Obesity-dependent molecular alterations in fatal COVID-19: A retrospective postmortem study of metabolomic profile of adipose tissue.

We investigated the effects of obesity on metabolic, inflammatory, and oxidative stress parameters in the adipose tissue of patients with fatal COVID-19. Postmortem biopsies of subcutaneous adipose tissue were obtained from 25 unvaccinated inpatients who passed from COVID-19, stratified as nonobese (N-OB; body mass index [BMI], 26.5 ± 2.3 kg m-2) or obese (OB BMI 34.2 ± 5.1 kg m-2). Univariate and multivariate analyses revealed that body composition was responsible for most of the variations detected in the metabolome, with greater dispersion observed in the OB group. Fifteen metabolites were major segregation factors. Results from the OB group showed higher levels of creatinine, myo-inositol, O-acetylcholine, and succinate, and lower levels of sarcosine. The N-OB group showed lower levels of glutathione peroxidase activity, as well as higher content of IL-6 and adiponectin. We revealed significant changes in the metabolomic profile of the adipose tissue in fatal COVID-19 cases, with high adiposity playing a key role in these observed variations. These findings highlight the potential involvement of metabolic and inflammatory pathways, possibly dependent on hypoxia, shedding light on the impact of obesity on disease pathogenesis and suggesting avenues for further research and possible therapeutic targets.

Impairment of aryl hydrocarbon receptor signalling promotes hepatic disorders in cancer cachexia.

BACKGROUND: The aryl hydrocarbon receptor (AHR) is expressed in the intestine and liver, where it has pleiotropic functions and target genes. This study aims to explore the potential implication of AHR in cancer cachexia, an inflammatory and metabolic syndrome contributing to cancer death. Specifically, we tested the hypothesis that targeting AHR can alleviate cachectic features, particularly through the gut-liver axis. METHODS: AHR pathways were explored in multiple tissues from four experimental mouse models of cancer cachexia (C26, BaF3, MC38 and APCMin/+ ) and from non-cachectic mice (sham-injected mice and non-cachexia-inducing [NC26] tumour-bearing mice), as well as in liver biopsies from cancer patients. Cachectic mice were treated with an AHR agonist (6-formylindolo(3,2-b)carbazole [FICZ]) or an antibody neutralizing interleukin-6 (IL-6). Key mechanisms were validated in vitro on HepG2 cells. RESULTS: AHR activation, reflected by the expression of Cyp1a1 and Cyp1a2, two major AHR target genes, was deeply reduced in all models (C26 and BaF3, P < 0.001; MC38 and APCMin/+ , P < 0.05) independently of anorexia. This reduction occurred early in the liver (P < 0.001; before the onset of cachexia), compared to the ileum and skeletal muscle (P < 0.01; pre-cachexia stage), and was intrinsically related to cachexia (C26 vs. NC26, P < 0.001). We demonstrate a differential modulation of AHR activation in the liver (through the IL-6/hypoxia-inducing factor 1α pathway) compared to the ileum (attributed to the decreased levels of indolic AHR ligands, P < 0.001), and the muscle. In cachectic mice, FICZ treatment reduced hepatic inflammation: expression of cytokines (Ccl2, P = 0.005; Cxcl2, P = 0.018; Il1b, P = 0.088) with similar trends at the protein levels, expression of genes involved in the acute-phase response (Apcs, P = 0.040; Saa1, P = 0.002; Saa2, P = 0.039; Alb, P = 0.003), macrophage activation (Cd68, P = 0.038) and extracellular matrix remodelling (Fga, P = 0.008; Pcolce, P = 0.025; Timp1, P = 0.003). We observed a decrease in blood glucose in cachectic mice (P < 0.0001), which was also improved by FICZ treatment (P = 0.026) through hepatic transcriptional promotion of a key marker of gluconeogenesis, namely, G6pc (C26 vs. C26 + FICZ, P = 0.029). Strikingly, these benefits on glycaemic disorders occurred independently of an amelioration of the gut barrier dysfunction. In cancer patients, the hepatic expression of G6pc was correlated to Cyp1a1 (Spearman's ρ = 0.52, P = 0.089) and Cyp1a2 (Spearman's ρ = 0.67, P = 0.020). CONCLUSIONS: With this set of studies, we demonstrate that impairment of AHR signalling contributes to hepatic inflammatory and metabolic disorders characterizing cancer cachexia, paving the way for innovative therapeutic strategies in this context.

Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital.

OBJECTIVES: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19). METHODS: This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. RESULTS: The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

Myokines in treatment-naïve patients with cancer-associated cachexia.

Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways.

Persistent symptoms and decreased health-related quality of life after symptomatic pediatric COVID-19: A prospective study in a Latin American tertiary hospital

OBJECTIVES: To prospectively evaluate demographic, anthropometric and health-related quality of life (HRQoL) in pediatric patients with laboratory-confirmed coronavirus disease 2019 (COVID-19) METHODS: This was a longitudinal observational study of surviving pediatric post-COVID-19 patients (n=53) and pediatric subjects without laboratory-confirmed COVID-19 included as controls (n=52) was performed. RESULTS: The median duration between COVID-19 diagnosis (n=53) and follow-up was 4.4 months (0.8-10.7). Twenty-three of 53 (43%) patients reported at least one persistent symptom at the longitudinal follow-up visit and 12/53 (23%) had long COVID-19, with at least one symptom lasting for >12 weeks. The most frequently reported symptoms at the longitudinal follow-up visit were headache (19%), severe recurrent headache (9%), tiredness (9%), dyspnea (8%), and concentration difficulty (4%). At the longitudinal follow-up visit, the frequencies of anemia (11% versus 0%, p=0.030), lymphopenia (42% versus 18%, p=0.020), C-reactive protein level of >30 mg/L (35% versus 0%, p=0.0001), and D-dimer level of >1000 ng/mL (43% versus 6%, p=0.0004) significantly reduced compared with baseline values. Chest X-ray abnormalities (11% versus 2%, p=0.178) and cardiac alterations on echocardiogram (33% versus 22%, p=0.462) were similar at both visits. Comparison of characteristic data between patients with COVID-19 at the longitudinal follow-up visit and controls showed similar age (p=0.962), proportion of male sex (p=0.907), ethnicity (p=0.566), family minimum monthly wage (p=0.664), body mass index (p=0.601), and pediatric pre-existing chronic conditions (p=1.000). The Pediatric Quality of Live Inventory 4.0 scores, median physical score (69 [0-100] versus 81 [34-100], p=0.012), and school score (60 [15-100] versus 70 [15-95], p=0.028) were significantly lower in pediatric patients with COVID-19 at the longitudinal follow-up visit than in controls. CONCLUSIONS: Pediatric patients with COVID-19 showed a longitudinal impact on HRQoL parameters, particularly in physical/school domains, reinforcing the need for a prospective multidisciplinary approach for these patients. These data highlight the importance of closer monitoring of children and adolescents by the clinical team after COVID-19.

Human Cachexia Induces Changes in Mitochondria, Autophagy and Apoptosis in the Skeletal Muscle.

Cachexia is a wasting syndrome characterized by the continuous loss of skeletal muscle mass due to imbalance between protein synthesis and degradation, which is related with poor prognosis and compromised quality of life. Dysfunctional mitochondria are associated with lower muscle strength and muscle atrophy in cancer patients, yet poorly described in human cachexia. We herein investigated mitochondrial morphology, autophagy and apoptosis in the skeletal muscle of patients with gastrointestinal cancer-associated cachexia (CC), as compared with a weight-stable cancer group (WSC). CC showed prominent weight loss and increased circulating levels of serum C-reactive protein, lower body mass index and decreased circulating hemoglobin, when compared to WSC. Electron microscopy analysis revealed an increase in intermyofibrillar mitochondrial area in CC, as compared to WSC. Relative gene expression of Fission 1, a protein related to mitochondrial fission, was increased in CC, as compared to WSC. LC3 II, autophagy-related (ATG) 5 and 7 essential proteins for autophagosome formation, presented higher content in the cachectic group. Protein levels of phosphorylated p53 (Ser46), activated caspase 8 (Asp384) and 9 (Asp315) were also increased in the skeletal muscle of CC. Overall, our results demonstrate that human cancer-associated cachexia leads to exacerbated muscle-stress response that may culminate in muscle loss, which is in part due to disruption of mitochondrial morphology, dysfunctional autophagy and increased apoptosis. To the best of our knowledge, this is the first report showing quantitative morphological alterations in skeletal muscle mitochondria in cachectic patients.

Non-alcoholic fatty liver disease and its treatment with n-3 polyunsaturated fatty acids.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is a common liver disease in Western countries. Metabolic disorders which are increasing in prevalence, such as dyslipidaemias, obesity and type 2 diabetes, are closely related to NAFLD. Insulin resistance is a prominent risk factor for NAFLD. Marine omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are able to decrease plasma triacylglycerol and diets rich in marine n-3 PUFAs are associated with a lower cardiovascular risk. Furthermore, marine n-3 PUFAs are precursors of pro-resolving and anti-inflammatory mediators. They can modulate lipid metabolism by enhancing fatty acid ß-oxidation and decreasing de novo lipogenesis. Therefore, they may play an important role in prevention and therapy of NAFLD. METHODS: This review aims to gather the currently information about marine n-3 PUFAs as a therapeutic approach in NAFLD. Actions of marine n-3 PUFAs on hepatic fat metabolism are reported, as well as studies addressing the effects of marine n-3 PUFAs in human subjects with NAFLD. RESULTS: A total seventeen published human studies investigating the effects of n-3 PUFAs on markers of NAFLD were found and twelve of these reported a decrease in liver fat and/or other markers of NAFLD after supplementation with n-3 PUFAs. The failure of n-3 PUFAs to decrease markers of NAFLD in five studies may be due to short duration, poor compliance, patient specific factors and the sensitivity of the methods used. CONCLUSIONS: Marine n-3 PUFAs are likely to be an important tool for NAFLD treatment, although further studies are required to confirm this.

Creatine supplementation as a possible new therapeutic approach for fatty liver disease: early findings.

Over the last few years, consistent data have demonstrated that creatine (Cr) supplementation prevents the accumulation of fat in rat liver as well as the progression of fatty liver disease in different situations. Studies have demonstrated that Cr is effective and prevents fatty liver in high-fat and choline-deficient diets and in hepatoma cells in vitro. Because Cr synthesis is responsible for a considerable consumption of hepatic methyl groups, studies have tested the idea that Cr supplementation could modulate phospholipid formation and VLDL secretion. Studies have also demonstrated Cr is able to modulate the expression of key genes related to fatty acid oxidation in hepatocyte cell culture and in rat liver. However, to date, the mechanism by which Cr exerts protective effects against fatty liver is poorly understood. Therefore, the present review aims to summarize the studies involving the therapeutic use of Cr supplementation on fatty liver disease and to explore the mechanisms involved in one-carbon and fatty acid metabolism for the preventive effects of Cr supplementation on fat liver accumulation. Although a small number of studies have been conducted to date, we consider Cr as a new and promising therapeutic strategy to control fat accumulation in the liver as well as the progression of fatty liver disease.

Fish oil decreases hepatic lipogenic genes in rats fasted and refed on a high fructose diet.

Fasting and then refeeding on a high-carbohydrate diet increases serum and hepatic triacylglycerol (TAG) concentrations compared to standard diets. Fructose is a lipogenic monosaccharide which stimulates de novo fatty acid synthesis. Omega-3 (n-3) fatty acids stimulate hepatic ß-oxidation, partitioning fatty acids away from TAG synthesis. This study investigated whether dietary n-3 fatty acids from fish oil (FO) improve the hepatic lipid metabolic response seen in rats fasted and then refed on a high-fructose diet. During the post-prandial (fed) period, rats fed a FO rich diet showed an increase in hepatic peroxisome proliferator-activated receptor α (PPAR-α) gene expression and decreased expression of carbohydrate responsive element binding protein (ChREBP), fatty acid synthase (FAS) and microsomal triglyceride transfer protein (MTTP). Feeding a FO rich diet for 7 days prior to 48 h of fasting resulted in lower hepatic TAG, lower PPAR-α expression and maintenance of hepatic n-3 fatty acid content. Refeeding on a high fructose diet promoted an increase in hepatic and serum TAG and in hepatic PPAR-α, ChREBP and MTTP expression. FO did not prevent the increase in serum and hepatic TAG after fructose refeeding, but did decrease hepatic expression of lipogenic genes and increased the n-3 fatty acid content of the liver. n-3 Fatty acids can modify some components of the hepatic lipid metabolic response to later feeding with a high fructose diet.

Dietary polyunsaturated fatty acid intake during late pregnancy affects fatty acid composition of mature breast milk.

OBJECTIVE: The aim of this study was to investigate how maternal polyunsaturated fatty acid intake at different periods during pregnancy affects the composition of polyunsaturated fatty acids in mature human milk. METHODS: A prospective study was conducted involving 45 pregnant women, aged between 18 and 35 y, who had full-term pregnancies and practiced exclusive or predominant breast-feeding. Mature breast milk samples were collected after the 5th postpartum week by manual expression; fatty acid composition was determined by gas chromatography. Fatty acid intake during pregnancy and puerperium was estimated through multiple 24-h dietary recalls. Linear regression models, adjusted by postpartum body mass index and deattenuated, were used to determine associations between estimated fatty acids in maternal diet during each trimester of pregnancy and fatty acid content in mature human milk. RESULTS: A positive association was identified between maternal intake of eicosapentaenoic acid (ß, 1.873; 95% confidence interval [CI], 0.545, 3.203) and docosahexaenoic acid (ß, 0.464; 95% CI, 0.212-0.714) during the third trimester of pregnancy, as well as the maternal dietary ω-3 to ω-6 ratio (ß, 0.093; 95% CI, 0.016-0.170) during the second and third trimesters and postpartum period, with these fatty acids content in mature breast milk. CONCLUSIONS: The maternal dietary docosahexaenoic acid and eicosapentaenoic acid content during late pregnancy may affect the fatty acid composition of mature breast milk. Additionally, the maternal dietary intake of ω-3 to ω-6 fatty acid ratio, during late pregnancy and the postpartum period, can affect the polyunsaturated fatty acid composition of breast milk.

Choline supplementation protects against liver damage by normalizing cholesterol metabolism in Pemt/Ldlr knockout mice fed a high-fat diet.

Dietary choline is required for proper structure and dynamics of cell membranes, lipoprotein synthesis, and methyl-group metabolism. In mammals, choline is synthesized via phosphatidylethanolamine N-methyltransferase (Pemt), which converts phosphatidylethanolamine to phosphatidylcholine. Pemt(-/-) mice have impaired VLDL secretion and developed fatty liver when fed a high-fat (HF) diet. Because of the reduction in plasma lipids, Pemt(-/-)/low-density lipoprotein receptor knockout (Ldlr(-/-)) mice are protected from atherosclerosis. The goal of this study was to investigate the importance of dietary choline in the metabolic phenotype of Pemt(-/-)/Ldlr(-/-) male mice. At 10-12 wk of age, Pemt(+/+)/Ldlr(-/-) (HF(+/+)) and half of the Pemt(-/-)/Ldlr(-/-) (HF(-/-)) mice were fed an HF diet with normal (1.3 g/kg) choline. The remaining Pemt(-/-)/Ldlr(-/-) mice were fed an HF diet supplemented (5 g/kg) with choline (HFCS(-/-) mice). The HF diet contained 60% of calories from fat and 1% cholesterol, and the mice were fed for 16 d. HF(-/-) mice lost weight and developed hepatomegaly, steatohepatitis, and liver damage. Hepatic concentrations of free cholesterol, cholesterol-esters, and triglyceride (TG) were elevated by 30%, 1.1-fold and 3.1-fold, respectively, in HF(-/-) compared with HF(+/+) mice. Choline supplementation normalized hepatic cholesterol, but not TG, and dramatically improved liver function. The expression of genes involved in cholesterol transport and esterification increased by 50% to 5.6-fold in HF(-/-) mice when compared with HF(+/+) mice. Markers of macrophages, oxidative stress, and fibrosis were elevated in the HF(-/-) mice. Choline supplementation normalized the expression of these genes. In conclusion, HF(-/-) mice develop liver failure associated with altered cholesterol metabolism when fed an HF/normal choline diet. Choline supplementation normalized cholesterol metabolism, which was sufficient to prevent nonalcoholic steatohepatitis development and improve liver function. Our data suggest that choline can promote liver health by maintaining cholesterol homeostasis.

Composição de ácidos graxos do leite materno em mulheres residentes em área distante da costa litorânea brasileira / Breast milk fatty acid composition of women living far from the coastal area in Brazil

OBJETIVOS: Avaliar a composição de ácidos graxos do leite humano maduro de mulheres residentes em área distante da costa litorânea brasileira. MÉTODOS: Amostras de leite materno maduro foram obtidas de 47 mulheres lactantes com idade entre 18 e 35 anos, que tiveram partos a termo e em aleitamento exclusivo ou predominante. A coleta de leite se deu a partir da 5ª semana pós-parto, por meio de ordenha manual. A composição de ácidos graxos do leite foi determinada por cromatografia gasosa. RESULTADOS: Verificou-se que a concentração de eicosapentaenoico (0,08%) foi superior ao observado em estudos brasileiros prévios. Entretanto, o teor de docosahexaenoico (0,09%) encontrado no leite humano foi um dos menores já verificados no mundo. O teor de ácidos graxos trans (2,05%) foi similar ao relatado em estudos nacionais prévios à obrigatoriedade de declaração do teor deste em rótulos de alimentos, sugerindo que esta medida não surtiu efeito na redução de seu teor na dieta habitual das mulheres. CONCLUSÕES: Baixo teor de docosahexaenoico e elevada concentração de ácidos graxos trans foram verificados no leite materno maduro de mulheres residentes em área distante da costa litorânea brasileira.

OBJECTIVES: To evaluate the fatty acid composition of mature human milk of women living far from the coastal area of Brazil. METHODS: Mature breast milk samples were obtained from 47 lactating women aged between 18 and 35 years, who delivered their babies at term and who exclusively or predominantly breastfed. Milk collection took place after the fifth week postpartum by hand expression. The fatty acid composition of the milk was determined by gas chromatography. RESULTS: It was observed that the concentration of eicosapentaenoic acid (0.08%) was higher than that observed in previous studies in Brazil. However, the content of docosahexaenoic acid (0.09%) found in human milk was one of the lowest verified in the world. The content of trans fatty acids (2.05%) was similar to that reported in national studies previous to the mandatory declaration of this fatty acid content in food labels, suggesting that this measure had no effect on reducing the content of this fatty acid in the usual diet of women. CONCLUSIONS: Low levels of docosahexaenoic acid and high concentrations of trans fatty acids were observed in mature breast milk of women living far from the coastal area in Brazil.

Breast milk fatty acid composition of women living far from the coastal area in Brazil.

OBJECTIVES: To evaluate the fatty acid composition of mature human milk of women living far from the coastal area of Brazil. METHODS: Mature breast milk samples were obtained from 47 lactating women aged between 18 and 35 years, who delivered their babies at term and who exclusively or predominantly breastfed. Milk collection took place after the fifth week postpartum by hand expression. The fatty acid composition of the milk was determined by gas chromatography. RESULTS: It was observed that the concentration of eicosapentaenoic acid (0.08%) was higher than that observed in previous studies in Brazil. However, the content of docosahexaenoic acid (0.09%) found in human milk was one of the lowest verified in the world. The content of trans fatty acids (2.05%) was similar to that reported in national studies previous to the mandatory declaration of this fatty acid content in food labels, suggesting that this measure had no effect on reducing the content of this fatty acid in the usual diet of women. CONCLUSIONS: Low levels of docosahexaenoic acid and high concentrations of trans fatty acids were observed in mature breast milk of women living far from the coastal area in Brazil.

Fructose and NAFLD: metabolic implications and models of induction in rats.

PURPOSE: The increase in fructose consumption is paralleled by a higher incidence of obesity worldwide. This monosaccharide is linked to metabolic syndrome, being associated with hypertriglyceridemia, hypertension, insulin resistance and diabetes mellitus. It is metabolized principally in the liver, where it can be converted into fatty acids, which are stored in the form of triglycerides leading to NAFLD. Several models of NAFLD use diets high in simple carbohydrates. Thus, this study aimed to describe the major metabolic changes caused by excessive consumption of fructose in humans and animals and to present liver abnormalities resulting from high intakes of fructose in different periods of consumption and experimental designs in Wistar rats. METHODS: Two groups of rats were fasted for 48 hours and refed for 24 or 48 hours with a diet containing 63% fructose. Another group of rats was fed an diet with 63% fructose for 90 days. RESULTS: Refeeding for 24 hours caused accumulation of large amounts of fat, compromising 100% of the hepatocytes. The amount of liver fat in animals refed for 48 hours decreased, remaining mostly in zone 2 (medium-zonal). In liver plates of Wistar rats fed 63% fructose for 45, 60 and 90 days it's possible to see that there is an increase in hepatocytes with fat accumulation according to the increased time; hepatic steatosis, however, is mild, compromising about 20% of the hepatocytes. CONCLUSIONS: Fructose is highly lipogenic, however the induction of chronic models in NAFLD requires long periods of treatment. The acute supply for 24 or 48 hours, fasted rats can cause big changes, liver steatosis with macrovesicular in all lobular zones.

Fructose and NAFLD: metabolic implications and models of induction in rats / Frutose e NAFLD: implicações metabólicas e modelos de indução em ratos

PURPOSE: The increase in fructose consumption is paralleled by a higher incidence of obesity worldwide. This monosaccharide is linked to metabolic syndrome, being associated with hypertriglyceridemia, hypertension, insulin resistance and diabetes mellitus. It is metabolized principally in the liver, where it can be converted into fatty acids, which are stored in the form of triglycerides leading to NAFLD. Several models of NAFLD use diets high in simple carbohydrates. Thus, this study aimed to describe the major metabolic changes caused by excessive consumption of fructose in humans and animals and to present liver abnormalities resulting from high intakes of fructose in different periods of consumption and experimental designs in Wistar rats. METHODS: Two groups of rats were fasted for 48 hours and reefed for 24 or 48 hours with a diet containing 63 percent fructose. Another group of rats was fed an diet with 63 percent fructose for 90 days. RESULTS: Refeeding for 24 hours caused accumulation of large amounts of fat, compromising 100 percent of the hepatocytes. The amount of liver fat in animals refed for 48 hours decreased, remaining mostly in zone 2 (medium-zonal). In liver plates of Wistar rats fed 63 percent fructose for 45, 60 and 90 days it's possible to see that there is an increase in hepatocytes with fat accumulation according to the increased time; hepatic steatosis, however, is mild, compromising about 20 percent of the hepatocytes. CONCLUSIONS: Fructose is highly lipogenic, however the induction of chronic models in NAFLD requires long periods of treatment. The acute supply for 24 or 48 hours, fasted rats can cause big changes, liver steatosis with macrovesicular in all lobular zones.

OBJETIVO: O aumento do consumo de frutose é concomitante a maior incidência mundial de obesidade. Este monossacarídeo está relacionado à Síndrome Metabólica, sendo vinculado à hipertrigliceridemia, hipertensão arterial, resistência à insulina e diabetes mellitus. É metabolizada principalmente no fígado, onde pode ser convertida em ácidos graxos, os quais serão estocados na forma de trigligérides ocasionando a esteatose hepática não alcoólica (NAFLD). Vários modelos de NAFLD utilizam dietas ricas em carboidratos simples. Desta forma, este trabalho teve como objetivos descrever as principais alterações metabólicas causadas pelo consumo excessivo de frutose em humanos e em animais e apresentar as alterações hepáticas decorrentes da alta ingestão de frutose em diferentes períodos de consumo e desenhos experimentais em ratos Wistar. MÉTODOS: Dois grupos de ratos Wistar foram mantidos em jejum durante 48 horas e realimentados por 24 ou 48 horas com dieta contendo 63 por cento de frutose. Outro grupo de ratos Wistar foi alimentado com 63 por cento de frutose durante 90 dias. RESULTADOS: A realimentação por 24 horas provocou acúmulo de grande quantidade de gordura. A quantidade de gordura hepática nos animais realimentados por 48 horas diminuiu, mantendo-se principalmente nas zona 2 (medio-zonal). Em fígados de ratos Wistar alimentados com 63 por cento de frutose até 90 dias foi possível observar que há aumento de hepatócitos com acúmulo de gordura consequente ao aumento do tempo, no entanto a esteatose hepática é leve (20 por cento). CONCLUSÕES: A frutose é altamente lipogênica, no entanto a indução de NAFLD em modelos crônicos necessita de longos períodos de tratamento. A oferta aguda, por 24 ou 48 horas, a ratos mantidos em jejum é capaz de ocasionar grandes mudanças hepáticas, com presença de esteatose macrovesicular em todas as zonas lobulares.

Caracterização da esteatose hepática não alcoólica induzida por dieta hipoprotéica em ratos / Characterization of nonalcoholic fatty liver disease in rats for low protein diet induced

Modelo de estudo: Estudo experimental. Objetivos: este estudo teve como objetivo avaliar e caracterizar a dieta hipoprotéica como um modelo experimental para estudo de EHNA. Métodos: foram utilizados ratos da linhagem Wistar divididos em dois grupos com dietas isocalóricas: controle (GC) no qual a dieta utilizada seguiu o preconizado pela AIN-93 e hipoprotéico (GH) com quantidade de proteína reduzida de 20% para 10%. As dietas e água foram ofertadas ad libitum por quatro semanas. Após esse período, os animais foram sacrificados e analisados: glicemia; nitrogênio urinário; proteína sérica; gordura hepática; colesterol; variação de peso e quantidade de ração consumida. Resultados: glicemia e nitrogênio urinário não apresentaram diferenças significativas entre GC e GH (p>0,05), a variação de peso no último dia do experimento foi significativa (p<0,02). A porcentagem de gordura hepática foi estatisticamente maior no GH, quando comparado ao GC (p<0,04). Foram menores o nível de colesterol (p<0,01) e proteína sérica (p<0,005) no GH. A quantidade de dieta consumida não foi diferente entre os grupos, considerando-se as médias de ingestão semanal. Conclusões: neste trabalho a dieta hipoprotéica constitui um modelo de indução de EHNA que pode ser caracterizada pela diminuição da proteína sérica e do colesterol plasmático e aumento da gordura hepática, entretanto não ocorreram alterações na glicemia sugerindo que não existiu mudança na sensibilidade à insulina, constituindo assim um modelo falho para estudar um dos principais fatores de risco para o estabelecimento da EHNA, a resistência à insulina.

Model of study: Experimental study. Objectives: this study had as objective evaluate and characterize a low protein diet as an experimental model for non alcoholic fatty liver disease(NAFLD). Methods: male Wistar rats were divided in two groups with isocaloric diets: control (GC) in which the used diet followed praised for the AIN-93 and the low protein (GH), with reduced amount of protein of 20% for 10%. The diets and water had been offered ad libitum over four weeks. After this period the animals were sacrificed and analyzed: glycemia; urinary nitrogen; serum protein; liver total lipids; cholesterol; weight variation and food consumed. Results: the glycemia and the urinary nitrogen had not presented significant differences between GC and GH (p>0,05). The change of weight in the last day of the experiment was significant (p<0,02). The percentage of total liver lipids was higher in the GH, when compared with the GC (p<0,04). There was lower levels of cholesterol (p<0,01) and serum protein (0,005) in GH. The food consumed was not different between the groups. Conclusions: in this paper the low protein diet constitutes a model of NAFLD induction that can be characterized for serum protein and plasmatic cholesterol and increased fat in the liver, however not alterations in the glycemia suggest no changes in insulin sensitivity, thus constituting a defective model to study one of the main factors of risk for the establishment of the NAFLD, the resistance to insulin.