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1.
Proc Natl Acad Sci U S A ; 117(27): 15837-15845, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32571957

RESUMO

Despite broad appreciation of their clinical utility, it has been unclear how vitamin B12 and folic acid (FA) function at the molecular level to directly prevent their hallmark symptoms of deficiency like anemia or birth defects. To this point, B12 and FA have largely been studied as cofactors for enzymes in the one-carbon (1C) cycle in facilitating the de novo generation of nucleotides and methylation of DNA and protein. Here, we report that B12 and FA function as natural antagonists of aryl hydrocarbon receptor (AhR). Our studies indicate that B12 and FA bind AhR directly as competitive antagonists, blocking AhR nuclear localization, XRE binding, and target gene induction mediated by AhR agonists like 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and 6-formylindolo[3,2-b]carbazole (FICZ). In mice, TCDD treatment replicated many of the hallmark symptoms of B12/FA deficiency and cotreatment with aryl hydrocarbon portions of B12/FA rescued mice from these toxic effects. Moreover, we found that B12/FA deficiency in mice induces AhR transcriptional activity and accumulation of erythroid progenitors and that it may do so in an AhR-dependent fashion. Consistent with these results, we observed that human cancer samples with deficient B12/FA uptake demonstrated higher transcription of AhR target genes and lower transcription of pathways implicated in birth defects. In contrast, there was no significant difference observed between samples with mutated and intact 1C cycle proteins. Thus, we propose a model in which B12 and FA blunt the effect of natural AhR agonists at baseline to prevent the symptoms that arise with AhR overactivation.


Assuntos
Ácido Fólico/metabolismo , Desnutrição/metabolismo , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Receptores de Hidrocarboneto Arílico/metabolismo , Vitamina B 12/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Carbazóis/farmacologia , Anormalidades Congênitas , Feminino , Deficiência de Ácido Fólico/tratamento farmacológico , Expressão Gênica , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias , Dibenzodioxinas Policloradas/farmacologia , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Deficiência de Vitamina B 12/tratamento farmacológico
2.
Braz J Med Biol Res ; 53(6): e9031, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401929

RESUMO

Malnutrition is still considered endemic in many developing countries. Malnutrition-enteric infections may cause lasting deleterious effects on lipid metabolism, especially in children living in poor settings. The regional basic diet (RBD), produced to mimic the Brazilian northeastern dietary characteristics (rich in carbohydrate and low in protein) has been used in experimental malnutrition models, but few studies have explored the effect of chronic RBD on liver function, a central organ involved in cholesterol metabolism. This study aimed to investigate whether RBD leads to liver inflammatory changes and altered reverse cholesterol metabolism in C57BL6/J mice compared to the control group, receiving a standard chow diet. To evaluate liver inflammation, ionized calcium-binding adapter protein-1 (IBA-1) positive cell counting, interleukin (IL)-1ß immunohistochemistry, and tumor necrosis factor (TNF)-α and IL-10 transcription levels were analyzed. In addition, we assessed reverse cholesterol transport by measuring liver apolipoprotein (Apo)E, ApoA-I, and lecithin-cholesterol acyltransferase (LCAT) by RT-PCR. Furthermore, serum alanine aminotransferase (ALT) was measured to assess liver function. RBD markedly impaired body weight gain compared with the control group (P<0.05). Higher hepatic TNF-α (P<0.0001) and IL-10 (P=0.001) mRNA levels were found in RBD-challenged mice, although without detectable non-alcoholic fatty liver disease. Marked IBA-1 immunolabeling and increased number of positive-IBA-1 cells were found in the undernourished group. No statistical difference in serum ALT was found. There was also a significant increase in ApoA mRNA expression in the undernourished group, but not ApoE and LCAT, compared with the control. Altogether our findings suggested that chronic RBD-induced malnutrition leads to liver inflammation with increased ApoA-I activity.


Assuntos
Apolipoproteína A-I/sangue , Dieta/efeitos adversos , Inflamação/metabolismo , Desnutrição/metabolismo , Animais , Apolipoproteína A-I/metabolismo , Brasil , Doença Crônica , Humanos , Inflamação/sangue , Inflamação/patologia , Fígado/metabolismo , Masculino , Desnutrição/sangue , Desnutrição/patologia , Camundongos , Camundongos Endogâmicos C57BL
3.
Nat Med ; 26(4): 589-598, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32235930

RESUMO

Direct evidence in humans for the impact of the microbiome on nutrient absorption is lacking. We conducted an extended inpatient study using two interventions that we hypothesized would alter the gut microbiome and nutrient absorption. In each, stool calorie loss, a direct proxy of nutrient absorption, was measured. The first phase was a randomized cross-over dietary intervention in which all participants underwent in random order 3 d of over- and underfeeding. The second was a randomized, double-blind, placebo-controlled pharmacologic intervention using oral vancomycin or matching placebo (NCT02037295). Twenty-seven volunteers (17 men and 10 women, age 35.1 ± 7.3, BMI 32.3 ± 8.0), who were healthy other than having impaired glucose tolerance and obesity, were enrolled and 25 completed the entire trial. The primary endpoints were the effects of dietary and pharmacological intervention on stool calorie loss. We hypothesized that stool calories expressed as percentage of caloric intake would increase with underfeeding compared with overfeeding and increase during oral vancomycin treatment. Both primary endpoints were met. Greater stool calorie loss was observed during underfeeding relative to overfeeding and during vancomycin treatment compared with placebo. Key secondary endpoints were to evaluate the changes in gut microbial community structure as evidenced by amplicon sequencing and metagenomics. We observed only a modest perturbation of gut microbial community structure with under- versus overfeeding but a more widespread change in community structure with reduced diversity with oral vancomycin. Increase in Akkermansia muciniphila was common to both interventions that resulted in greater stool calorie loss. These results indicate that nutrient absorption is sensitive to environmental perturbations and support the translational relevance of preclinical models demonstrating a possible causal role for the gut microbiome in dietary energy harvest.


Assuntos
Microbioma Gastrointestinal/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Desnutrição/metabolismo , Desnutrição/microbiologia , Nutrientes/farmacocinética , Vancomicina/administração & dosagem , Administração Oral , Adolescente , Adulto , Restrição Calórica , Estudos Cross-Over , Dieta , Método Duplo-Cego , Metabolismo Energético/efeitos dos fármacos , Fezes/microbiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vancomicina/farmacologia , Verrucomicrobia/isolamento & purificação , Adulto Jovem
4.
Artigo em Inglês | MEDLINE | ID: mdl-31676441

RESUMO

Maternal undernutrition during late gestation accelerates body fat mobilization to provide more energy for foetal growth and development, which unbalances metabolic homeostasis and results in serious lipid metabolism disorder. However, detailed regulatory mechanisms are poorly understood. Here, a sheep model was used to explore the regulatory role of PPARA/RXRA signalling in hepatic lipid metabolism in undernutrition based on RNA sequencing and cell experiments. KOG function classification showed that lipid transport and metabolism was markedly altered in an undernourished model. In detail, when compared with the controls, fatty acid transport and oxidation and triglyceride metabolism were up-regulated in an undernourished model, while fatty acid synthesis, steroid synthesis, and phospholipid metabolism were down-regulated. Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis demonstrated that PPARA/RXRA signalling pathway was altered. Moreover, PPARA signalling associated genes were positively correlated with hepatic non-esterified fatty acid (NEFA) levels, while retinol metabolism associated genes were negatively correlated with blood beta-hydroxybutyric acid (BHBA) levels. Results of primary hepatocytes showed that NEFAs could activate PPARA signalling and facilitate fatty acid oxidation (FAO) and ketogenesis, while BHBA could inhibit RXRA signalling and repress FAO and ketogenesis. Excessively accumulated NEFAs in hepatocytes promoted triglyceride synthesis. Furthermore, activation of PPARA/RXRA signalling by WY14643 and 9-cis-retinoic acid could enhance FAO and ketogenesis and reduce NEFAs accumulation and esterification. Our findings elucidate the regulatory mechanisms of NEFAs and BHBA on lipid metabolism as well as the potential role of the PPARA/RXRA signalling pathway in hepatic lipid metabolism, which may contribute to exploring new strategies to maintain lipid metabolic homeostasis in human beings.


Assuntos
Ácidos Graxos não Esterificados/metabolismo , Fígado/metabolismo , Desnutrição/metabolismo , PPAR alfa/metabolismo , Receptor X Retinoide alfa/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Alitretinoína/administração & dosagem , Animais , Modelos Animais de Doenças , Feminino , Homeostase/efeitos dos fármacos , Homeostase/fisiologia , Humanos , Lipogênese/efeitos dos fármacos , Fígado/patologia , Desnutrição/patologia , Troca Materno-Fetal/efeitos dos fármacos , Troca Materno-Fetal/fisiologia , Oxirredução/efeitos dos fármacos , Gravidez , Pirimidinas/administração & dosagem , Ovinos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
5.
Am J Clin Nutr ; 111(1): 207-218, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31697329

RESUMO

BACKGROUND: Undernutrition is associated with an elevated risk of mortality among children in low- and middle-income countries. Small-quantity lipid-based nutrient supplements (LNS) have been evaluated as a method to prevent undernutrition and improve infant development, but the effects on mortality are unknown. OBJECTIVE: Our objective was to evaluate the effect of LNS on all-cause mortality among children 6-24 mo old. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials of LNS designed to prevent undernutrition, with or without other interventions. Literature was searched in May 2019 and trials were included if they enrolled children between 6 and 24 mo old and the period of supplementation lasted ≥6 mo. We extracted data from participant flow diagrams and contacted study investigators to request data. We conducted a meta-analysis to produce summary RR estimates. RESULTS: We identified 18 trials conducted in 11 countries that enrolled 41,280 children and reported 586 deaths. The risk of mortality was lower in the LNS arms than in the non-LNS comparison arms (RR: 0.73; 95% CI: 0.59, 0.89; 13 trials). Estimates were similar when trials with maternal LNS intervention arms were added or when alternative formulations of LNS were excluded. The results appeared stronger in trials in which LNS were compared with passive control arms. Excluding these contrasts and only comparing multicomponent arms with LNS groups and comparison groups that contained all the same components without LNS attenuated the effect estimate (RR: 0.82; 95% CI: 0.61, 1.10). CONCLUSIONS: LNS provided for the prevention of undernutrition may reduce the risk of mortality, but more trials with appropriate comparison groups allowing isolation of the effect of LNS alone are needed.This study was registered at www.crd.york.ac.uk/PROSPERO as CRD42019128718.


Assuntos
Metabolismo dos Lipídeos , Desnutrição/dietoterapia , Desnutrição/mortalidade , Desenvolvimento Infantil , Gorduras na Dieta/metabolismo , Feminino , Humanos , Lactente , Fenômenos Fisiológicos da Nutrição do Lactente , Masculino , Desnutrição/metabolismo , Nutrientes/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto
6.
J Orthop Res ; 38(4): 695-707, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31729041

RESUMO

Impaired fracture healing continues to be a significant public health issue. This is more frequently observed in aging populations and patients with co-morbidities that can directly influence bone repair. Tremendous progress has been made in the development of biologics to enhance and accelerate the healing process; however, side-effects persist that can cause significant discomfort and tissue damage. This has been the impetus for the development of safe and natural strategies to hasten natural bone healing. Of the many possible approaches, nutrition represents a safe, affordable, and non-invasive strategy to positively influence each phase of fracture repair. However, our understanding of how healing can be hindered by malnutrition or enhanced with nutritional supplementation has lagged behind the advancements in both surgical management and the knowledge of molecular and cellular drivers of skeletal fracture repair. This review serves to bridge this knowledge gap as well as define the importance of nutrition during fracture healing. The extant literature clearly indicates that pre-existing nutritional deficiencies should be corrected, and nutritional status should be carefully monitored to prevent the development of malnutrition for the best possible healing outcome. It remains unclear, however, whether the provision of nutrients beyond sufficiency has any benefit on fracture repair and patient outcomes. The combined body of pre-clinical studies using a variety of animal models suggests a promising role of nutrition as an adjuvant therapy to facilitate fracture repair, but extensive research is needed, specifically at the clinical level, to clarify the utility of nutritional interventions in orthopedics. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:695-707, 2020.


Assuntos
Suplementos Nutricionais , Consolidação da Fratura , Fraturas Ósseas/metabolismo , Desnutrição/metabolismo , Animais , Humanos , Desnutrição/dietoterapia
7.
Lancet ; 395(10217): 75-88, 2020 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-31852605

RESUMO

Malnutrition has historically been researched and addressed within two distinct silos, focusing either on undernutrition, food insecurity, and micronutrient deficiencies, or on overweight, obesity, and dietary excess. However, through rapid global nutrition transition, an increasing proportion of individuals are exposed to different forms of malnutrition during the life course and have the double burden of malnutrition (DBM) directly. Long-lasting effects of malnutrition in early life can be attributed to interconnected biological pathways, involving imbalance of the gut microbiome, inflammation, metabolic dysregulation, and impaired insulin signalling. Life-course exposure to early undernutrition followed by later overweight increases the risk of non-communicable disease, by imposing a high metabolic load on a depleted capacity for homoeostasis, and in women increases the risk of childbirth complications. These life-course trajectories are shaped both by societal driving factors-ie, rapidly changing diets, norms of eating, and physical activity patterns-and by broader ecological factors such as pathogen burden and extrinsic mortality risk. Mitigation of the DBM will require major societal shifts regarding nutrition and public health, to implement comprehensive change that is sustained over decades, and scaled up into the entire global food system.


Assuntos
Desnutrição/metabolismo , Obesidade/metabolismo , Sobrepeso/metabolismo , África ao Sul do Saara/epidemiologia , Idade de Início , Exercício Físico , Feminino , Microbioma Gastrointestinal , Humanos , Indonésia/epidemiologia , Masculino , Desnutrição/epidemiologia , Desnutrição/microbiologia , Redes e Vias Metabólicas , Estado Nutricional , Obesidade/epidemiologia , Obesidade/microbiologia , Sobrepeso/epidemiologia , Sobrepeso/microbiologia , Prevalência
8.
Ann Nutr Metab ; 75(2): 119-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31743902

RESUMO

Indicators reflecting the double burden of malnutrition are rarely measured in nutrition surveys and are needed to strengthen national data systems. Indicators such as body composition reflect both metabolic response to undernutrition and obesity risk and nutrition-related noncommunicable diseases. Stable isotope techniques (SITs) provide accurate data on body composition, exclusive breastfeeding and vitamin A status that are otherwise problematic with routine methods. Integration of SIT-derived nutrition indicators in data systems could improve the design and evaluation of programmes focused on obesity prevention, food fortification and infant and young child feeding practices. The Working Group at the symposium considered "how SIT-derived nutrition indicators may be integrated into surveillance systems to strengthen data availability and capacity at national and regional levels". Practical considerations for the use of SITs include cost, sample size, rigorous training and logistics. It was concluded that SITs are best suited, at present, for use in sub-samples of population surveys and for validating tools that can be scaled-up more easily in population surveys. In the long term, SITs could be applied to larger surveys following potential innovations in more affordable, hand-held devices for analysis of stable isotope enrichment in the field and simpler specimen collection protocols.


Assuntos
Deutério/análise , Desnutrição/epidemiologia , Hipernutrição/epidemiologia , Isótopos de Oxigênio/análise , Biomarcadores , Composição Corporal , Peso Corporal , Aleitamento Materno , Deutério/administração & dosagem , Países em Desenvolvimento , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Desnutrição/metabolismo , Desnutrição/prevenção & controle , Hipernutrição/metabolismo , Hipernutrição/prevenção & controle , Isótopos de Oxigênio/administração & dosagem , Vigilância da População , Risco , Tamanho da Amostra
9.
Endocr J ; 66(11): 943-952, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31564683

RESUMO

Malnutrition occurs when nutrient intake is too low for any reason and occurs regardless of gender or age. Therefore, besides loss of eating or digestive functionality due to illness, malnutrition can occur when a healthy individual undergoes an extreme diet and biases their nutrition, or when athletes exerts more energy than they can replenish through food. It has recently been reported that in Japan, the mortality rate of leaner individuals is equal to or higher than that of obese people. It is important to understand what homeostatic maintenance mechanism is behind this when the body is under hypotrophic conditions. Such mechanisms are generally endocranially controlled. We address this fundamental concern in this paper by focusing on peptide hormones. We introduce a mechanism for survival in a malnourished state via the regulation of food intake and temperature. Additionally, we will discuss the latest findings and future prospects for research on changes in the endocrine environment associated with malnutrition associated with exercise. We also review changes in next-generation endocrine environments when caused by malnutrition brought on by dieting.


Assuntos
Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Desnutrição/metabolismo , Hormônios Peptídicos/metabolismo , Temperatura Corporal , Dieta Redutora , Ingestão de Energia , Epigênese Genética , Exercício Físico/fisiologia , Feminino , Grelina/metabolismo , Hormônio do Crescimento/metabolismo , Humanos , Insulina/metabolismo , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Leptina/metabolismo , Neuropeptídeo Y/metabolismo , Hormônios Peptídicos/genética , Peptídeo YY/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Esportes , Termogênese
10.
Curr Med Sci ; 39(5): 679-684, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31612382

RESUMO

Diet has been shown to play an important role in human physiology. It is a predominant exogenous factor regulating the composition of gut microbiota, and dietary intervention holds promise for treatment of diseases such as obesity, type 2 diabetes, and malnutrition. Furthermore, it was reported that diet has significant effects on physiological processes of C. elegans, including reproduction, fat storage, and aging. To reveal novel signaling pathways responsive to different diets, C. elegans and its bacterial diet were used as an interspecies model system to mimic the interaction between host and gut microbiota. Most signaling pathways identified in C. elegans are highly conserved across different species, including humans. A better understanding of these pathways can, therefore, help to develop interventions for human diseases. In this article, we summarize recent achievements on molecular mechanisms underlying the response of C. elegans to different diets and discuss their relevance to human health.


Assuntos
Envelhecimento/genética , Caenorhabditis elegans/fisiologia , Escherichia coli/genética , Microbioma Gastrointestinal/fisiologia , Redes e Vias Metabólicas/genética , Animais , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Dieta/métodos , Modelos Animais de Doenças , Escherichia coli/química , Escherichia coli/metabolismo , Humanos , Desnutrição/genética , Desnutrição/metabolismo , Desnutrição/microbiologia , Obesidade/genética , Obesidade/metabolismo , Obesidade/microbiologia , Interferência de RNA , RNA Bacteriano/antagonistas & inibidores , RNA Bacteriano/genética , RNA Bacteriano/metabolismo , Reprodução/genética , Transdução de Sinais
11.
Vet Clin North Am Equine Pract ; 35(3): 469-479, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587972

RESUMO

The domestic donkey is a unique equid species with specific nutritional requirements. This article examines the importance of feeding strategies that mimic the donkey's natural environment using poor nutritional quality fibers and access to browsing materials. The relationship between nutrition and health is examined and practical approaches to the healthy and sick donkey are discussed.


Assuntos
Equidae/metabolismo , Doenças dos Cavalos/metabolismo , Desnutrição/veterinária , Ração Animal/normas , Animais , Doenças dos Cavalos/etiologia , Cavalos , Desnutrição/etiologia , Desnutrição/metabolismo , Necessidades Nutricionais
12.
Nutrients ; 11(9)2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31527523

RESUMO

: Undernutrition is a major public health problem leading to 1 in 5 of all deaths in children under 5 years. Undernutrition leads to growth stunting and/or wasting and is often associated with environmental enteric dysfunction (EED). EED mechanisms leading to growth failure include intestinal hyperpermeability, villus blunting, malabsorption and gut inflammation. As non-invasive methods for investigating gut function in undernourished children are limited, pre-clinical models are relevant to elucidating the pathophysiological processes involved in undernutrition and EED, and to identifying novel therapeutic strategies. In many published models, undernutrition was induced using protein or micronutrient deficient diets, but these experimental models were not associated with EED. Enteropathy models mainly used gastrointestinal injury triggers. These models are presented in this review. We found only a few studies investigating the combination of undernutrition and enteropathy. This highlights the need for further developments to establish an experimental model reproducing the impact of undernutrition and enteropathy on growth, intestinal hyperpermeability and inflammation, that could be suitable for preclinical evaluation of innovative therapeutic intervention.


Assuntos
Transtornos da Nutrição Infantil/fisiopatologia , Enterite/fisiopatologia , Transtornos da Nutrição do Lactente/fisiopatologia , Síndromes de Malabsorção/fisiopatologia , Desnutrição/fisiopatologia , Estado Nutricional , Fenômenos Fisiológicos da Nutrição Animal , Animais , Transtornos da Nutrição Infantil/metabolismo , Transtornos da Nutrição Infantil/microbiologia , Pré-Escolar , Modelos Animais de Doenças , Metabolismo Energético , Enterite/metabolismo , Enterite/microbiologia , Microbioma Gastrointestinal , Humanos , Lactente , Transtornos da Nutrição do Lactente/metabolismo , Transtornos da Nutrição do Lactente/microbiologia , Fenômenos Fisiológicos da Nutrição do Lactente , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/fisiopatologia , Síndromes de Malabsorção/metabolismo , Síndromes de Malabsorção/microbiologia , Desnutrição/metabolismo , Desnutrição/microbiologia , Permeabilidade
13.
Reproduction ; 158(5): 429-440, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31518996

RESUMO

Adiponectin (ADIPOQ, encoded by Adipoq) is an important white adipose-derived adipokine linked to energy homeostasis and reproductive function. This study aims to reveal the expression and role of the adiponectin system in the ovaries under acute malnutrition. In this study, 48-h food deprivation significantly inhibited ovarian growth by suppressing cell proliferation and inducing cell apoptosis in the ovaries of gonadotrophin-primed immature mice. It was also accompanied by significantly decelerated basic metabolism (glucose, triacylglycerol and cholesterol), varied steroid hormones (follicle-stimulating hormone, luteinizing hormone and estradiol) and vanishment of the peri-ovarian fat. It is noteworthy that after acute fasting, the adiponectin levels in ovaries rather than in blood were significantly elevated. Immunohistochemical study demonstrated that adiponectin and its receptors (ADIPOR1 and ADIPOR2) primarily appeared in ovarian somatic and/or germ cells, and their protein expressions were upregulated in the ovaries from fasted mice. Further in vitro study verified that ADIPOR1/2 agonist obviously inhibited follicle-stimulating hormone-induced oocyte meiotic resumption, while the antagonist significantly enhanced the percentage of oocyte maturation in the absence of follicle-stimulating hormone. Furthermore, the build up of peri-ovarian fat under physiological status in mice showed a positive correlation with both the hypertrophy of adipocytes and growth of ovaries. Taken together, these findings indicate that the upregulation of the adiponectin system disturbs the normal female reproductive function under the malnutrition status, and it may be associated with the loss of peri-ovarian fat depots.


Assuntos
Adiponectina/fisiologia , Restrição Calórica/efeitos adversos , Jejum/fisiologia , Desnutrição/fisiopatologia , Ovário/fisiologia , Doença Aguda , Adipócitos/fisiologia , Adiponectina/farmacologia , Tecido Adiposo/metabolismo , Adiposidade/fisiologia , Animais , Metabolismo Energético/fisiologia , Feminino , Desnutrição/complicações , Desnutrição/metabolismo , Desnutrição/patologia , Camundongos , Ovário/metabolismo , Ovário/patologia , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia
14.
J Neurosci ; 39(39): 7689-7702, 2019 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-31391260

RESUMO

Epidemiological studies suggest that poor nutrition during pregnancy influences offspring predisposition to experience developmental and psychiatric disorders. Animal studies have shown that maternal undernutrition leads to behavioral impairment, which is linked to alterations in monoaminergic systems and inflammation in the brain. In this study, we focused on the ethanolamine plasmalogen of the brain as a possible contributor to behavioral disturbances observed in offspring exposed to maternal undernutrition. Maternal food or protein restriction between gestational day (GD) 5.5 and GD 10.5 resulted in hyperactivity of rat male adult offspring. Genes related to the phospholipid biosynthesis were found to be activated in the PFC, but not in the NAcc or striatum, in the offspring exposed to prenatal undernutrition. Corresponding to these gene activations, increased ethanolamine plasmalogen (18:0p-22:6) was observed in the PFC using mass spectrometry imaging. A high number of crossings and the long time spent in the center area were observed in the offspring exposed to prenatal undernutrition and were mimicked in adult rats via the intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome. Additionally, plasmalogen (18:0p-22:6) increased only in the PFC, and not in the NAcc or striatum. These results suggest that brain plasmalogen is one of the key molecules to control behavior, and its injection using liposome is a potential therapeutic approach for cognitive impairment.SIGNIFICANCE STATEMENT Maternal undernutrition correlates to developmental and psychiatric disorders. Here, we found that maternal undernutrition in early pregnancy led to hyperactivity in rat male offspring and induced gene activation of phospholipid-synthesizing enzyme and elevation of ethanolamine plasmalogen (18:0p-22:6) level in the PFC. Intravenous injection of ethanolamine plasmalogen (18:0p-22:6) incorporated into the liposome maintained crossing activity and the activity was circumscribed to the center area for a long time period, as in prenatally undernourished offspring with aberrant behavior. Furthermore, the amount of ethanolamine plasmalogen (18:0p-22:6) increased in the PFC of the rat after injection. Our result suggests that brain plasmalogen is one of the key molecules to control behavior and that its injection using liposome is a potential therapeutic approach for cognitive impairment.


Assuntos
Comportamento Animal/fisiologia , Desnutrição/complicações , Plasmalogênios/metabolismo , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Feminino , Masculino , Desnutrição/metabolismo , Gravidez , Ratos , Ratos Wistar
15.
Nutr Hosp ; 36(Spec No3): 63-69, 2019 Aug 27.
Artigo em Espanhol | MEDLINE | ID: mdl-31368337

RESUMO

Introduction: Chronic kidney disease patients often also present protein-calorie malnutrition, and it is a powerful predictor of morbidity and mortality. In this article, causes and management are shown, highlighting oral and parenteral nutritional supplementation, especially during dialysis process.


Assuntos
Desnutrição/etiologia , Nutrição Parenteral , Diálise Renal , Insuficiência Renal Crônica/complicações , Humanos , Desnutrição/diagnóstico , Desnutrição/metabolismo , Desnutrição/prevenção & controle , Necessidades Nutricionais , Desnutrição Proteico-Calórica/etiologia , Desnutrição Proteico-Calórica/metabolismo , Desnutrição Proteico-Calórica/terapia , Diálise Renal/efeitos adversos , Insuficiência Renal Crônica/metabolismo , Síndrome de Emaciação/etiologia , Síndrome de Emaciação/metabolismo
16.
Metab Brain Dis ; 34(6): 1607-1613, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31410775

RESUMO

Schizophrenia is a kind of neurodevelopmental disease. Epidemiological data associates schizophrenia with prenatal exposure to famine. Relevant prenatal protein deprivation (PPD) rodent models support this result by observing decreasing prepulse inhibition, altered hippocampal morphology and impaired memory in offspring. All these abnormalities are highly consistent with the pathophysiology of schizophrenia. We developed a prenatal famine rat model by restricting daily diet of the pregnant rat to 50% of low protein diet. A metabolomics study of prefrontal cortex was performed to integrate GC-TOFMS and UPLC-QTOFMS. Thirteen controls and thirteen famine offspring were used to differentiate in PLS-DA (partial least squares-discriminate analysis) model. Furthermore, metabolic pathways and diseases were enriched via KEGG and HMDB databases, respectively. A total of 67 important metabolites were screened out according to the multivariate analysis. Schizophrenia was the most statistical significant disease (P = 0.0016) in our famine model. These metabolites were enriched in key metabolic pathways related to energy metabolism and glutamate metabolism. Based on these important metabolites, further discussion speculated famine group was characterized by higher level of oxidized damage compared to control group. We proposed that oxidative stress might be the pathogenesis of prenatal undernutrition which is induced schizophrenia.


Assuntos
Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna/fisiologia , Estresse Oxidativo/fisiologia , Córtex Pré-Frontal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Esquizofrenia/metabolismo , Animais , Dieta com Restrição de Proteínas , Modelos Animais de Doenças , Feminino , Espectrometria de Massas , Metaboloma , Metabolômica , Gravidez , Ratos , Ratos Sprague-Dawley
17.
Nutrients ; 11(9)2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31443528

RESUMO

Severe food restriction (FR) impairs cardiac performance, although the causative mechanisms remain elusive. Since proteins associated with calcium handling may contribute to cardiac dysfunction, this study aimed to evaluate whether severe FR results in alterations in the expression and activity of Ca2+-handling proteins that contribute to impaired myocardial performance. Male 60-day-old Wistar-Kyoto rats were fed a control or restricted diet (50% reduction in the food consumed by the control group) for 90 days. Body weight, body fat pads, adiposity index, as well as the weights of the soleus muscle and lung, were obtained. Cardiac remodeling was assessed by morphological measures. The myocardial contractile performance was analyzed in isolated papillary muscles during the administration of extracellular Ca2+ and in the absence or presence of a sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) specific blocker. The expression of Ca2+-handling regulatory proteins was analyzed via Western Blot. Severe FR resulted in a 50% decrease in body weight and adiposity measures. Cardiac morphometry was substantially altered, as heart weights were nearly twofold lower in FR rats. Papillary muscles isolated from FR hearts displayed mechanical dysfunction, including decreased developed tension and reduced contractility and relaxation. The administration of a SERCA2a blocker led to further decrements in contractile function in FR hearts, suggesting impaired SERCA2a activity. Moreover, the FR rats presented a lower expression of L-type Ca2+ channels. Therefore, myocardial dysfunction induced by severe food restriction is associated with changes in the calcium-handling properties in rats.


Assuntos
Sinalização do Cálcio , Cálcio/metabolismo , Restrição Calórica , Cardiopatias/etiologia , Desnutrição/complicações , Mitocôndrias Cardíacas/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Músculos Papilares/metabolismo , Adiposidade , Animais , Canais de Cálcio Tipo L/metabolismo , Modelos Animais de Doenças , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Masculino , Desnutrição/metabolismo , Desnutrição/patologia , Desnutrição/fisiopatologia , Mitocôndrias Cardíacas/patologia , Miócitos Cardíacos/patologia , Músculos Papilares/patologia , Músculos Papilares/fisiopatologia , Ratos Endogâmicos WKY , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Perda de Peso
18.
J Proteomics ; 208: 103492, 2019 09 30.
Artigo em Inglês | MEDLINE | ID: mdl-31434010

RESUMO

Protein malnutrition is a risk factor for developing visceral leishmaniasis. Because we previously demonstrated that protein malnutrition and infection with Leishmania infantum disrupts the splenic microarchitecture in BALB/c mice, alters T cell-subsets and increases splenic parasite load, we hypothesize that splenic microenvironment is precociously compromised in infected animals that suffered a preceding malnutrition. To evaluate this, we characterized the abundance of proteins secreted in the splenic interstitial fluid (IF) using an iTRAQ-based quantitative proteomics approach. In addition, local levels of pro-inflammatory and proliferation molecules were analyzed. Whereas well-nourished infected animals showed increased IL-1ß and IL-2 levels, malnourished-infected mice displayed significant reduction of these cytokines. Remarkably, a two-weeks infection with L. infantum already modified protein abundance in the splenic IF of well-nourished mice, but malnourished animals failed to respond to infection in the same fashion. Malnutrition induced significant reduction of chemotactic and pro-inflammatory molecules as well as of proteins involved in nucleic acid and amino acid metabolism, indicating an impaired proliferative microenvironment. Accordingly, a significant decrease in Ki67 expression was observed, suggesting that splenocyte proliferation is compromised in malnourished animals. Together, our results show that malnutrition compromises the splenic microenvironment and alters the immune response to the parasite in malnourished individuals. SIGNIFICANCE: Protein malnutrition is recognized as an important epidemiological risk factor for developing visceral leishmaniasis (VL). Locally secreted factors present in the interstitial fluid have important roles in initiating immune responses and in regulating fluid volume during inflammation. However, the regulation of secreted factors under pathological conditions such as malnutrition and infection are widely unknown. To analyze how protein malnutrition alters secreted proteins involved in the immune response to L. infantum infection we evaluated the proteomic profile of the interstitial fluid of the spleen in malnourished BALB/c mice infected with L. infantum. Our work revealed new elements that contribute to the understanding of the immunopathological events in the spleen of malnourished animals infected with L. infantum and opens new pathways for consideration of other aspects that could improve VL treatment in malnourished individuals.


Assuntos
Proliferação de Células , Líquido Extracelular/metabolismo , Perfilação da Expressão Gênica , Leishmania infantum/metabolismo , Leishmaniose Visceral/metabolismo , Desnutrição/metabolismo , Proteômica , Baço/metabolismo , Animais , Líquido Extracelular/parasitologia , Inflamação/metabolismo , Inflamação/parasitologia , Inflamação/patologia , Leishmaniose Visceral/patologia , Masculino , Desnutrição/parasitologia , Desnutrição/patologia , Camundongos , Camundongos Endogâmicos BALB C , Baço/parasitologia , Baço/patologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-31355153

RESUMO

Detrimental effects of malnutrition on immune responses to pathogens have long been recognized and it is considered a main risk factor for various infectious diseases, including visceral leishmaniasis (VL). Thymus is a target of both malnutrition and infection, but its role in the immune response to Leishmania infantum in malnourished individuals is barely studied. Because we previously observed thymic atrophy and significant reduction in cellularity and chemokine levels in malnourished mice infected with L. infantum, we postulated that the thymic microenvironment is severely compromised in those animals. To test this, we analyzed the microarchitecture of the organ and measured the protein abundance in its interstitial space in malnourished BALB/c mice infected or not with L. infantum. Malnourished-infected animals exhibited a significant reduction of the thymic cortex:medulla ratio and altered abundance of proteins secreted in the thymic interstitial fluid. Eighty-one percent of identified proteins are secreted by exosomes and malnourished-infected mice showed significant decrease in exosomal proteins, suggesting that exosomal carrier system, and therefore intrathymic communication, is dysregulated in those animals. Malnourished-infected mice also exhibited a significant increase in the abundance of proteins involved in lipid metabolism and tricarboxylic acid cycle, suggestive of a non-proliferative microenvironment. Accordingly, flow cytometry analysis revealed decreased proliferation of single positive and double positive T cells in those animals. Together, the reduced cortical area, decreased proliferation, and altered protein abundance suggest a dysfunctional thymic microenvironment where T cell migration, proliferation, and maturation are compromised, contributing for the thymic atrophy observed in malnourished animals. All these alterations could affect the control of the local and systemic infection, resulting in an impaired response to L. infantum infection.


Assuntos
Interações Hospedeiro-Patógeno/imunologia , Leishmania infantum/imunologia , Leishmaniose Visceral/imunologia , Desnutrição/imunologia , Linfócitos T/imunologia , Timo/imunologia , Animais , Transporte Biológico , Movimento Celular , Proliferação de Células , Ciclo do Ácido Cítrico/genética , Ciclo do Ácido Cítrico/imunologia , Exossomos/imunologia , Exossomos/metabolismo , Exossomos/parasitologia , Líquido Extracelular/imunologia , Líquido Extracelular/metabolismo , Líquido Extracelular/parasitologia , Galectina 1/genética , Galectina 1/imunologia , Regulação da Expressão Gênica , Interações Hospedeiro-Patógeno/genética , Imunidade Inata , Leishmania infantum/crescimento & desenvolvimento , Leishmaniose Visceral/genética , Leishmaniose Visceral/metabolismo , Leishmaniose Visceral/parasitologia , Metabolismo dos Lipídeos , Masculino , Desnutrição/genética , Desnutrição/metabolismo , Desnutrição/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Plasminogênio/genética , Plasminogênio/imunologia , Proteoma/genética , Proteoma/imunologia , Linfócitos T/parasitologia , Timo/metabolismo , Timo/parasitologia
20.
Food Funct ; 10(8): 5018-5031, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31355385

RESUMO

Maternal restriction of dietary proteins during pregnancy and lactation is known to induce renal disease in later life. High fructose intake causes metabolic syndrome, which results in an increased risk of chronic kidney disease development. We investigated whether quercetin intake during lactation affects high-fructose-diet-induced inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring exposed to maternal normal-protein (NP) or low-protein (LP) diets. Pregnant Wistar rats received diets containing 20% (NP) or 8% (LP) casein, and 0 or 0.2% quercetin containing NP diets (NP/NP or NP/NPQ) in experiment (Expt.) 1 and 0 or 0.2% quercetin containing LP diets (LP/LP or LP/LPQ) in Expt. 2 during lactation. At weaning, pups that received a diet of distilled water (Wa) or 10% fructose solution (Fr) were divided into six groups: NP/NP/Wa, NP/NP/Fr, NP/NPQ/Fr in Expt. 1, and LP/LP/Wa, LP/LP/Fr, LP/LPQ/Fr in Expt. 2. At week 12, macrophage infiltration, mRNA levels of TNF-α and IL-6, and markers of autophagy flux in the kidneys of male offspring were examined. We found that macrophage number and, TNF-α and IL-6 mRNA levels increased in the kidneys of the NP/NP/Fr or LP/LP/Fr, respectively. Conversely, macrophage number and IL-6 levels in the NP/NPQ/Fr or LP/LPQ/Fr decreased. LC3B-II levels were downregulated in the NP/NP/Fr or LP/LP/Fr rats. In contrast, LC3B-II levels were upregulated, while p62 levels were downregulated in the NP/NPQ/Fr and LP/LPQ/Fr rats. In conclusion, maternal quercetin intake during lactation may cause long-term alterations in inflammation and autophagy flux in the kidneys of high-fructose-diet-fed adult female offspring.


Assuntos
Autofagia/efeitos dos fármacos , Frutose/efeitos adversos , Nefropatias/prevenção & controle , Desnutrição/complicações , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Quercetina/administração & dosagem , Animais , Feminino , Frutose/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Rim/efeitos dos fármacos , Rim/imunologia , Rim/fisiopatologia , Nefropatias/etiologia , Nefropatias/imunologia , Nefropatias/fisiopatologia , Lactação , Masculino , Desnutrição/metabolismo , Fenômenos Fisiológicos da Nutrição Materna , Gravidez , Efeitos Tardios da Exposição Pré-Natal/etiologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
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