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A Western lifestyle with high salt consumption can lead to hypertension and cardiovascular disease. High salt may additionally drive autoimmunity by inducing T helper 17 (TH17) cells, which can also contribute to hypertension. Induction of TH17 cells depends on gut microbiota; however, the effect of salt on the gut microbiome is unknown. Here we show that high salt intake affects the gut microbiome in mice, particularly by depleting Lactobacillus murinus. Consequently, treatment of mice with L. murinus prevented salt-induced aggravation of actively induced experimental autoimmune encephalomyelitis and salt-sensitive hypertension by modulating TH17 cells. In line with these findings, a moderate high-salt challenge in a pilot study in humans reduced intestinal survival of Lactobacillus spp., increased TH17 cells and increased blood pressure. Our results connect high salt intake to the gut-immune axis and highlight the gut microbiome as a potential therapeutic target to counteract salt-sensitive conditions.
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Microbioma Gastrointestinal/efeitos dos fármacos , Lactobacillus/efeitos dos fármacos , Lactobacillus/isolamento & purificação , Cloreto de Sódio/farmacologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Animais , Autoimunidade/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/microbiologia , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/terapia , Fezes/microbiologia , Humanos , Hipertensão/induzido quimicamente , Ácidos Indolacéticos/metabolismo , Indóis/metabolismo , Intestinos/citologia , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/microbiologia , Lactobacillus/imunologia , Ativação Linfocitária/efeitos dos fármacos , Contagem de Linfócitos , Masculino , Camundongos , Projetos Piloto , Cloreto de Sódio/administração & dosagem , Simbiose , Células Th17/citologia , Triptofano/metabolismoRESUMO
PURPOSE: We present a methodological overview of a respiration chamber at the Experimental and Clinical Research Center in Berlin, Germany. Since 2010, we investigated 750 healthy subjects and patients with various diseases. We routinely measure resting energy expenditure (REE), dietary-induced thermogenesis, and activity energy expenditure. METHODS: The chamber is a pull calorimeter with a total volume of 11,000 L. The majority of measurements is done with a flow rate of 120 L/min, yielding a favorable time constant of 1.53 h. The gas analysis system consists of two paramagnetic O2 sensors and two infrared CO2 sensors, one for incoming and one for outgoing air samples. O2 and CO2 sensors are calibrated simultaneously before each measurement with a 6 min calibration routine. To verify the accuracy of the whole the calorimetric system, it is validated every 2 weeks by 2 h acetone burning tests. RESULTS: Validation factors (calculated/measured) of 20 representative 2 h acetone burning tests were 1.03 ± 0.03 for [Formula: see text], 1.02 ± 0.02 for [Formula: see text], 0.99 ± 0.02 for RER, and 1.03 ± 0.03 for EE. Four repeated 60 min REE measurements of a healthy woman showed variabilities of 231.9 ± 4.8 ml/min for [Formula: see text] (CV 2.1%), 166.0 ± 6.3 ml/min for [Formula: see text] (CV 3.8%), 0.73 ± 0.03 for RER (CV 4.6%), and 4.55 ± 0.07 kJ/min for EE (CV 1.6%). CONCLUSIONS: The data presented show that our respiration chamber produces precise and valid EE measurements with an exceptionally fast responsiveness.
Assuntos
Acetona , Dióxido de Carbono , Feminino , Humanos , Berlim , Calorimetria Indireta , Metabolismo Energético , Respiração , Estudos de Casos e ControlesRESUMO
BACKGROUND: Physical activity improves insulin sensitivity in obesity. Hypoxia training is claimed to augment this effect. We tested the hypothesis that normobaric hypoxia training would improve insulin sensitivity in obese patients with metabolic syndrome. METHODS: In a randomized controlled trial, 23 obese men with metabolic syndrome who were not informed of the FiO2 conditions underwent a 6-week physical exercise intervention under ambient (n = 11; FiO2 21%) conditions or hypoxia (n = 12; FiO2 15%) using a normobaric hypoxic chamber. Three 60-min sessions of interval training were performed each week at 60% of individual VÌO2max. Assessment of myocellular insulin sensitivity by euglycemic hyperinsulinemic clamp was performed in 21 of these subjects before and after 6 weeks of training. Comprehensive phenotyping also included biopsies of subcutaneous adipose tissues. RESULTS: The intermittent moderate physical exercise protocol did not substantially change the myocellular insulin sensitivity within 6 weeks under normoxic conditions (ISIClamp: 0.035 (IQR 0.016-0.075) vs. 0.037 (IQR 0.026-0.056) mg* kg-1 *min-1/(mU* l-1); p = 0.767). In contrast, ISIClamp improved during hypoxia training (0.028 (IQR 0.018-0.035) vs. 0.038 (IQR 0.024-0.060) mg * kg-1 *min-1/(mU *l-1); p < 0.05). Between group comparison of ISIClamp change revealed a small difference between groups (Cohen's d = 0.26). Within the hypoxic group, improvement of ISIClamp during training was associated with individual increase of circulating vascular endothelial growth factor (VEGF) levels (r = 0.678, p = 0.015), even if mean VEGF levels were not modified by any training condition. Atrial natriuretic peptide (ANP) system components were not associated with increased ISIClamp during hypoxic training. CONCLUSIONS: Physical training under hypoxic conditions could partially augment the favorable effects of exercise alone on myocellular insulin sensitivity in obese men with metabolic syndrome. Concomitant changes in VEGF might represent an underlying pathophysiological mechanism.
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Exercício Físico/fisiologia , Resistência à Insulina/fisiologia , Síndrome Metabólica , Músculo Esquelético/metabolismo , Obesidade , Idoso , Humanos , Hipóxia , Masculino , Síndrome Metabólica/complicações , Síndrome Metabólica/metabolismo , Síndrome Metabólica/terapia , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/metabolismo , Obesidade/terapia , Oxigênio/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
The functional dynamics and cellular sources of oxidative stress are central to understanding MS pathogenesis but remain elusive, due to the lack of appropriate detection methods. Here we employ NAD(P)H fluorescence lifetime imaging to detect functional NADPH oxidases (NOX enzymes) in vivo to identify inflammatory monocytes, activated microglia, and astrocytes expressing NOX1 as major cellular sources of oxidative stress in the central nervous system of mice affected by experimental autoimmune encephalomyelitis (EAE). This directly affects neuronal function in vivo, indicated by sustained elevated neuronal calcium. The systemic involvement of oxidative stress is mirrored by overactivation of NOX enzymes in peripheral CD11b(+) cells in later phases of both MS and EAE. This effect is antagonized by systemic intake of the NOX inhibitor and anti-oxidant epigallocatechin-3-gallate. Together, this persistent hyper-activation of oxidative enzymes suggests an "oxidative stress memory" both in the periphery and CNS compartments, in chronic neuroinflammation.
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Encefalomielite Autoimune Experimental/enzimologia , Esclerose Múltipla/enzimologia , NADPH Oxidases/metabolismo , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/uso terapêutico , Astrócitos/efeitos dos fármacos , Astrócitos/enzimologia , Astrócitos/patologia , Antígeno CD11b/metabolismo , Cálcio/metabolismo , Catequina/análogos & derivados , Catequina/uso terapêutico , Doença Crônica , Progressão da Doença , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/patologia , Inibidores Enzimáticos/uso terapêutico , Acetato de Glatiramer/uso terapêutico , Humanos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia de Fluorescência/métodos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/patologia , NADPH Oxidases/antagonistas & inibidores , Neurônios/efeitos dos fármacos , Neurônios/enzimologia , Neurônios/patologia , Estresse Oxidativo/efeitos dos fármacosRESUMO
Several studies provide evidence for the existence of a hypermetabolic state of biological origin in recently weight recovered patients with anorexia nervosa. It remains unclear if current nutritional rehabilitation strategies are consistent with the resulting high energy requirements. Further insight into specific pathophysiological characteristics of energetic efficiency in patients with anorexia nervosa will help us to provide evidence based nutritional guidance. Basic nutritional research in this field is urgently required.
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Anorexia Nervosa/terapia , Transtornos da Alimentação e da Ingestão de Alimentos/terapia , Ciências da Nutrição , Anorexia Nervosa/metabolismo , Transtornos da Alimentação e da Ingestão de Alimentos/metabolismo , Humanos , Terapia NutricionalRESUMO
BACKGROUND AND PURPOSE: Muscle wasting is a common complication accompanying stroke. Although it is known to impair poststroke recovery, the mechanisms of subacute catabolism after stroke have not been investigated in detail. The aim of this study is to investigate mechanisms of local and systemic catabolism and muscle wasting (sarcopenia) in a model of ischemic stroke systematically. METHODS: Changes in body composition and catabolic activation in muscle tissue were studied in a mouse model of acute cerebral ischemia (temporal occlusion of the middle cerebral artery). Tissue wasting (nuclear magnetic resonance spectroscopy), tissue catabolism (caspases-3 and -6, myostatin), and proteasome activity were assessed. Food intake, activity levels, and energy expenditure were assessed, and putative mechanisms of postischemic wasting were tested with appropriate interventions. RESULTS: Severe weight loss in stroke animals (day 3: weight loss, -21.7%) encompassed wasting of muscle (-12%; skeletal and myocardium) and fat tissue (-27%). Catabolic signaling and proteasome activity were higher in stroke animals in the contralateral and in the ipsilateral leg. Cerebral infarct severity correlated with catabolic activity only in the contralateral leg but not in the ipsilateral leg. Lower energy expenditure in stroke animals together with normal food intake and activity levels suggests compensatory mechanisms to regain weight. Interventions (high caloric feeding, ß-receptor blockade, and antibiotic treatment) failed to prevent proteolytic activation and muscle wasting. CONCLUSIONS: Catabolic pathways of muscle tissue are activated after stroke. Impaired feeding, sympathetic overactivation, or infection cannot fully explain this catabolic activation. Wasting of the target muscle of the disrupted innervation correlated to severity of brain injury. Our data indicate the presence of a stroke-specific sarcopenia.
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Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Sarcopenia/etiologia , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/metabolismo , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atrofia Muscular/metabolismo , Atrofia Muscular/patologia , Sarcopenia/metabolismo , Sarcopenia/patologia , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/patologiaRESUMO
Autosomal dominant spinocerebellar ataxia type 1 (SCA1) is a genetic movement disorder with neuronal loss in the cerebellum, brainstem, and other cerebral regions. The course of SCA1 is accompanied with progressive weight loss and amyotrophia-the causes for that remain, however, unclear. We tested the hypothesis that an imbalance between energy intake and expenditure contributes to weight loss in SCA1 patients. Anthropometric measures, energy intake (food records), and resting (calorimetry) and free-living (accelerometry) energy expenditure were determined in 10 patients with genetically proven SCA1 and 10 healthy controls closely matched for age, sex, and body composition. At rest, energy expenditure per kilogram fat-free mass was 22 % and fat oxidation rate 28 % higher in patients vs. controls indicating an increased catabolic state. Under free-living conditions, total energy expenditure and daily step counts were significantly lower in patients vs. controls. However, most patients were able to maintain energy intake and expenditure in a balanced state. Resting energy expenditure, fat oxidation, and activity energy expenditure per step count are higher, whereas 24-h total energy expenditure is lower in SCA1 patients vs. healthy controls. An altered autonomic nervous system activity, gait ataxia, and a decreased physical activity might contribute to this outcome.
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Ingestão de Energia/fisiologia , Metabolismo Energético/fisiologia , Doenças Metabólicas/etiologia , Ataxias Espinocerebelares/complicações , Acelerometria , Adolescente , Adulto , Idoso , Antropometria , Glicemia , Calorimetria , Estudos de Casos e Controles , Jejum , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Masculino , Doenças Metabólicas/sangue , Doenças Metabólicas/diagnóstico , Pessoa de Meia-Idade , Ataxias Espinocerebelares/sangue , Ataxias Espinocerebelares/genética , Estatísticas não Paramétricas , Adulto JovemRESUMO
RATIONALE: Critical illness myopathy (CIM) has no known cause and no treatment. Immobilization and impaired glucose metabolism are implicated. OBJECTIVES: We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects of evoked muscle contraction. METHODS: In a prospective observational and interventional pilot study, we screened 874 mechanically ventilated patients with a sepsis-related organ-failure assessment score greater than or equal to 8 for 3 consecutive days in the first 5 days of intensive care unit stay. Thirty patients at risk for CIM underwent euglycemic-hyperinsulinemic clamp, muscle microdialysis studies, and muscle biopsies. Control subjects were healthy. In five additional patients at risk for CIM, we performed corresponding analyses after 12-day, daily, unilateral electrical muscle stimulation with the contralateral leg as control. MEASUREMENTS AND MAIN RESULTS: We performed successive muscle biopsies and assessed systemic insulin sensitivity and signal transduction pathways of glucose utilization at the mRNA and protein level and glucose transporter-4 (GLUT4) localization in skeletal muscle tissue. Skeletal muscle GLUT4 was trapped at perinuclear spaces, most pronounced in patients with CIM, but resided at the sarcolemma in control subjects. Glucose metabolism was not stimulated during euglycemic-hyperinsulinergic clamp. Insulin signal transduction was competent up to p-Akt activation; however, p-adenosine monophosphate-activated protein kinase (p-AMPK) was not detectable in CIM muscle. Electrical muscle stimulation increased p-AMPK, repositioned GLUT4, locally improved glucose metabolism, and prevented type-2 fiber atrophy. CONCLUSIONS: Insufficient GLUT4 translocation results in decreased glucose supply in patients with CIM. Failed AMPK activation is involved. Evoked muscle contraction may prevent muscle-specific AMPK failure, restore GLUT4 disposition, and diminish protein breakdown. Clinical trial registered with http://www.controlled-trials.com (registration number ISRCTN77569430).
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Transportador de Glucose Tipo 4/metabolismo , Insulina/metabolismo , Insulina/farmacologia , Contração Muscular , Doenças Musculares/fisiopatologia , Adulto , Idoso , Análise de Variância , Biópsia/métodos , Estado Terminal , Estimulação Elétrica/métodos , Feminino , Técnica Clamp de Glucose/métodos , Transportador de Glucose Tipo 4/genética , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/farmacologia , Masculino , Microdiálise/métodos , Pessoa de Meia-Idade , Doenças Musculares/complicações , Doenças Musculares/genética , Doenças Musculares/patologia , Escores de Disfunção Orgânica , Projetos Piloto , Estudos Prospectivos , Respiração Artificial , Sepse/complicações , Transdução de SinaisRESUMO
BACKGROUND: A fasting conference and scientific symposium on fasting were held in Berlin in June 2023. Researchers and clinicians from around the world shared new findings, clinical insights, and work in progress during a three-day program. SUMMARY: Different fasting regimens, including prolonged, short-term, intermittent fasting and time-restricted eating (TRE) were discussed for preventive and therapeutic settings. Experimental and clinical findings shared ranged from biochemical and cellular fasting responses to fasting-mimicking agents, the role of the gut microbiome and immunological effects. Clinically, a special focus was placed upon metabolic, autoimmune, neurodegenerative, and oncological diseases. The discussion also covered how modern technologies, practical adaptations to traditional protocols, and a supportive network of specialized physicians can assist in the practical application of fasting, among other subjects. KEY MESSAGES: Dose-response relationships, gender aspects, and the subjective experience of fasting seem promising for future research, while further investigation of religious fasting may offer deeper insights into motivational and health aspects.
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Although fasting is increasingly applied for disease prevention and treatment, consensus on terminology is lacking. Using Delphi methodology, an international, multidisciplinary panel of researchers and clinicians standardized definitions of various fasting approaches in humans. Five online surveys and a live online conference were conducted with 38 experts, 25 of whom completed all 5 surveys. Consensus was achieved for the following terms: "fasting" (voluntary abstinence from some or all foods or foods and beverages), "modified fasting" (restriction of energy intake to max. 25% of energy needs), "fluid-only fasting," "alternate-day fasting," "short-term fasting" (lasting 2-3 days), "prolonged fasting" (≥4 consecutive days), and "religious fasting." "Intermittent fasting" (repetitive fasting periods lasting ≤48 h), "time-restricted eating," and "fasting-mimicking diet" were discussed most. This study provides expert recommendations on fasting terminology for future research and clinical applications, facilitating communication and cross-referencing in the field.
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Consenso , Jejum , Terminologia como Assunto , Jejum/fisiologia , Humanos , Técnica DelphiRESUMO
BACKGROUND: Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal-dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia. METHODS: Within a sub-analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex-specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis. RESULTS: Within the 2-year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P < 0.01). After 9 months, women and men had lost 2.6 ± 3.8 and 0.8 ± 1.5 kg (P < 0.05) in body weight, respectively, and after 21 months, they had lost 4.1 ± 6.6 and 1.0 ± 3.3 kg (P < 0.05), respectively. On everolimus, caloric intake was significantly lower in women versus men (1510 ± 128 vs. 2264 ± 216 kcal/day, P < 0.05), caused mainly by a lower fat and protein intake in women versus men. Cognitive restraints, disinhibition and hunger remained unchanged. In a subgroup of patients resting metabolic rate was unchanged whereas OGL-induced thermogenesis was reduced (7 ± 2 vs. 11 ± 2 kcal, P < 0.05). Fasting and OGL-induced fat oxidation was increased (P < 0.05) on versus off everolimus. In adipose tissue, fasting lipolytic activity was increased, but lipolytic activity was inhibited similarly after the OGL on versus off everolimus, respectively. In skeletal muscle, postprandial glucose uptake and aerobic glycolysis was reduced in patients on everolimus. CONCLUSIONS: mTOR inhibition by everolimus induces body weight reduction, specifically in female patients. This effect is possibly caused by a centrally mediated reduced food (fat and protein) intake and by centrally/peripherally mediated increased fat oxidation (systemic) and mobilization (adipose tissue). Glucose uptake and oxidation might be reduced in skeletal muscle. This could lead to cachexia and, possibly, muscle wasting. Therefore, our results have important implications for patients recieving immune-suppressive mTOR inhibition therapy.
Assuntos
Caquexia , Rim Policístico Autossômico Dominante , Masculino , Adulto , Humanos , Feminino , Caquexia/etiologia , Everolimo/farmacologia , Everolimo/uso terapêutico , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Rim Policístico Autossômico Dominante/complicações , Peso Corporal , Redução de Peso , Serina-Treonina Quinases TOR/metabolismo , Homeostase , GlucoseRESUMO
Objective: In the field of non-treatable muscular dystrophies, promising new gene and cell therapies are being developed and are entering clinical trials. Objective assessment of therapeutic effects on motor function is mandatory for economical and ethical reasons. Main shortcomings of existing measurements are discontinuous data collection in artificial settings as well as a major focus on walking, neglecting the importance of hand and arm movements for patients' independence. We aimed to create a digital tool to measure muscle function with an emphasis on upper limb motility. Methods: suMus provides a custom-made App running on smartwatches. Movement data are sent to the backend of a suMus web-based platform, from which they can be extracted as CSV data. Fifty patients with neuromuscular diseases assessed the pool of suMus activities in a first orientation phase. suMus performance was hence validated in four upper extremity exercises based on the feedback of the orientation phase. We monitored the arm metrics in a cohort of healthy volunteers using the suMus application, while completing each exercise at low frequency in a metabolic chamber. Collected movement data encompassed average acceleration, rotation rate as well as activity counts. Spearman rank tests correlated movement data with energy expenditure from the metabolic chamber. Results: Our novel application "suMus," sum of muscle activity, collects muscle movement data plus Patient-Related-Outcome-Measures, sends real-time feedback to patients and caregivers and provides, while ensuring data protection, a long-term follow-up of disease course. The application was well received from the patients during the orientation phase. In our pilot study, energy expenditure did not differ between overnight fasted and non-fasted participants. Acceleration ranged from 1.7 ± 0.7 to 3.2 ± 0.5 m/sec2 with rotation rates between 0.9 ± 0.5 and 2.0 ± 3.4 rad/sec. Acceleration and rotation rate as well as derived activity counts correlated with energy expenditure values measured in the metabolic chamber for one exercise (r = 0.58, p < 0.03). Conclusion: In the analysis of slow frequency movements of upper extremities, the integration of the suMus application with smartwatch sensors characterized motion parameters, thus supporting a use in clinical trial outcome measures. Alternative methodologies need to complement indirect calorimetry in validating accelerometer-derived energy expenditure data.
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BACKGROUND&AIMS: Long term improvement of body weight and metabolism is highly requested in obesity. The specific impact of weight loss associated temporary negative energy balance or modified body composition on metabolism and weight regain is unclear. METHODS: We randomly assigned 80 post-menopausal women (BMI 33.9 (32.2-36.8)kg/m2) to an intervention (IG) or control group (CG). IG underwent a dietary three month-weight loss intervention followed by a four week-weight maintenance period without negative energy balance. The CG was instructed to keep their weight stable. Phenotyping was performed at baseline (M0), after weight loss (M3), the maintenance period (M4) and 24-month follow-up (M24). Co-primary outcomes were changes of insulin sensitivity (ISIClamp) and lean body mass (LBM). Energy metabolism and adipose gene expression were secondary endpoints. RESULTS: Between March 2012 and July 2015, 479 subjects were screened for eligibility. 80 subjects were randomly assigned to IG (n = 40) or CG (n = 40). The total number of dropouts was 18 (IG: n = 13, CG: n = 5). LBM and ISIClamp were stable in the CG between M0 and M3, but were changed in the IG at M3 (LBM: -1.4 (95%CI -2.2-(-0.6)) kg and ISIClamp: +0.020 (95%CI 0.012-0.028) mg·kg-1·min-1/(mU·l-1)) (p < 0.01 and p < 0.05 for IG vs. CG, respectively). Effects on LBM, ISIClamp, FM and BMI were preserved until M4. Lower resting energy expenditure per LBM (REELBM) at M3 and stronger difference of REELBM between M3 and M4 (ΔREELBM-M3M4), which indicates a thrifty phenotype, were positively associated with FM regain at M24 (p = 0.022 and p = 0.044, respectively). Gene set enrichment analysis revealed a relationship of this phenotype to weight loss-induced adaption of adipose FGFR1 signaling. CONCLUSION: Negative energy balance had no additional effect on insulin sensitivity. FGFR1 signaling might be involved in the adaption of energy expenditure to temporary negative energy balance, which indicates a thrifty phenotype susceptible to weight regain. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01105143, https://clinicaltrials.gov/ct2/show/NCT01105143, date of registration: April 16th, 2010.
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Resistência à Insulina , Sobrepeso , Feminino , Humanos , Pós-Menopausa , Obesidade/metabolismo , Composição Corporal , Metabolismo Energético , Aumento de Peso , Redução de Peso , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
[This corrects the article DOI: 10.3389/fmolb.2022.1042231.].
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Introduction: Atrial natriuretic peptide (ANP), a hormone secreted from the heart, controls cardiovascular and renal functions including arterial blood pressure and natriuresis. ANP also exerts metabolic effects in adipose tissue, liver and skeletal muscle, and interacts with the secretion of adipokines. We tested the hypothesis that ANP lowers concentrations of the anorexigenic adipokine leptin in healthy humans in vivo. Methods: Human ANP or matching placebo was infused intravenously (iv) into healthy men in a controlled clinical trial. Results: Within 135 minutes of iv ANP infusion, we observed an acute decrease in plasma leptin levels compared to controls. Free fatty acids markedly increased with ANP infusion in vivo, indicating activated lipolysis. In human SGBS adipocytes, ANP suppressed leptin release. Discussion: The study shows that the cardiac hormone ANP reduces the levels of the anorexigenic adipokine leptin in healthy humans, providing further support for ANP as a cardiomyokine in a heart - adipose tissue axis. (registered in the German Clinical Trials Register and the WHO International Clinical Trials Registry Platform was granted under DRKS00024559).
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Fator Natriurético Atrial , Leptina , Humanos , Masculino , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Fator Natriurético Atrial/farmacologia , Fator Natriurético Atrial/metabolismo , Leptina/metabolismo , LipóliseRESUMO
BACKGROUND: Sepsis-induced intensive care unit-acquired weakness (ICUAW) features profound muscle atrophy and attenuated muscle regeneration related to malfunctioning satellite cells. Transforming growth factor beta (TGF-ß) is involved in both processes. We uncovered an increased expression of the TGF-ß receptor II (TßRII)-inhibitor SPRY domain-containing and SOCS-box protein 1 (SPSB1) in skeletal muscle of septic mice. We hypothesized that SPSB1-mediated inhibition of TßRII signalling impairs myogenic differentiation in response to inflammation. METHODS: We performed gene expression analyses in skeletal muscle of cecal ligation and puncture- (CLP) and sham-operated mice, as well as vastus lateralis of critically ill and control patients. Pro-inflammatory cytokines and specific pathway inhibitors were used to quantitate Spsb1 expression in myocytes. Retroviral expression plasmids were used to investigate the effects of SPSB1 on TGF-ß/TßRII signalling and myogenesis in primary and immortalized myoblasts and differentiated myotubes. For mechanistical analyses we used coimmunoprecipitation, ubiquitination, protein half-life, and protein synthesis assays. Differentiation and fusion indices were determined by immunocytochemistry, and differentiation factors were quantified by qRT-PCR and Western blot analyses. RESULTS: SPSB1 expression was increased in skeletal muscle of ICUAW patients and septic mice. Tumour necrosis factor (TNF), interleukin-1ß (IL-1ß), and IL-6 increased the Spsb1 expression in C2C12 myotubes. TNF- and IL-1ß-induced Spsb1 expression was mediated by NF-κB, whereas IL-6 increased the Spsb1 expression via the glycoprotein 130/JAK2/STAT3 pathway. All cytokines reduced myogenic differentiation. SPSB1 avidly interacted with TßRII, resulting in TßRII ubiquitination and destabilization. SPSB1 impaired TßRII-Akt-Myogenin signalling and diminished protein synthesis in myocytes. Overexpression of SPSB1 decreased the expression of early (Myog, Mymk, Mymx) and late (Myh1, 3, 7) differentiation-markers. As a result, myoblast fusion and myogenic differentiation were impaired. These effects were mediated by the SPRY- and SOCS-box domains of SPSB1. Co-expression of SPSB1 with Akt or Myogenin reversed the inhibitory effects of SPSB1 on protein synthesis and myogenic differentiation. Downregulation of Spsb1 by AAV9-mediated shRNA attenuated muscle weight loss and atrophy gene expression in skeletal muscle of septic mice. CONCLUSIONS: Inflammatory cytokines via their respective signalling pathways cause an increase in SPSB1 expression in myocytes and attenuate myogenic differentiation. SPSB1-mediated inhibition of TßRII-Akt-Myogenin signalling and protein synthesis contributes to a disturbed myocyte homeostasis and myogenic differentiation that occurs during inflammation.
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Interleucina-6 , Proteínas Proto-Oncogênicas c-akt , Animais , Camundongos , Citocinas , Inflamação , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Miogenina/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfaRESUMO
UNLABELLED: Obesity-related hepatic steatosis is a major risk factor for metabolic and cardiovascular disease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lipids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects were randomized to either reduced carbohydrate (n = 84) or reduced fat (n = 86), total energy restricted diet (-30% of energy intake before diet) for 6 months. Body composition was estimated by bioimpedance analyses and abdominal fat distribution by magnetic resonance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glucose tolerance testing. In all, 102 subjects completed the diet intervention with measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight, total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intrahepatic lipids (>5.56%) lost ≈7-fold more intrahepatic lipids compared with those with low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in visceral fat mass and insulin sensitivity were similar between subgroups, with low and high baseline intrahepatic lipids. CONCLUSION: A prolonged hypocaloric diet low in carbohydrates and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the traditional low-fat hypocaloric diet. The decrease in intrahepatic lipids appears to be independent of visceral fat loss and is not tightly coupled with changes in whole body insulin sensitivity during 6 months of an energy restricted diet.
Assuntos
Restrição Calórica , Dieta com Restrição de Gorduras , Fígado Gorduroso/dietoterapia , Sobrepeso/dietoterapia , Adulto , Dieta com Restrição de Carboidratos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Estudos ProspectivosRESUMO
OBJECTIVE: The utility of bioelectrical impedance analysis (BIA) in patients with anorexia nervosa (AN) is imperfectly defined. Furthermore, any advantage accrued by BIA with vector analysis (BIVA) is unknown. METHOD: We conducted a retrospective analysis of 57 women with AN admitted to our service who underwent BIA and BIVA. Twenty-seven women were observed during short-term (3 weeks) and 13 women during longer-term (3 months) weight gain. RESULTS: Bioelectrical impedance analysis produced implausible results in 47% of the patients. BIVA demonstrated low body cell mass and highly variable extracellular water (ECW) volume, ranging from volume contraction to volume expansion on admission and during treatment. BIVA suggested that short-term weight gain predominantly consisted of ECW volume, whereas longer-term weight gain resulted in increased hydrated body cell mass. CONCLUSION: Conventional BIA has little utility in these patients. However, BIVA could be a suitable alternative in the medical management reflecting ECW volume changes and later genuine tissue mass increases.
Assuntos
Anorexia Nervosa/diagnóstico , Composição Corporal/fisiologia , Impedância Elétrica , Adulto , Anorexia Nervosa/fisiopatologia , Anorexia Nervosa/terapia , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Humanos , Pessoa de Meia-Idade , Pletismografia de Impedância , Reprodutibilidade dos Testes , Estudos RetrospectivosRESUMO
BACKGROUND: Men and women with valvular heart disease have different risk profiles for clinical endpoints. Non-esterified fatty acids (NEFA) are possibly involved in cardio-metabolic disease. However, it is unclear whether NEFA concentrations are associated with physical performance in patients undergoing transcatheter aortic valve implantation (TAVI) and whether there are sex-specific effects. METHODS: To test the hypothesis that NEFA concentration is associated with sex-specific physical performance, we prospectively analysed data from one hundred adult patients undergoing TAVI. NEFA concentrations, physical performance and anthropometric parameters were measured before and 6 and 12 months after TAVI. Physical performance was determined by a six-minute walking test (6-MWT) and self-reported weekly bicycle riding time. RESULTS: Before TAVI, NEFA concentrations were higher in patients (44 women, 56 men) compared to the normal population. Median NEFA concentrations at 6 and 12 months after TAVI were within the reference range reported in the normal population in men but not women. Men but not women presented with an increased performance in the 6-MWT over time (p = 0.026, p = 0.142, respectively). Additionally, men showed an increased ability to ride a bicycle after TAVI compared to before TAVI (p = 0.034). NEFA concentrations before TAVI correlated with the 6-MWT before TAVI in women (Spearman's rho -0.552; p = 0.001) but not in men (Spearman's rho -0.007; p = 0.964). No association was found between NEFA concentrations and physical performance 6 and 12 months after TAVI. CONCLUSIONS: NEFA concentrations improved into the reference range in men but not women after TAVI. Men but not women have an increased physical performance after TAVI. No association between NEFA and physical performance was observed in men and women after TAVI.
Assuntos
Biomarcadores/sangue , Ácidos Graxos não Esterificados/sangue , Desempenho Físico Funcional , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/cirurgia , Ciclismo , Índice de Massa Corporal , Feminino , Humanos , Masculino , Estudos Prospectivos , Valores de Referência , Fatores de Risco , Fatores Sexuais , Resultado do Tratamento , CaminhadaRESUMO
High salt intake ranks among the most important risk factors for noncommunicable diseases. Western diets, which are typically high in salt, are associated with a high prevalence of obesity. High salt is thought to be a potential risk factor for obesity independent of energy intake, although the underlying mechanisms are insufficiently understood. A high salt diet could influence energy expenditure (EE), specifically diet-induced thermogenesis (DIT), which accounts for about 10% of total EE. We aimed to investigate the influence of high salt on DIT. In a randomized, double-blind, placebo-controlled, parallel-group study, 40 healthy subjects received either 6 g/d salt (NaCl) or placebo in capsules over 2 weeks. Before and after the intervention, resting EE, DIT, body composition, food intake, 24 h urine analysis, and blood pressure were obtained. EE was measured by indirect calorimetry after a 12 h overnight fast and a standardized 440 kcal meal. Thirty-eight subjects completed the study. Salt intake from foods was 6 g/d in both groups, resulting in a total salt intake of 12 g/d in the salt group and 6 g/d in the placebo group. Urine sodium increased by 2.29 g/d (p < 0.0001) in the salt group, indicating overall compliance. The change in DIT differed significantly between groups (placebo vs. salt, p = 0.023). DIT decreased by 1.3% in the salt group (p = 0.048), but increased by 0.6% in the placebo group (NS). Substrate oxidation indicated by respiratory exchange ratio, body composition, resting blood pressure, fluid intake, hydration, and urine volume did not change significantly in either group. A moderate short-term increase in salt intake decreased DIT after a standardized meal. This effect could at least partially contribute to the observed weight gain in populations consuming a Western diet high in salt.