The role of FGF21 in the metabolic response to amino acid restriction

[eng] Obesity and associated metabolic diseases have reached epidemic proportions, affecting not only high-income countries but also low- and middle-income ones. In this context, the search for therapeutic approaches to treat obesity is becoming a priority worldwide. In this regard, the metabolic hormone fibroblast growth factor 21 (FGF21) has been identified as a potential candidate for the treatment of obesity and metabolic syndrome. Previous work by our group described that FGF21 is highly induced in liver in response to leucine deprivation and that the transcription factor ATF4 mediates this induction. The present work is the follow-up of this initial observation. To delve deeper into the molecular mechanisms that regulate FGF21 expression during leucine deprivation, we focused on the transcriptional repressor Rev-erbα, which functions both as a core repressive component of the cell autonomous clock and as a regulator of metabolic genes. Our results reveal a consistent negative correlation between Fgf21 and the Pgc-1α/heme/Rev-erbα axis across various nutritional states and that a decrease in Rev-erbα activity enhances the ATF4-mediated upregulation of the human FGF21 promoter. Consequently, we propose a model whereby the induction of Fgf21 upon leucine deprivation is the consequence of the sum of two factors: binding of the activator ATF4 to the promoter and the absence of the repressor Rev-erbα. Given the coincidence between the effects of leucine deprivation and those observed during FGF21 treatment, we analysed the role of FGF21 during leucine deprivation. In the current study, we demonstrate that weight loss, downregulation of key lipogenic genes in liver and WAT, and BAT activation in response to leucine deprivation are partly FGF21-dependent. Given the unfeasibility to translate single amino acid deprivation to humans, we focussed on low-protein diets (LPDs) as a more realistic approach. The LPD increased circulating FGF21 levels with an associated upregulated expression in liver. Analysis of serum human samples from the PREDIMED study extended the correlation between LPD and FGF21 to humans. The ATF4-mediated upregulation of Fgf21 in liver was partially responsible for the weight loss observed in mice fed a LPD, since the liver specific Fgf21 knockout mice (LFgf21KO) mice were partially protected from this loss. Focusing on the effects of FGF21 on scWAT and given the capacity of FGF21 to produce the browning of white fat depots, we examined the activation of the thermogenic programme in this tissue. Accordingly, scWAT browning caused by the LPD did not occur in mice lacking hepatic Fgf21. As UCP1 activity is related to EE, the blunted induction of Ucp1 in the LPD-fed LFgf21KO mice, may contribute to the reduction in weight loss observed in this mouse model under these circumstances. The administration of the b-blocker propranolol to protein-restricted mice allowed us to distinguish between the roles of FGF21 and noradrenaline. While Ucp1 expression was upregulated independently of adrenergic signalling, Dio2 and Pparγ expression was blunted by propranolol treatment. These results point to the induction of Ucp1 as a direct effect of liver-delivered FGF21 on scWAT and discard a CNS-mediated effect. In addition, the LPD improved glucose tolerance, and this improvement was not observed in LFgf21KO mice, indicating a role of FGF21 in glucose metabolism during protein restriction. Our findings show that the effects of a LPD depend, at least in part, on the circulating levels of FGF21 and consequently on the liver production of this growth factor. Given the parallelism between the results of our study in humans and those in mice, we postulate that modulation of dietary protein content can bring about changes in the circulating levels of FGF21 in mice and humans.[cat] L’obesitat i les malalties metabòliques que en deriven són un problema de salut mundial. En aquest context, la recerca d’estratègies terapèutiques pel tractament de l’obesitat ha esdevingut una prioritat. En aquest sentit, el factor metabòlic fibroblast growth factor 21 (FGF21), ha estat identificat com a un prometedor candidat pel tractament de l’obesitat i la síndrome metabòlica. El nostre laboratori va descriure que en resposta a la privació de leucina els nivells de FGF21 augmenten dràsticament i que el factor de transcripció activating transcription factor (ATF4) n’és el responsable. Els resultats d’aquesta tesi són la continuació i desenvolupament d’aquesta observació inicial. Aprofundint en els mecanismes de regulació que controlen l’expressió de FGF21 en resposta a la privació de leucina, els nostres resultats indiquen que el repressor transcripcional Rev-erbα participa significativament en aquesta regulació i que la disminució dels nivells de Rev-erbα correlacionen amb una activació del promotor de FGF21. A més a més, en aquest estudi demostrem que la pèrdua de pes, la disminució de l’expressió de gens lipogènics en fetge i teixit adipós blanc, així com l’activació del teixit adipós marró en resposta a la privació de leucina són, al menys parcialment, dependents de FGF21. Finalment, amb la finalitat de fer els nostres resultats traslladables a humans, demostrem que una dieta amb baix contingut proteic augmenta les nivells circulants de FGF21 en ratolins i humans, i que això succeeix a través de l’increment d’ATF4. L’increment dels nivells de FGF21 degut a la restricció proteica provoquen l’increment de l’expressió dels gens termogènics en el teixit adipós blanc subcutani, la pèrdua de pes i la millora la tolerància a la glucosa. El conjunt d’aquest resultats destaquen el paper clau del factor FGF21 com a mediador dels efectes metabòlics que es produeixen durant la restricció d’aminoàcids i suggereixen la disminució del contingut de proteïna de la dieta com a estratègia per incrementar-ne els nivells

Action potential propagation: ion current or intramembrane electric field?

The established action potential propagation mechanisms do not satisfactorily explain propagation on myelinated axons given the current knowledge of biological channels and membranes. The flow across ion channels presents two possible effects: the electric potential variations across the lipid bilayers (action potential) and the propagation of an electric field through the membrane inner part. The proposed mechanism is based on intra-membrane electric field propagation, this propagation can explain the action potential saltatory propagation and its constant delay independent of distance between Ranvier nodes in myelinated axons.Peer ReviewedPostprint (author's final draft

Per què una Dècada de l'Educació per a un futur sostenible (2005-2014)? Crida de Nacions Unides a tots els educadors.

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Evaluating the potential use of a dairy industry residue to induce denitrification in polluted water bodies: a flow-through experiment

Improving the effectiveness and economics of strategies to remediate groundwater nitrate pollution is a matter of concern. In this context, the addition of whey into aquifers could provide a feasible solution to attenuate nitrate contamination by inducing heterotrophic denitrification, while recycling an industry residue. Before its application, the efficacy of the treatment must be studied at laboratory-scale to optimize the application strategy in order to avoid the generation of harmful intermediate compounds. To do this, a flow-through denitrification experiment using whey as organic C source was performed, and different C/N ratios and injection periodicities were tested. The collected samples were analyzed to determine the chemical and isotopic composition of N and C compounds. The results proved that whey could promote denitrification. Nitrate was completely removed when using either a 3.0 or 2.0 C/N ratio. However, daily injection with C/N ratios from 1.25 to 1.5 seemed advantageous, since this strategy decreased nitrate concentration to values below the threshold for water consumption while avoiding nitrite accumulation and whey release with the outflow. The isotopic results confirmed that nitrate attenuation was due to denitrification and that the production of DIC was related to bacterial whey oxidation. Furthermore, the isotopic data suggested that when denitrification was not complete, the outflow could present a mix of denitrified and nondenitrified water. The calculated isotopic fractionation values (ε15NNO3/N2 and ε18ONO3/N2) might be applied in the future to quantify the efficiency of the bioremediation treatments by whey application at field-scale

Nutritional regulation of fibroblast growth factor 21: from macronutrients to bioactive dietary compounds

Obesity is a worldwide health problem mainly due to its associated comorbidities. Fibroblast growth factor 21 (FGF21) is a peptide hormone involved in metabolic homeostasis in healthy individuals and considered a promising therapeutic candidate for the treatment of obesity. FGF21 is predominantly produced by the liver but also by other tissues, such as white adipose tissue (WAT), brown adipose tissue (BAT), skeletal muscle, and pancreas in response to different stimuli such as cold and different nutritional challenges that include fasting, high-fat diets (HFDs), ketogenic diets, some amino acid-deficient diets, low protein diets, high carbohydrate diets or specific dietary bioactive compounds. Its target tissues are essentially WAT, BAT, skeletal muscle, heart and brain. The effects of FGF21 in extra hepatic tissues occur through the fibroblast growth factor receptor (FGFR)-1c together with the co-receptor β-klotho (KLB). Mechanistically, FGF21 interacts directly with the extracellular domain of the membrane bound cofactor KLB in the FGF21- KLB-FGFR complex to activate FGFR substrate 2α and ERK1/2 phosphorylation. Mice lacking KLB are resistant to both acute and chronic effects of FGF21. Moreover, the acute insulin sensitizing effects of FGF21 are also absent in mice with specific deletion of adipose KLB or FGFR1. Most of the data show that pharmacological administration of FGF21 has metabolic beneficial effects. The objective of this review is to compile existin

Nitrate and Nitrite Attenuation by Fe(II) Minerals: Biotic and Abiotic Reactions

Nitrate (NO3-) pollution of groundwaterhas become a relevant issue and anenvironmental priority as it is related toecological and human health problems(Rivett et al. 2008) and its concentration is still above the threshold limit of 50mg/L in many areas (Nitrate Directive, 91/676/EEC). Contamination sources of NO3 - are linked to extensive use of fertilizers, inappropriate placement of animal waste and spills from septic system effluents

Feasibility of using rural waste products to increase the denitrification efficiency in a surface flow constructed wetland

A surface flow constructed wetland (CW) was set in the Lerma gully to decrease nitrate (NO3−) pollution from agricultural runoff water. The water flow rate and NO3− concentration were monitored at the inlet and the outlet, and sampling campaigns were performed which consisted of collecting six water samples along the CW flow line. After two years of operation, the NO3− attenuation was limited at a flow rate of ~2.5 L/s and became negligible at ~5.5 L/s. The present work aimed to assess the feasibility of using rural waste products (wheat hay, corn stubble, and animal compost) to induce denitrification in the CW, to assess the effect of temperature on this process, and to trace the efficiency of the treatment by using isotopic tools. In the first stage, microcosm experiments were performed. Afterwards, the selected waste material was applied in the CW, and the treatment efficiency was evaluated by means of a chemical and isotopic characterization and using the isotopic fractionation (ε) values calculated from laboratory experiments to avoid field-scale interference. The microcosms results showed that the stubble was the most appropriate material for application in the CW, but the denitrification rate was found to decrease with temperature. In the CW, biostimulation in autumn-winter promoted NO3− attenuation between two weeks and one month (a reduction in NO3− between 1.2 and 1.5 mM was achieved). After the biostimulation in spring-summer, the attenuation was maintained for approximately three months (NO3− reduction between 0.1 and 1.5 mM). The ε15NNO3/N2 and ε18ONO3/N2 values obtained from the laboratory experiments allowed to estimate the induced denitrification percentage. At an approximate average flow rate of 16 L/s, at least 60% of NO3− attenuation was achieved in the CW. The field samples exhibited a slope of 1.0 for δ18O-NO3− versus δ15N-NO3−, similar to those of the laboratory experiments (0.9-1.2). Plant uptake seemed to play a minor role in NO3− attenuation in the CW. Hence, the application of stubble in the CW allowed the removal of large amounts of NO3− from the Lerma gully, especially when applied during the warm months, but its efficacy was limited to a short time period (up to three months)

Readmission for Acute Exacerbation within 30 Days of Discharge Is Associated with a Subsequent Progressive Increase in Mortality Risk in COPD Patients: A Long-Term Observational Study

Background and Objective Twenty per cent of chronic obstructive pulmonary disease (COPD) patients are readmitted for acute exacerbation (AECOPD) within 30 days of discharge. The prognostic significance of early readmission is not fully understood. The objective of our study was to estimate the mortality risk associated with readmission for acute exacerbation within 30 days of discharge in COPD patients. Methods The cohort (n = 378) was divided into patients readmitted (n = 68) and not readmitted (n = 310) within 30 days of discharge. Clinical, laboratory, microbiological, and severity data were evaluated at admission and during hospital stay, and mortality data were recorded at four time points during follow-up: 30 days, 6 months, 1 year and 3 years. Results Patients readmitted within 30 days had poorer lung function, worse dyspnea perception and higher clinical severity. Two or more prior AECOPD (HR, 2.47; 95% CI, 1.51-4.05) was the only variable independently associated with 30-day readmission. The mortality risk during the follow-up period showed a progressive increase in patients readmitted within 30 days in comparison to patients not readmitted; moreover, 30-day readmission was an independent risk factor for mortality at 1 year (HR, 2.48; 95% CI, 1.10-5.59). In patients readmitted within 30 days, the estimated absolute increase in the mortality risk was 4% at 30 days (number needed to harm NNH, 25), 17% at 6-months (NNH, 6), 19% at 1-year (NNH, 6) and 24% at 3 years (NNH, 5). Conclusion In conclusion a readmission for AECOPD within 30 days is associated with a progressive increased long-term risk of death

Propiedades psicométricas de la versión española de la escala Mindful Attention Awareness Scale (MAAS)

La Mindful Attention Awareness Scale (MAAS) es una escala sencilla y de rápida administración que evalúa, de forma global, la capacidad disposicional de un individuo de estar atento y consciente de la experiencia del momento presente en la vida cotidiana. La escala es un autoinfome unifactorial de 15 ítems con visión del constructo mindfulness centrada en la variable atención/consciencia. El instrumento puede ser utilizado en sujetos con o sin experiencia en meditación y es ampliamente utilizado en investigación. Con el objetivo de establecer las propiedades psicométricas de la MAAS, se administró a un total de 385 sujetos, 201 pertenecientes a una muestra clínica y 184 a una muestra control de estudiantes universitarios. Los análisis psicométricos de la versión española de la MAAS muestran buenas propiedades, tanto en términos de validez como de fiabilidad. El instrumento presentó una buena validez convergente con la Five Facets Mindfulness Questionnaire (FFMQ) así como discriminante respecto a la clínica depresiva. Así mismo obtuvo unos buenos índices de fiabilidad (α de Cronbach de 0,89), una buena estabilidad temporal y replica la estructura unifactorial original que agrupa el 42,8% de la varianza total. Los resultados obtenidos resultan congruentes con los estudios realizados con la versión en inglés del instrumento. La MAAS es un instrumento de simple y rápida administración que nos permite evaluar la capacidad general de mindfulness de un individuo y que puede ser utilizado tanto en la investigación clínica como en sujetos sanos

Characterisation of the natural attenuation of chromium contamination in the presence of nitrate using isotopic methods. A case study from the Matanza-Riachuelo river basin, Argentina

The groundwater contamination by hexavalent chromium (Cr(VI)) in a site of the Matanza-Riachuelo River basin (MRB), Argentina, has been evaluated by determining the processes that control the natural mobility and attenuation of Cr(VI) in the presence of high nitrate (NO3−) contents. The groundwater Cr(VI) concentrations ranged between 1.9E-5 mM and 0.04 mM, while the NO3− concentrations ranged between 0.5 mM and 3.9 mM