increased food intake, abdominal fat deposition, and elevated leptin levels but no marked change in body weight. Furthermore, BoNT/B expression in adult tanycytes promotes fatty acid storage, leading to glucose intolerance and insulin resistance. Notably, these metabolic disturbances occur despite a compensatory increase in insulin secretion, observed both in response to exogenous glucose boluses in vivo and in isolated pancreatic islets. Intriguingly, these metabolic alterations are associated with impaired spatial memory in BoNT/B-expressing mice. CONCLUSIONS: These findings underscore the central role of tanycytes in brain-periphery communication and highlight their potential implication in the age-related development of type 2 diabetes and cognitive decline. Our tanycytic BoNT/B mouse model provides a robust platform for studying how these conditions progress over time, from prediabetic states to full-blown metabolic and cognitive disorders, and the mechanistic contribution of tanycytes to their development. The recognition of the impact of tanycytic transcytosis on hormone transport opens new avenues for developing targeted therapies that could address both metabolic disorders and their associated cognitive comorbidities, which often emerge or worsen with advancing age.
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Metabolismo Energético , Células Ependimogliales , Glucosa , Homeostasis , Animales , Masculino , Ratones , Glucosa/metabolismo , Células Ependimogliales/metabolismo , Cognición/efectos de los fármacos , Leptina/metabolismo , Ratones Endogámicos C57BL , Hipotálamo/metabolismo , Obesidad/metabolismoRESUMEN
It is increasingly accepted that alterations of the early life environment may have lasting impacts on physiological functions. In particular, epidemiological and animal studies have indicated that changes in growth and nutrition during childhood and adolescence can impair reproductive function. However, the precise biological mechanisms that underlie these programming effects of neonatal nutrition on reproduction are still poorly understood. Here, we used a mouse model of divergent litter size to investigate the effects of early postnatal overnutrition and undernutrition on the maturation of hypothalamic circuits involved in reproductive function. Neonatally undernourished females display attenuated postnatal growth associated with delayed puberty and defective development of axonal projections from the arcuate nucleus to the preoptic region. These alterations persist into adulthood and specifically affect the organization of neural projections containing kisspeptin, a key neuropeptide involved in pubertal activation and fertility. Neonatal overfeeding also perturbs the development of neural projections from the arcuate nucleus to the preoptic region, but it does not result in alterations in kisspeptin projections. These studies indicate that alterations in the early nutritional environment cause lasting and deleterious effects on the organization of neural circuits involved in the control of reproduction, and that these changes are associated with lifelong functional perturbations.
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Regulación del Desarrollo de la Expresión Génica/fisiología , Hipotálamo/citología , Red Nerviosa/fisiología , Neuronas/fisiología , Estado Nutricional/fisiología , Reproducción/fisiología , Factores de Edad , Animales , Animales Recién Nacidos , Peso Corporal , Mapeo Encefálico , Femenino , Hormona Liberadora de Gonadotropina/metabolismo , Hipotálamo/crecimiento & desarrollo , Kisspeptinas/metabolismo , Tamaño de la Camada , Hormona Luteinizante/metabolismo , Masculino , Desnutrición/metabolismo , Desnutrición/patología , Ratones , Fibras Nerviosas/fisiología , Neuroquinina B/metabolismo , Neuronas/metabolismo , Ovariectomía , Hipernutrición/metabolismo , Hipernutrición/patología , Factores SexualesRESUMEN
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. We previously showed that Perilipin 2 (Plin2), a member of lipid droplet protein family, is markedly increased in fatty liver, and its reduction in the liver of diet-induced obese mice by antisense oligonucleotide (ASO) decreased steatosis and enhanced insulin sensitivity. Plin2-ASO treatment markedly suppressed lipogenic gene expression. To gain a better understanding of the biological role of Plin2 in liver, we performed microarray analysis to determine genes differentially regulated by Plin2-ASO compared with a control (scrambled) oligonucleotide (Cont). Male C57BL/6J mice on a high-fat diet were treated with Plin2- or Cont-ASO for 4 wk. Plin2-ASO decreased hepatic triglycerides, and this was associated with changes in expression of 1,363 genes. We analyzed the data for functional clustering and validated the expression of representative genes using real-time PCR. On the high-fat diet, Plin2-ASO decreased the expression of enzymes involved in fatty acid metabolism (acsl1, lipe) and steroid metabolism (hmgcr, hsd3b5, hsd17b2), suggesting that Plin2 affects hepatic lipid metabolism at the transcriptional level. Plin2-ASO also increased the expression of genes involved in regulation of hepatocyte proliferation (afp, H19), mitosis (ccna2, incenp, sgol1), and extracellular matrix (col1a1, col3a1, mmp8). Plin2-ASO had similar effects on gene expression in chow-fed mice. Together, these results indicate that Plin2 has diverse metabolic and structural roles in the liver, and its downregulation promotes hepatic fibrosis and proliferation.
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Metabolismo de los Lípidos/fisiología , Hígado/metabolismo , Proteínas de la Membrana/genética , Oligonucleótidos Antisentido/genética , Oligonucleótidos Antisentido/uso terapéutico , Animales , Hígado Graso/tratamiento farmacológico , Expresión Génica/efectos de los fármacos , Metabolismo de los Lípidos/genética , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Enfermedad del Hígado Graso no Alcohólico , Perilipina-2RESUMEN
BACKGROUND AND PURPOSE: We examined students perceived changes in their attention, motivation, affect, and time perception following the implementation of the pandemic-related restrictions. METHODS: One year after the restrictions were implemented, we surveyed students' (N = 153) perceived changes in their experiences relative to their remembered pre- and early-pandemic ones, as well as their predicted future changes. RESULTS: Consistent with prior work, when students compared their current experiences (March/April 2021) to their remembered pre-pandemic ones, they perceived increases in mind-wandering, technology use, external distraction, and negative affect, as well as decreases in focus, flow, motivation, and time perception. Although somewhat attenuated, students also noted changes in these behaviours when comparing the memory of their early pandemic experiences to their current experiences. Finally, they further anticipated negative changes in their future experiences, possibly due to continued pandemic-related isolation. IMPLICATIONS: Reducing students' sense of isolation might improve their cognitive and affective experiences.
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Bachillerato en Enfermería , Pandemias , Humanos , Aprendizaje , Estudiantes/psicología , Competencia ClínicaRESUMEN
Smith et al. (2019) found standing resulted in better performance than sitting in three different cognitive control paradigms: a Stroop task, a task-switching, and a visual search paradigm. Here, we conducted close replications of the authors' three experiments using larger sample sizes than the original work. Our sample sizes had essentially perfect power to detect the key postural effects reported by Smith et al. The results from our experiments revealed that, in contrast to Smith et al., the postural interactions were quite limited in magnitude in addition to being only a fraction of the size of the original effects. Moreover, our results from Experiment 1 are consistent with two recent replications (Caron et al., 2020; Straub et al., 2022), which reported no meaningful influences of posture on the Stroop effect. In all, the current research provides further converging evidence that postural influences on cognition do not appear to be as robust, as was initially reported in prior work.
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Cognición , Desempeño Psicomotor , Humanos , Atención , Test de Stroop , PosturaRESUMEN
The glucagon-like peptide 1 (Glp-1) has emerged as a hormone with broad pharmacological potential in type 2 diabetes (T2D) treatment, notably by improving ß cell functions. The cell-cycle regulator and transcription factor E2f1 is involved in glucose homeostasis by modulating ß cell mass and function. Here, we report that ß cell-specific genetic ablation of E2f1 (E2f1ß-/-) impairs glucose homeostasis associated with decreased expression of the Glp-1 receptor (Glp1r) in E2f1ß-/- pancreatic islets. Pharmacological inhibition of E2F1 transcriptional activity in nondiabetic human islets decreases GLP1R levels and blunts the incretin effect of GLP1R agonist exendin-4 (ex-4) on insulin secretion. Overexpressing E2f1 in pancreatic ß cells increases Glp1r expression associated with enhanced insulin secretion mediated by ex-4. Interestingly, ex-4 induces retinoblastoma protein (pRb) phosphorylation and E2f1 transcriptional activity. Our findings reveal critical roles for E2f1 in ß cell function and suggest molecular crosstalk between the E2F1/pRb and GLP1R signaling pathways.
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Diabetes Mellitus Tipo 2 , Células Secretoras de Insulina , Diabetes Mellitus Tipo 2/metabolismo , Factor de Transcripción E2F1/genética , Factor de Transcripción E2F1/metabolismo , Exenatida/farmacología , Receptor del Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismoRESUMEN
Alzheimer's disease (AD) is the leading cause of dementia. While impaired glucose homeostasis has been shown to increase AD risk and pathological loss of tau function, the latter has been suggested to contribute to the emergence of the glucose homeostasis alterations observed in AD patients. However, the links between tau impairments and glucose homeostasis, remain unclear. In this context, the present study aimed at investigating the metabolic phenotype of a new tau knock-in (KI) mouse model, expressing, at a physiological level, a human tau protein bearing the P301L mutation under the control of the endogenous mouse Mapt promoter. Metabolic investigations revealed that, while under chow diet tau KI mice do not exhibit significant metabolic impairments, male but not female tau KI animals under High-Fat Diet (HFD) exhibited higher insulinemia as well as glucose intolerance as compared to control littermates. Using immunofluorescence, tau protein was found colocalized with insulin in the ß cells of pancreatic islets in both mouse (WT, KI) and human pancreas. Isolated islets from tau KI and tau knock-out mice exhibited impaired glucose-stimulated insulin secretion (GSIS), an effect recapitulated in the mouse pancreatic ß-cell line (MIN6) following tau knock-down. Altogether, our data indicate that loss of tau function in tau KI mice and, particularly, dysfunction of pancreatic ß cells might promote glucose homeostasis impairments and contribute to metabolic changes observed in AD.
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OBJECTIVES: Glucokinase (GCK) is critical for glucosensing. In rats, GCK is expressed in hypothalamic tanycytes and appears to play an essential role in feeding behavior. In this study, we investigated the distribution of GCK-expressing tanycytes in mice and their role in the regulation of energy balance. METHODS: In situ hybridization, reporter gene assay, and immunohistochemistry were used to assess GCK expression along the third ventricle in mice. To evaluate the impact of GCK-expressing tanycytes on arcuate neuron function and mouse physiology, Gck deletion along the ventricle was achieved using loxP/Cre recombinase technology in adult mice. RESULTS: GCK expression was low along the third ventricle, but detectable in tanycytes facing the ventromedial arcuate nucleus from bregma -1.5 to -2.2. Gck deletion induced the death of this tanycyte subgroup through the activation of the BAD signaling pathway. The ablation of GCK-expressing tanycytes affected different aspects of energy balance, leading to an increase in adiposity in mice. This phenotype was systematically associated with a defect in NPY neuron function. In contrast, the regulation of glucose homeostasis was mostly preserved, except for glucoprivic responses. CONCLUSIONS: This study describes the role of GCK in tanycyte biology and highlights the impact of tanycyte loss on the regulation of energy balance.
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Células Ependimogliales/metabolismo , Glucoquinasa/genética , Adiposidad , Animales , Metabolismo Energético , Glucoquinasa/deficiencia , Glucoquinasa/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
The nuclear bile acid (BA) receptor farnesoid X receptor (FXR) is a major regulator of metabolic/energy homeostasis in peripheral organs. Indeed, enterohepatic-expressed FXR controls metabolic processes (BA, glucose and lipid metabolism, fat mass, body weight). The central nervous system (CNS) regulates energy homeostasis in close interaction with peripheral organs. While FXR has been reported to be expressed in the brain, its function has not been studied so far. We studied the role of FXR in brain control of energy homeostasis by treating wild-type and FXR-deficient mice by intracerebroventricular (ICV) injection with the reference FXR agonist GW4064. Here we show that pharmacological activation of brain FXR modifies energy homeostasis by affecting brown adipose tissue (BAT) function. Brain FXR activation decreases the rate-limiting enzyme in catecholamine synthesis, tyrosine hydroxylase (TH), and consequently the sympathetic tone. FXR activation acts by inhibiting hypothalamic PKA-CREB induction of TH expression. These findings identify a function of brain FXR in the control of energy homeostasis and shed new light on the complex control of energy homeostasis by BA through FXR.
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Hypothalamic glucose sensing enables an organism to match energy expenditure and food intake to circulating levels of glucose, the main energy source of the brain. Here, we established that tanycytes of the arcuate nucleus of the hypothalamus, specialized glia that line the wall of the third ventricle, convert brain glucose supplies into lactate that they transmit through monocarboxylate transporters to arcuate proopiomelanocortin neurons, which integrate this signal to drive their activity and to adapt the metabolic response to meet physiological demands. Furthermore, this transmission required the formation of extensive connexin-43 gap junction-mediated metabolic networks by arcuate tanycytes. Selective suppression of either tanycytic monocarboxylate transporters or gap junctions resulted in altered feeding behavior and energy metabolism. Tanycytic intercellular communication and lactate production are thus integral to the mechanism by which hypothalamic neurons that regulate energy and glucose homeostasis efficiently perceive alterations in systemic glucose levels as a function of the physiological state of the organism.
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Núcleo Arqueado del Hipotálamo/metabolismo , Células Ependimogliales/metabolismo , Glucosa/metabolismo , Ácido Láctico/metabolismo , Proopiomelanocortina/metabolismo , Animales , Metabolismo Energético , Conducta Alimentaria/fisiología , Uniones Comunicantes/metabolismo , Técnicas de Silenciamiento del Gen , Homeostasis , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Neurológicos , Transportadores de Ácidos Monocarboxílicos/antagonistas & inhibidores , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Proteínas Musculares/antagonistas & inhibidores , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Neuronas/metabolismo , Transducción de Señal , Simportadores/antagonistas & inhibidores , Simportadores/genética , Simportadores/metabolismoRESUMEN
Metabolic health depends on the brain's ability to control food intake and nutrient use versus storage, processes that require peripheral signals such as the adipocyte-derived hormone, leptin, to cross brain barriers and mobilize regulatory circuits. We have previously shown that hypothalamic tanycytes shuttle leptin into the brain to reach target neurons. Here, using multiple complementary models, we show that tanycytes express functional leptin receptor (LepR), respond to leptin by triggering Ca2+ waves and target protein phosphorylation, and that their transcytotic transport of leptin requires the activation of a LepR-EGFR complex by leptin and EGF sequentially. Selective deletion of LepR in tanycytes blocks leptin entry into the brain, inducing not only increased food intake and lipogenesis but also glucose intolerance through attenuated insulin secretion by pancreatic ß-cells, possibly via altered sympathetic nervous tone. Tanycytic LepRb-EGFR-mediated transport of leptin could thus be crucial to the pathophysiology of diabetes in addition to obesity, with therapeutic implications.
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Encéfalo/metabolismo , Células Ependimogliales/metabolismo , Receptores ErbB/metabolismo , Leptina/metabolismo , Metabolismo de los Lípidos , Páncreas/metabolismo , Receptores de Leptina/metabolismo , Diabetes Mellitus/etiología , Diabetes Mellitus/metabolismo , Metabolismo Energético , Células Secretoras de Insulina/metabolismo , FosforilaciónRESUMEN
OBJECTIVES: Genome-wide association studies have reported that DNA polymorphisms at the CDKN2A locus modulate fasting glucose in human and contribute to type 2 diabetes (T2D) risk. Yet the causal relationship between this gene and defective energy homeostasis remains elusive. Here we sought to understand the contribution of Cdkn2a to metabolic homeostasis. METHODS: We first analyzed glucose and energy homeostasis from Cdkn2a-deficient mice subjected to normal or high fat diets. Subsequently Cdkn2a-deficient primary adipose cells and human-induced pluripotent stem differentiated into adipocytes were further characterized for their capacity to promote browning of adipose tissue. Finally CDKN2A levels were studied in adipocytes from lean and obese patients. RESULTS: We report that Cdkn2a deficiency protects mice against high fat diet-induced obesity, increases energy expenditure and modulates adaptive thermogenesis, in addition to improving insulin sensitivity. Disruption of Cdkn2a associates with increased expression of brown-like/beige fat markers in inguinal adipose tissue and enhances respiration in primary adipose cells. Kinase activity profiling and RNA-sequencing analysis of primary adipose cells further demonstrate that Cdkn2a modulates gene networks involved in energy production and lipid metabolism, through the activation of the Protein Kinase A (PKA), PKG, PPARGC1A and PRDM16 signaling pathways, key regulators of adipocyte beiging. Importantly, CDKN2A expression is increased in adipocytes from obese compared to lean subjects. Moreover silencing CDKN2A expression during human-induced pluripotent stem cells adipogenic differentiation promoted UCP1 expression. CONCLUSION: Our results offer novel insight into brown/beige adipocyte functions, which has recently emerged as an attractive therapeutic strategy for obesity and T2D. Modulating Cdkn2a-regulated signaling cascades may be of interest for the treatment of metabolic disorders.
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Adipocitos Marrones/metabolismo , Adipogénesis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Obesidad/metabolismo , Adipocitos Marrones/citología , Animales , Células Cultivadas , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Redes Reguladoras de Genes , Glucosa/metabolismo , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , TermogénesisRESUMEN
Parkinson's disease is a progressive neurodegenerative disorder characterized by loss of dopaminergic neurons, pathological accumulation of alpha-synuclein and motor symptoms, but also by non-motor symptoms. Metabolic abnormalities including body weight loss have been reported in patients and could precede by several years the emergence of classical motor manifestations. However, our understanding of the pathophysiological mechanisms underlying body weight loss in PD is limited. The present study investigated the links between alpha-synuclein accumulation and energy metabolism in transgenic mice overexpressing Human wild-type (WT) alpha-synuclein under the Thy1 promoter (Thy1-aSYN mice). Results showed that Thy1-aSYN mice gained less body weight throughout life than WT mice, with significant difference observed from 3 months of age. Body composition analysis of 6-month-old transgenic animals showed that body mass loss was due to lower adiposity. Thy1-aSYN mice displayed lower food consumption, increased spontaneous activity, as well as a reduced energy expenditure compared to control mice. While no significant change in glucose or insulin responses were observed, Thy1-aSYN mice had significantly lower plasmatic levels of insulin and leptin than control animals. Moreover, the pathological accumulation of alpha-synuclein in the hypothalamus of 6-month-old Thy1-aSYN mice was associated with a down-regulation of the phosphorylated active form of the signal transducer and activator of transcription 3 (STAT3) and of Rictor (the mTORC2 signaling pathway), known to couple hormonal signals with the maintenance of metabolic and energy homeostasis. Collectively, our results suggest that (i) metabolic alterations are an important phenotype of alpha-synuclein overexpression in mice and that (ii) impaired STAT3 activation and mTORC2 levels in the hypothalamus may underlie the disruption of feeding regulation and energy metabolism in Thy1-aSYN mice.
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The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients.