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While common obesity accounts for an increasing global health burden, its monogenic forms have taught us underlying mechanisms via more than 20 single-gene disorders. Among these, the most common mechanism is central nervous system dysregulation of food intake and satiety, often accompanied by neurodevelopmental delay (NDD) and autism spectrum disorder. In a family with syndromic obesity, we identified a monoallelic truncating variant in POU3F2 (alias BRN2) encoding a neural transcription factor, which has previously been suggested as a driver of obesity and NDD in individuals with the 6q16.1 deletion. In an international collaboration, we identified ultra-rare truncating and missense variants in another ten individuals sharing autism spectrum disorder, NDD, and adolescent-onset obesity. Affected individuals presented with low-to-normal birth weight and infantile feeding difficulties but developed insulin resistance and hyperphagia during childhood. Except for a variant leading to early truncation of the protein, identified variants showed adequate nuclear translocation but overall disturbed DNA-binding ability and promotor activation. In a cohort with common non-syndromic obesity, we independently observed a negative correlation of POU3F2 gene expression with BMI, suggesting a role beyond monogenic obesity. In summary, we propose deleterious intragenic variants of POU3F2 to cause transcriptional dysregulation associated with hyperphagic obesity of adolescent onset with variable NDD.
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Trastorno del Espectro Autista , Trastornos del Neurodesarrollo , Síndrome de Prader-Willi , Adolescente , Humanos , Trastorno del Espectro Autista/genética , Hiperfagia/genética , Hiperfagia/complicaciones , Trastornos del Neurodesarrollo/genética , Obesidad/complicaciones , Síndrome de Prader-Willi/complicaciones , Síndrome de Prader-Willi/genética , ProteínasRESUMEN
Glomerular-tubular crosstalk within the kidney has been proposed, but the paracrine signals enabling this remain largely unknown. The cold-shock protein Y-box binding protein 1 (YBX1) is known to regulate inflammation and kidney diseases but its role in podocytes remains undetermined. Therefore, we analyzed mice with podocyte specific Ybx1 deletion (Ybx1ΔPod). Albuminuria was increased in unchallenged Ybx1ΔPod mice, which surprisingly was associated with reduced glomerular, but enhanced tubular damage. Tubular toll-like receptor 4 (TLR4) expression, node-like receptor protein 3 (NLRP3) inflammasome activation and kidney inflammatory cell infiltrates were all increased in Ybx1ΔPod mice. In vitro, extracellular YBX1 inhibited NLRP3 inflammasome activation in tubular cells. Co-immunoprecipitation, immunohistochemical analyses, microscale cell-free thermophoresis assays, and blunting of the YBX1-mediated TLR4-inhibition by a unique YBX1-derived decapeptide suggests a direct interaction of YBX1 and TLR4. Since YBX1 can be secreted upon post-translational acetylation, we hypothesized that YBX1 secreted from podocytes can inhibit TLR4 signaling in tubular cells. Indeed, mice expressing a non-secreted YBX1 variant specifically in podocytes (Ybx1PodK2A mice) phenocopied Ybx1ΔPod mice, demonstrating a tubular-protective effect of YBX1 secreted from podocytes. Lipopolysaccharide-induced tubular injury was aggravated in Ybx1ΔPod and Ybx1PodK2A mice, indicating a pathophysiological relevance of this glomerular-tubular crosstalk. Thus, our data show that YBX1 is physiologically secreted from podocytes, thereby negatively modulating sterile inflammation in the tubular compartment, apparently by binding to and inhibiting tubular TLR4 signaling. Hence, we have uncovered an YBX1-dependent molecular mechanism of glomerular-tubular crosstalk.
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Enfermedades Renales , Podocitos , Ratones , Animales , Inflamasomas/metabolismo , Receptor Toll-Like 4/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Respuesta al Choque por Frío , Riñón/metabolismo , Podocitos/metabolismo , Enfermedades Renales/metabolismo , Inflamación/metabolismoRESUMEN
Cognitive impairment is common in extracerebral diseases such as chronic kidney disease (CKD). Kidney transplantation reverses cognitive impairment, indicating that cognitive impairment driven by CKD is therapeutically amendable. However, we lack mechanistic insights allowing development of targeted therapies. Using a combination of mouse models (including mice with neuron-specific IL-1R1 deficiency), single cell analyses (single-nuclei RNA-sequencing and single-cell thallium autometallography), human samples and in vitro experiments we demonstrate that microglia activation impairs neuronal potassium homeostasis and cognition in CKD. CKD disrupts the barrier of brain endothelial cells in vitro and the blood-brain barrier in vivo, establishing that the uremic state modifies vascular permeability in the brain. Exposure to uremic conditions impairs calcium homeostasis in microglia, enhances microglial potassium efflux via the calcium-dependent channel KCa3.1, and induces p38-MAPK associated IL-1ß maturation in microglia. Restoring potassium homeostasis in microglia using a KCa3.1-specific inhibitor (TRAM34) improves CKD-triggered cognitive impairment. Likewise, inhibition of the IL-1ß receptor 1 (IL-1R1) using anakinra or genetically abolishing neuronal IL-1R1 expression in neurons prevent CKD-mediated reduced neuronal potassium turnover and CKD-induced impaired cognition. Accordingly, in CKD mice, impaired cognition can be ameliorated by either preventing microglia activation or inhibiting IL-1R-signaling in neurons. Thus, our data suggest that potassium efflux from microglia triggers their activation, which promotes microglia IL-1ß release and IL-1R1-mediated neuronal dysfunction in CKD. Hence, our study provides new mechanistic insight into cognitive impairment in association with CKD and identifies possible new therapeutic approaches.
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BACKGROUND: Despite mechanistic studies linking retinol and RBP4 (retinol binding protein 4) to the pathogenesis of cardiovascular diseases (CVD) and type 2 diabetes (T2D), epidemiological evidence is still conflicting. We investigated whether conflicting results of previous studies may be explained by differences in the association of retinol and RBP4 with cardiometabolic risk across subgroups with distinct sex, hypertension state, liver, or kidney function. METHODS: We used case-cohorts nested in the EPIC (European Prospective Investigation Into Cancer and Nutrition)-Potsdam cohort (N=27 548) comprising a random sample of participants (n=2500) and all physician-verified cases of incident CVD (n=508, median follow-up time 8.2 years) and T2D (n=820, median follow-up time 6.3 years). We estimated nonlinear and linear multivariable-adjusted associations between the biomarkers and cardiometabolic diseases by restricted cubic splines and Cox regression, respectively, testing potential interactions with hypertension, liver, and kidney function. Additionally, we performed 2-sample Mendelian Randomization analyses in publicly available data. RESULTS: The association of retinol with cardiometabolic risk was modified by hypertension state (P interaction CVD<0.001; P interaction T2D<0.001). Retinol was associated with lower cardiometabolic risk in participants with treated hypertension (hazard ratioper SD [95% CI]: CVD, 0.71 [0.56-0.90]; T2D, 0.81 [0.70-0.94]) but with higher cardiometabolic risk in normotensive participants (CVD, 1.32 [1.06-1.64]; T2D, 1.15 [0.98-1.36]). Our analyses also indicated a significant interaction between RBP4 and hypertension on CVD risk (P interaction=0.04). Regarding T2D risk, we observed a u-shaped association with RBP4 in women (P nonlinearity=0.01, P effect=0.02) and no statistically significant association in men. The biomarkers' interactions with liver or kidney function were not statistically significant. Hypertension state-specific associations for retinol concentrations with cardiovascular mortality risk were replicated in National Health and Nutrition Examination Survey III. CONCLUSIONS: Our findings suggest a hypertension-dependent relationship between plasma retinol and cardiometabolic risk and complex interactions of RBP4 with sex and hypertension on cardiometabolic risk.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Hipertensión , Biomarcadores , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Femenino , Humanos , Hipertensión/complicaciones , Hipertensión/diagnóstico , Hipertensión/epidemiología , Masculino , Encuestas Nutricionales , Estudios Prospectivos , Proteínas Plasmáticas de Unión al Retinol , Factores de Riesgo , Vitamina ARESUMEN
Dysfunction of mesangial cells plays a major role in the pathogenesis of diabetic kidney disease (DKD), the leading cause of kidney failure. However, the underlying molecular mechanisms are incompletely understood. By unbiased gene expression analysis of glucose-exposed mesangial cells, we identified the transmembrane receptor CD248 as the most upregulated gene, and the maladaptive unfolded protein response (UPR) as one of the most stimulated pathways. Upregulation of CD248 was further confirmed in glucose-stressed mesangial cells in vitro, in kidney glomeruli isolated from diabetic mice (streptozotocin; STZ and db/db models, representing type 1 and type 2 diabetes mellitus, respectively) in vivo, and in glomerular kidney sections from patients with DKD. Time course analysis revealed that glomerular CD248 induction precedes the onset of albuminuria, mesangial matrix expansion and maladaptive UPR activation (hallmarked by transcription factor C/EBP homologous protein (CHOP) induction) but is paralleled by loss of the adaptive UPR regulator spliced X box binding protein (XBP1). Mechanistically, CD248 promoted maladaptive UPR signaling via inhibition of the inositol requiring enzyme 1α (IRE1α)-mediated transcription factor XBP1 splicing in vivo and in vitro. CD248 induced a multiprotein complex comprising heat shock protein 90, BH3 interacting domain death agonist (BID) and IRE1α, in which BID impedes IRE1α-mediated XBP1 splicing and induced CHOP mediated maladaptive UPR signaling. While CD248 knockout ameliorated DKD-associated glomerular dysfunction and reverses maladaptive unfolded protein response signaling, concomitant XBP1 deficiency abolished the protective effect in diabetic CD248 knockout mice, supporting a functional interaction of CD248 and XBP1 in vivo. Hence, CD248 is a novel mesangial cell receptor inducing maladaptive UPR signaling in DKD.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Nefropatías Diabéticas , Animales , Ratones , Antígenos CD/metabolismo , Antígenos de Neoplasias , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/genética , Nefropatías Diabéticas/genética , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada , HumanosRESUMEN
RATIONALE: While thrombin is the key protease in thrombus formation, other coagulation proteases, such as fXa (factor Xa) or aPC (activated protein C), independently modulate intracellular signaling via partially distinct receptors. OBJECTIVES: To study the differential effects of fXa or fIIa (factor IIa) inhibition on gene expression and inflammation in myocardial ischemia-reperfusion injury. METHODS AND RESULTS: Mice were treated with a direct fIIa inhibitor (fIIai) or direct fXa inhibitor (fXai) at doses that induced comparable anticoagulant effects ex vivo and in vivo (tail-bleeding assay and FeCl3-induced thrombosis). Myocardial ischemia-reperfusion injury was induced via left anterior descending ligation. We determined infarct size and in vivo aPC generation, analyzed gene expression by RNA sequencing, and performed immunoblotting and ELISA. The signaling-only 3K3A-aPC variant and inhibitory antibodies that blocked all or only the anticoagulant function of aPC were used to determine the role of aPC. Doses of fIIai and fXai that induced comparable anticoagulant effects resulted in a comparable reduction in infarct size. However, unbiased gene expression analyses revealed marked differences, including pathways related to sterile inflammation and inflammasome regulation. fXai but not fIIai inhibited sterile inflammation by reducing the expression of proinflammatory cytokines (IL [interleukin]-1ß, IL-6, and TNFα [tumor necrosis factor alpha]), as well as NF-κB (nuclear factor kappa B) and inflammasome activation. This anti-inflammatory effect was associated with reduced myocardial fibrosis 28 days post-myocardial ischemia-reperfusion injury. Mechanistically, in vivo aPC generation was higher with fXai than with fIIai. Inhibition of the anticoagulant and signaling properties of aPC abolished the anti-inflammatory effect associated with fXai, while inhibiting only the anticoagulant function of aPC had no effect. Combining 3K3A-aPC with fIIai reduced the inflammatory response, mimicking the fXai-associated effect. CONCLUSIONS: We showed that specific inhibition of coagulation via direct oral anticoagulants had differential effects on gene expression and inflammation, despite comparable anticoagulant effects and infarct sizes. Targeting individual coagulation proteases induces specific cellular responses unrelated to their anticoagulant effect.
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Antiinflamatorios/uso terapéutico , Inhibidores del Factor Xa/uso terapéutico , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Proteína C/uso terapéutico , Animales , Antiinflamatorios/farmacología , Inhibidores del Factor Xa/farmacología , Inflamasomas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , FN-kappa B/metabolismo , Proteína C/farmacologíaRESUMEN
PURPOSE: During lactation, bone turnover increases, reflecting the mobilization of Calcium from maternal skeletal stores and resulting in bone loss. However, mechanisms are not yet fully understood, and previous studies have been comparatively small. We aim to assess bone metabolism during lactation by comparing bone-metabolism-related-parameters between large cohorts of lactating and nonlactating women. METHODS: In a retrospective cohort study, we recruited 779 postpartum women and 742 healthy, nonpregnant, nonlactating controls. Postpartum women were examined 3 and 6 months after delivery and retrospectively assigned to either the exclusively breastfeeding (exc-bf) group if they had exclusively breastfed or the nonexclusively breastfeeding (nonexc-bf) group if they had not exclusively breastfed up to the respective visit. Serum levels of PTH, Estradiol, total Calcium, Phosphate, and bone turnover markers (ßCTX, P1NP, Osteocalcin) were compared between the groups. RESULTS: Bone turnover markers were significantly increased in exc-bf and nonexc-bf women compared with the controls (all ps < .001). ßCTX was approximately twice as high in exc-bf women than in the controls. PTH levels were marginally higher in exc-bf (p < .001) and nonexc-bf women (p = .003) compared with the controls (6 months). Estradiol was suppressed in exc-bf women compared with the controls (p < .001, 3 months). CONCLUSION: Exc-bf and even nonexc-bf states are characterized by an increase in bone formation and resorption markers. The PTH data distribution of exc-bf, nonexc-bf, and control groups in the underpart of the reference range suggest that lactational bone loss is relatively independent of PTH.
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Calcio , Lactancia , Femenino , Humanos , Estudios Retrospectivos , Hormona Paratiroidea , Remodelación Ósea , Estradiol , Densidad ÓseaRESUMEN
OBJECTIVE: This study aimed to investigate whether the sex steroid precursor hormone dehydroepiandrosterone sulphate (DHEA-S), sex hormone-binding globulin (SHBG) and testosterone (TT) are associated with temporomandibular (TM) pain on palpation in male adolescents. METHODS: Out of the LIFE Child study dataset containing 1022 children and adolescents aged 10-18 years (496 males, 48.5%), we used a subsample of 273 male adolescents (mean age: 13.8 ± 2.3 years) in advanced pubertal development (PD) to analyse the association between hormones and TM pain. The Tanner scale was applied to describe the stage of PD. Pain on palpation of the temporalis and masseter muscles and the TM joints (palpation pain) was assessed using the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD). Serum levels of sex hormones (DHEA-S, SHBG and TT) were determined using standardised laboratory analyses. Free TT was estimated from the ratio between TT and SHBG (free androgen index[FAI]). We calculated the risk of perceived positive palpation pain for male participants as a function of hormone levels (DHEA-S, FAI) taking into account age and body mass index (BMI). RESULTS: Among more developed (Tanner stage 4-5) male adolescents, 22.7% (n = 62) reported palpation pain in the TM region. In these participants, FAI levels were approximately half that of individuals without such pain (p < .01). DHEA-S levels were about 30% lower in the pain group (p < .01). In multivariable regression analyses, the odds ratio (OR) for pain on palpation decreased to 0.75 (95% confidence interval [CI]: 0.57-0.98) per 10 units of FAI level compared to those without pain, after controlling for the effects of age and adjusted BMI. We observed the same effect for this subgroup per unit of DHEA-S serum level (OR = 0.71; 95% CI: 0.53-0.94). CONCLUSION: At subclinical lower levels of serum free TT and DHEA-S, male adolescents are more likely to report pain on standardised palpation of the masticatory muscles and/or TM joints. This finding supports the hypothesis that sex hormones may influence pain reporting.
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Hormonas Esteroides Gonadales , Testosterona , Adolescente , Masculino , Humanos , Niño , Estudios Transversales , Dolor , DeshidroepiandrosteronaRESUMEN
OBJECTIVE: Although anorexia nervosa (AN) in males has recently gained attention, knowledge of its psychological and physiological outcomes is still scarce. We explore sex-specific characteristics of long-term remitted AN with respect to residual eating disorder (ED) psychopathology, body image, and endocrinology. METHOD: We recruited 33 patients with AN in remission for at least 18 months (24 women, 9 men) and 36 matched healthy controls (HCs). Eating disorder psychopathology and body image ideals were assessed via clinical interviews, questionnaires, and an interactive 3D body morphing tool. Plasma levels of leptin, free triiodothyronine, cortisol, and sex hormones were quantified. Univariate models controlled for age and weight were used to test for the effects of diagnosis and sex. RESULTS: Both patient groups showed residual ED psychopathology but normal weight and hormone levels relative to HCs. Male remitted patients demonstrated significantly stronger muscularity-focused body image ideals, evident in interviews, self-reports, and behavioural data, than both female patients and HCs. CONCLUSIONS: Sex-specific body image characteristics in patients with remitted AN point towards the need to adjust test instruments and diagnostic criteria to male-specific psychopathology. In the future, sufficiently powered studies should evaluate the risk of men with AN developing muscle dysmorphia in the long term.
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Anorexia Nerviosa , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Femenino , Masculino , Anorexia Nerviosa/psicología , Imagen Corporal/psicología , Hidrocortisona , Encuestas y CuestionariosRESUMEN
Efficient therapies for diabetic kidney disease (DKD), now the leading cause of kidney failure, are lacking. One hallmark of DKD is sterile inflammation (inflammation in absence of microorganisms), but the underlying molecular mechanisms remain poorly understood. The NLRP3 inflammasome (innate immune system receptors and sensors regulating activation of caspase-1) is a mechanism of sterile inflammation known to be activated by metabolic stimuli and reactive metabolites associated with DKD, including inflammasome activation in podocytes. However, whether NLRP3 inflammasome activation in podocytes contributes to sterile inflammation and glomerular damage in DKD remains unknown. Here, we found that kidney damage, as reflected by increased albuminuria, glomerular mesangial expansion and glomerular basement membrane thickness was aggravated in hyperglycemic mice with podocyte-specific expression of an Nlrp3 gain-of-function mutant (Nlrp3A350V). In contrast, hyperglycemic mice with podocyte-specific Nlrp3 or Caspase-1 deficiency showed protection against DKD. Intriguingly, podocyte-specific Nlrp3 deficiency was fully protective, while podocyte-specific caspase-1 deficiency was only partially protective. Podocyte-specific Nlrp3, but not caspase-1 deficiency, maintained glomerular autophagy in hyperglycemic mice, suggesting that podocyte Nlrp3 exerts both canonical and non-canonical effects. Thus, podocyte NLRP3 inflammasome activation is both sufficient and required for DKD and supports the concept that podocytes exert some immune cell-like functions. Hence, as podocyte NLRP3 exerts non-canonical and canonical effects, targeting NLRP3 may be a promising therapeutic approach in DKD.
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Diabetes Mellitus , Nefropatías Diabéticas , Podocitos , Animales , Diabetes Mellitus/metabolismo , Nefropatías Diabéticas/genética , Nefropatías Diabéticas/metabolismo , Inflamasomas/metabolismo , Inflamación/metabolismo , Ratones , Ratones Obesos , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Podocitos/metabolismoRESUMEN
11-Oxygenated androgens (11-OAs) are being discussed as potential biomarkers in diagnosis and therapy control of disorders with androgen excess such as congenital adrenal hyperplasia and polycystic ovary syndrome. However, quantification of 11-OAs by liquid chromatography-tandem mass spectrometry (LC-MS/MS) still relies on extensive sample preparation including liquid-liquid extraction, derivatization and partial long runtimes, which is unsuitable for high-throughput analysis under routine laboratory settings. For the first time, an established online-solid-phase extraction-LC-MS/MS (online-SPE-LC-MS/MS) method for the quantitation of seven serum steroids in daily routine use was extended and validated to include 11-ketoandrostenedione, 11-ketotestosterone, 11ß-hydroxyandrostenedione and 11ß-hydroxytestosterone. Combining a simple protein precipitation step with fast chromatographic separation and ammonium fluoride-modified ionization resulted in a high-throughput method (6.6 min run time) featuring lower limits of quantification well below endogenous ranges (63-320 pmol/L) with recoveries between 85% and 117% (CVs ≤ 15%). Furthermore, the ability of this method to distinguish between adrenal and gonadal androgens was shown by comparing 11-OAs in patients with hyperandrogenemia to healthy controls. Due to the single shot multiplex design of the method, potential clinically relevant ratios of 11-OAs and corresponding androgens were readily available. The fully validated method covering endogenous concentration levels is ready to investigate the diagnostic values of 11-OAs in prospective studies and clinical applications.
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Andrógenos , Síndrome del Ovario Poliquístico , Femenino , Humanos , Andrógenos/metabolismo , Cromatografía Liquida/métodos , Espectrometría de Masas en Tándem/métodos , Estudios Prospectivos , Esteroides , Síndrome del Ovario Poliquístico/diagnósticoRESUMEN
Obesity develops early in childhood and is accompanied by early signs of adipose tissue (AT) dysfunction and metabolic disease in children. In order to analyse the molecular processes during obesity-related AT accumulation in children, we investigated genome-wide expression profiles in AT samples, isolated adipocytes, and stromal vascular fraction (SVF) cells and assessed their relation to obesity as well as biological and functional AT parameters. We detected alterations in gene expression associated with obesity and related parameters, i.e., BMI SDS, adipocyte size, macrophage infiltration, adiponectin, and/or leptin. While differential gene expression in AT and adipocytes shared an enrichment in metabolic pathways and pathways related to extracellular structural organisation, SVF cells showed an overrepresentation in inflammatory pathways. In adipocytes, we found the strongest positive association for epidermal growth factor-like protein 6 (EGFL6) with adipocyte hypertrophy. EGFL6 was also upregulated during in vitro adipocyte differentiation. In children, EGFL6 expression was positively correlated to parameters of AT dysfunction and metabolic disease such as macrophage infiltration into AT, hs-CRP, leptin levels, and HOMA-IR. In conclusion, we provide evidence for early alterations in AT gene expression related to AT dysfunction in children and identified EGFL6 as potentially being involved in processes underlying the pathogenesis of metabolic disease.
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Tejido Adiposo , Leptina , Adipocitos/metabolismo , Tejido Adiposo/metabolismo , Proteínas de Unión al Calcio/genética , Proteínas de Unión al Calcio/metabolismo , Moléculas de Adhesión Celular/metabolismo , Niño , Perfilación de la Expresión Génica , Humanos , Leptina/genética , Leptina/metabolismo , Obesidad/metabolismoRESUMEN
BACKGROUND: Brain-derived neurotrophic factor (BDNF) influences brain plasticity and feeding behaviour, and it has been linked to anorexia nervosa in numerous studies. Findings in mostly adult patients point to reduced serum BDNF levels in the acute stage of anorexia nervosa and rising levels with weight recovery. However, it is unclear whether this increase leads to normalization or supranormal levels, a difference that is potentially important for the etiology of anorexia nervosa and relapse. METHODS: We measured serum BDNF at admission (n = 149), discharge (n = 130), 1-year follow-up (n = 116) and 2.5-year follow-up (n = 76) in adolescent female patients with anorexia nervosa hospitalized for the first time, and in healthy controls (n = 79). We analyzed associations with body mass index, eating disorder psychopathology and comorbidities. RESULTS: Serum BDNF was only nominally lower at admission in patients with anorexia nervosa compared to healthy controls, but it increased continuously and reached supranormal levels at 2.5-year follow-up. BDNF was inversely associated with eating disorder psychopathology at discharge and positively associated with previous weight gain at 1-year follow-up. LIMITATIONS: We compensated for attrition and batch effects using statistical measures. CONCLUSION: In this largest longitudinal study to date, we found only nonsignificant reductions in BDNF in the acute stage of anorexia nervosa, possibly because of a shorter illness duration in adolescent patients. Supranormal levels of BDNF at 2.5-year follow-up could represent a pre-existing trait or a consequence of the illness. Because of the anorexigenic effect of BDNF, it might play an important predisposing role for relapse and should be explored further in studies that test causality.
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Anorexia Nerviosa/metabolismo , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Hospitalización , Adolescente , Femenino , Humanos , Estudios Longitudinales , RecurrenciaRESUMEN
BACKGROUND: Diabetic nephropathy (dNP), now the leading cause of ESKD, lacks efficient therapies. Coagulation protease-dependent signaling modulates dNP, in part via the G protein-coupled, protease-activated receptors (PARs). Specifically, the cytoprotective protease-activated protein C (aPC) protects from dNP, but the mechanisms are not clear. METHODS: A combination of in vitro approaches and mouse models evaluated the role of aPC-integrin interaction and related signaling in dNP. RESULTS: The zymogen protein C and aPC bind to podocyte integrin-ß3, a subunit of integrin-αvß3. Deficiency of this integrin impairs thrombin-mediated generation of aPC on podocytes. The interaction of aPC with integrin-αvß3 induces transient binding of integrin-ß3 with G α13 and controls PAR-dependent RhoA signaling in podocytes. Binding of aPC to integrin-ß3via its RGD sequence is required for the temporal restriction of RhoA signaling in podocytes. In podocytes lacking integrin-ß3, aPC induces sustained RhoA activation, mimicking the effect of thrombin. In vivo, overexpression of wild-type aPC suppresses pathologic renal RhoA activation and protects against dNP. Disrupting the aPC-integrin-ß3 interaction by specifically deleting podocyte integrin-ß3 or by abolishing aPC's integrin-binding RGD sequence enhances RhoA signaling in mice with high aPC levels and abolishes aPC's nephroprotective effect. Pharmacologic inhibition of PAR1, the pivotal thrombin receptor, restricts RhoA activation and nephroprotects RGE-aPChigh and wild-type mice.Conclusions aPC-integrin-αvß3 acts as a rheostat, controlling PAR1-dependent RhoA activation in podocytes in diabetic nephropathy. These results identify integrin-αvß3 as an essential coreceptor for aPC that is required for nephroprotective aPC-PAR signaling in dNP.
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Nefropatías Diabéticas/prevención & control , Integrina beta3/fisiología , Podocitos/fisiología , Proteína C/fisiología , Proteína de Unión al GTP rhoA/fisiología , Animales , Citoprotección , Receptor de Proteína C Endotelial/fisiología , Subunidades alfa de la Proteína de Unión al GTP G12-G13/fisiología , Células HEK293 , Humanos , Ratones , Ratones Endogámicos C57BL , Receptor PAR-1/fisiologíaRESUMEN
Procoagulant extracellular vesicles (EV) and platelet activation have been associated with gestational vascular complications. EV-induced platelet-mediated placental inflammasome activation has been shown to cause preeclampsia-like symptoms in mice. However, the effect of EV-mediated placental thrombo-inflammation on trophoblast differentiation remains unknown. Here, we identify that the EV-induced thrombo-inflammatory pathway modulates trophoblast morphology and differentiation. EVs and platelets reduce syncytiotrophoblast differentiation while increasing giant trophoblast and spongiotrophoblast including the glycogen-rich cells. These effects are platelet-dependent and mediated by the NLRP3 inflammasome. In humans, inflammasome activation was negatively correlated with trophoblast differentiation marker GCM1 and positively correlated with blood pressure. These data identify a crucial role of EV-induced placental thrombo-inflammation on altering trophoblast differentiation and suggest platelet activation or inflammasome activation as a therapeutic target in order to achieve successful placentation.
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Vesículas Extracelulares/genética , Inflamación/genética , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Complicaciones Cardiovasculares del Embarazo/genética , Animales , Plaquetas/metabolismo , Plaquetas/patología , Diferenciación Celular/genética , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Vesículas Extracelulares/metabolismo , Femenino , Humanos , Inflamasomas/genética , Inflamación/metabolismo , Inflamación/patología , Ratones , Activación Plaquetaria/genética , Embarazo , Complicaciones Cardiovasculares del Embarazo/patología , Factores de Transcripción/genética , Trofoblastos/metabolismo , Trofoblastos/patologíaRESUMEN
BACKGROUND: Resting state functional magnetic resonance imaging studies have identified functional connectivity patterns associated with acute undernutrition in anorexia nervosa (AN), but few have investigated recovered patients. Thus, a trait connectivity profile characteristic of the disorder remains elusive. Using state-of-the-art graph-theoretic methods in acute AN, the authors previously found abnormal global brain network architecture, possibly driven by local network alterations. To disentangle trait from starvation effects, the present study examines network organization in recovered patients. METHODS: Graph-theoretic metrics were used to assess resting-state network properties in a large sample of female patients recovered from AN (recAN, n = 55) compared with pairwise age-matched healthy controls (HC, n = 55). RESULTS: Indicative of an altered global network structure, recAN showed increased assortativity and reduced global clustering as well as small-worldness compared with HC, while no group differences at an intermediate or local network level were evident. However, using support-vector classifier on local metrics, recAN and HC could be separated with an accuracy of 70.4%. CONCLUSIONS: This pattern of results suggests that long-term recovered patients have an aberrant global brain network configuration, similar to acutely underweight patients. While the finding of increased assortativity may represent a trait marker of AN, the remaining findings could be seen as a scar following prolonged undernutrition.
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Anorexia Nerviosa/fisiopatología , Vías Nerviosas/fisiopatología , Adolescente , Adulto , Anorexia Nerviosa/diagnóstico por imagen , Mapeo Encefálico , Estudios de Casos y Controles , Femenino , Humanos , Vías Nerviosas/diagnóstico por imagen , Adulto JovenRESUMEN
Dietary methionine restriction (MR) is well known to reduce body weight by increasing energy expenditure (EE) and insulin sensitivity. An elevated concentration of circulating fibroblast growth factor 21 (FGF21) has been implicated as a potential underlying mechanism. The aims of our study were to test whether dietary MR in the context of a high-fat regimen protects against type 2 diabetes in mice and to investigate whether vegan and vegetarian diets, which have naturally low methionine levels, modulate circulating FGF21 in humans. New Zealand obese (NZO) mice, a model for polygenic obesity and type 2 diabetes, were placed on isocaloric high-fat diets (protein, 16 kcal%; carbohydrate, 52 kcal%; fat, 32 kcal%) that provided methionine at control (Con; 0.86% methionine) or low levels (0.17%) for 9 wk. Markers of glucose homeostasis and insulin sensitivity were analyzed. Among humans, low methionine intake and circulating FGF21 levels were investigated by comparing a vegan and a vegetarian diet to an omnivore diet and evaluating the effect of a short-term vegetarian diet on FGF21 induction. In comparison with the Con group, MR led to elevated plasma FGF21 levels and prevented the onset of hyperglycemia in NZO mice. MR-fed mice exhibited increased insulin sensitivity, higher plasma adiponectin levels, increased EE, and up-regulated expression of thermogenic genes in subcutaneous white adipose tissue. Food intake and fat mass did not change. Plasma FGF21 levels were markedly higher in vegan humans compared with omnivores, and circulating FGF21 levels increased significantly in omnivores after 4 d on a vegetarian diet. These data suggest that MR induces FGF21 and protects NZO mice from high-fat diet-induced glucose intolerance and type 2 diabetes. The normoglycemic phenotype in vegans and vegetarians may be caused by induced FGF21. MR akin to vegan and vegetarian diets in humans may offer metabolic benefits via increased circulating levels of FGF21 and merits further investigation.-Castaño-Martinez, T., Schumacher, F., Schumacher, S., Kochlik, B., Weber, D., Grune, T., Biemann, R., McCann, A., Abraham, K., Weikert, C., Kleuser, B., Schürmann, A., Laeger, T. Methionine restriction prevents onset of type 2 diabetes in NZO mice.
Asunto(s)
Diabetes Mellitus Tipo 2/prevención & control , Metionina/administración & dosificación , Adiponectina/sangre , Tejido Adiposo , Alimentación Animal , Animales , Biomarcadores , Glucemia , Dieta , Factores de Crecimiento de Fibroblastos/sangre , Humanos , Hiperglucemia/prevención & control , Insulina/sangre , Leptina/sangre , Hígado/metabolismo , Masculino , Ratones , Ratones Obesos , Veganos , Aumento de PesoRESUMEN
PURPOSE: The gut-brain axis could be a possible key factor in the pathophysiology of anorexia nervosa. The neuropeptide peptide YY3-36, secreted by endocrine L cells of the gastrointestinal tract, is a known regulator of appetite and food intake. The objective of this study was to investigate peptide YY3-36 plasma concentrations at different stages of anorexia nervosa in a combined cross-sectional and longitudinal design to differentiate between effects of acute undernutrition and more enduring characteristics. METHODS: We measured fasting plasma peptide YY3-36 concentrations in young patients with acute anorexia nervosa (n = 47) and long-term recovered patients (n = 35) cross-sectionally in comparison to healthy control participants (n = 58), and longitudinally over the course of inpatient treatment. Physical activity was controlled as it may modulate peptide YY secretion. RESULTS: There was no group difference in peptide YY3-36 concentration among young acutely underweight anorexia nervosa patients, long-term recovered anorexia nervosa patients, and healthy control participants. Longitudinally, there was no change in peptide YY3-36 concentration after short-term weight rehabilitation. For acute anorexia nervosa patients at admission to treatment, there was a negative correlation between peptide YY3-36 concentration and body mass index. CONCLUSIONS: The current study provides additional evidence for a normal basal PYY3-36 concentration in AN. Future studies should study multiple appetite-regulating peptides and their complex interplay and also use research designs including a food challenge.
Asunto(s)
Anorexia Nerviosa , Péptido YY , Apetito , Índice de Masa Corporal , Estudios Transversales , Humanos , DelgadezRESUMEN
BACKGROUND: Gray matter (GM) 'pseudoatrophy' is well-documented in patients with anorexia nervosa (AN), but changes in white matter (WM) are less well understood. Here we investigated the dynamics of microstructural WM brain changes in AN patients during short-term weight restoration in a combined longitudinal and cross-sectional study design. METHODS: Diffusion-weighted images were acquired in young AN patients before (acAN-Tp1, n = 56) and after (acAN-Tp2, n = 44) short-term weight restoration as well as in age-matched healthy controls (HC, n = 60). Images were processed using Tract-Based-Spatial-Statistics to compare fractional anisotropy (FA) across groups and timepoints. RESULTS: In the cross-sectional comparison, FA was significantly reduced in the callosal body in acAN-Tp1 compared with HC, while no differences were found between acAN-Tp2 and HC. In the longitudinal arm, FA increased with weight gain in acAN-Tp2 relative to acAN-Tp1 in large parts of the callosal body and the fornix, while it decreased in the right corticospinal tract. CONCLUSIONS: Our findings reveal that dynamic, bidirectional changes in WM microstructure in young underweight patients with AN can be reversed with brief weight restoration therapy. These results parallel those previously observed in GM and suggest that alterations in WM in non-chronic AN are also state-dependent and rapidly reversible with successful intervention.
Asunto(s)
Anorexia Nerviosa/patología , Anorexia Nerviosa/terapia , Cuerpo Calloso/patología , Delgadez/patología , Delgadez/terapia , Aumento de Peso , Sustancia Blanca/patología , Adolescente , Adulto , Anorexia Nerviosa/diagnóstico por imagen , Niño , Cuerpo Calloso/diagnóstico por imagen , Estudios Transversales , Imagen de Difusión Tensora , Femenino , Humanos , Estudios Longitudinales , Rehabilitación Psiquiátrica , Delgadez/diagnóstico por imagen , Sustancia Blanca/diagnóstico por imagen , Adulto JovenRESUMEN
Heart failure (HF) is a disabling condition involving complex vascular, neurohormonal and immune systems' interactions. Osteoprotegerin (OPG), a bone-regulatory cytokine, has been suggested to play a key role in skeletal, vascular, and immune biology, with elevated levels observed in both experimental and clinical HF. In the present study we aimed to identify clinical OPG correlates and investigated whether elevated OPG, as a marker of HF vascular and immune activation, may interact with N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of HF neurohormonal activation, thus synergistically increasing HF risk. We used a case-cohort study, nested within the European Prospective Investigation into Cancer and Nutrition-Potsdam, comprising 2647 participants including 252 incident HF cases identified during a mean follow-up of 8.2 ± 1.6 years. In both men and women significant positive associations were observed between OPG and age, smoking, prevalent diabetes, C-reactive protein, sex hormone-binding globulin, and additionally prevalent coronary heart disease and uric acid in men only. In women, OPG was furthermore positively related to hypertension and fetuin-A. After multivariable adjustment each doubling of OPG was associated with a 3.01-fold increased HF risk (95 % CI 1.49-6.06) in men. A significant interaction was observed between OPG and NT-proBNP. In men, a combination of high levels of both OPG and NT-proBNP, compared to a combination of low levels, was associated with an approximately fivefold increased HF risk. In women, no associations were observed. These findings suggest that, in men, the activation of different immune, neurohormonal, and vascular pathophysiological pathways may confer increased HF risk.