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1.
Biochemistry (Mosc) ; 84(11): 1329-1345, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31760921

RESUMO

Obesity is a major risk factor for type 2 diabetes and metabolic syndrome and an essential medical and social problem. In the first part of the review, we briefly highlight the biochemical basis of metabolic disbalance in obesity and evolution of our views on the mechanisms of insulin resistance development in insulin-sensitive tissues. Because obesity relates to the disturbance in the normal physiology of fat tissue, the second part of the review focuses on latent inflammation that develops in obesity and is supported by immune cells. Finally, the problem of adipocyte hypertrophy, reduced regenerative potential of fat progenitor cells, and impaired renewal of fat depots is discussed in the context of type 2 diabetes pathogenesis.


Assuntos
Inflamação/patologia , Resistência à Insulina , Obesidade/patologia , Adipogenia , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Animais , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Inflamação/metabolismo , Linfócitos/citologia , Linfócitos/imunologia , Linfócitos/metabolismo , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Obesidade/complicações , Obesidade/metabolismo
2.
Life Sci ; 237: 116914, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31622606

RESUMO

AIMS: The aim of the presente study was to examine the effects of oral gallic acid (GA) administration on the brown adipose tissue of obese mice fed with high-fat diet. New mechanisms and interactions pathways in thermogenesis were accessed through bioinformatics analyses. MAIN METHODS: Swiss male mice were divided into four groups and fed during 60 days with: standard diet, standard diet combined with gallic acid, high-fat diet and high-fat diet combined with gallic acid. Body weight, food intake, and blood parameters (glucose tolerance test, total-cholesterol, high-density low-c, triglyceride and glucose levels) were evaluated. Brown and subcutaneous white adipose tissue histological analysis were performed. SIRT1 and PGC1-α mRNA expression in the brown adipose tissue were assessed. KEY FINDINGS: Our main findings showed that the gallic acid improved glucose tolerance and metabolic parameters. These results were accompanied by bioinformatics analyses that evidenced SIRT1 as main target in the thermogenesis process, confirmed as increased SIRT1 mRNA expression was evidenced in the brown adipose tissue. SIGNIFICANCE: Together, the data suggest that the gallic acid effect in brown adipose tissue may improve body metabolism, glucose homeostasis and increase thermogenesis.


Assuntos
Tecido Adiposo Marrom/metabolismo , Biologia Computacional/métodos , Dieta Hiperlipídica/efeitos adversos , Ácido Gálico/farmacologia , Metaboloma/efeitos dos fármacos , Obesidade/metabolismo , Sirtuína 1/metabolismo , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/patologia , Animais , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/etiologia , Sirtuína 1/genética , Termogênese/efeitos dos fármacos
3.
Arq Gastroenterol ; 56(3): 270-275, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31633724

RESUMO

BACKGROUND: Metabolic risk factors of non alcoholic fatty liver disease (NAFLD) in non diabetic teetotallers who constitute a definite group are not well defined. OBJECTIVE: To identify the metabolic risk factors of NAFLD if any in non diabetic subjects who do not consume alcohol. METHODS: In a cross sectional study the effect of metabolic parameters (BMI, individual lipid levels, hemoglobinA1c (HbA1c), HOMA IR and the metabolic syndrome components) of 150 consecutive non diabetic teetotallers (90 with normal glucose tolerance and 60 prediabetics) on their NFS (quantifiable severity parameter of NAFLD) was studied by linear regression analysis. Similar study was done in the normal glucose tolerance and prediabetes groups separately. These parameters were then compared with those of 75 matched diabetic teetotallers with NAFLD. To analyse further the difference between normal glucose tolerance, prediabetic and overt diabetic groups, binary logistic regression of the factors was carried out taking prediabetes and diabetes as outcome variable. RESULTS: All the metabolic parameters were significantly higher in diabetics compared to non diabetics and in prediabetics compared to those with normal glucose tolerance except high-density lipoprotein cholesterol. Triglyceride, high-density lipoprotein cholesterol and BMI significantly predicted NFS in the overall (adjusted R2 68.7%, P=0.000) and normal glucose tolerance groups (adjusted R2 73.2%, P=0.000) whereas BMI, triglyceride, low-density lipoprotein cholesterol and HbA1c did in prediabetics (adjusted R2 89%, P=0.000). The metabolic syndrome was significantly associated with NFS in the overall and prediabetic groups. High triglyceride (odds ratio1.08), low-density lipoprotein cholesterol (odds ratio1.03) and HbA1c (odds ratio 11.54) were positively associated with prediabetes compared to normal glucose tolerance group. CONCLUSION: In nondiabetic teetotallers dyslipidemias are the prime contributors to the development of NAFLD.


Assuntos
Dislipidemias/metabolismo , Resistência à Insulina/fisiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Idoso , Índice de Massa Corporal , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Dislipidemias/sangue , Feminino , Hemoglobina A Glicada/análise , Humanos , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/etiologia , Obesidade/metabolismo , Fatores de Risco , Triglicerídeos/sangue
4.
Arq Gastroenterol ; 56(3): 294-299, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31633728

RESUMO

BACKGROUND: During weight gain, most of the excess adipose tissue accumulates in the trunk. This alters the body shape and makes collection of anthropometric measurements, especially waist circumference (WC), difficult. OBJECTIVE: To evaluate the sensitivity and applicability of additional abdominal measurements in order to assess body composition of obese women. METHODS: A total of 30 women between 20 and 50 years of age and BMI above 30 kg/m² were assessed. Three WC measurements, were performed: at the umbilical scar designated as WC1 and at 8 and 16 cm above the umbilical scar, designated as WC2, and WC3 respectively. The correlation (r) between these anthropometric measurements and their sum was assessed against the parameters fat mass (FM), free fat mass (FFM), body fat percentage (%BF), and trunk fat percentage (%TF), obtained by total and trunk segmental bioelectric impedance analysis (BIA) as well as by the golden standard total and trunk dual energy X-ray absorptiometry (DXA). RESULTS: The measurements WC1, WC2, WC3, and their sum correlated strongly and moderately with the parameters FM, FFM, and %BF in total BIA and in both total DXA and trunk DXA. CONCLUSION: The results demonstrated a robust correlation between the sum of the three WC measurements and total and trunk DXA in obese women suggesting that such measurements may be a good indicator of body and trunk fat in women, actually superior to BIA results. The use of these three measurements may be an alternative for the assessment of body and trunk fat, in those cases in which the body shape due to adipose tissue trunk accumulation makes accurate classical measurement (WC1) difficult.


Assuntos
Gordura Abdominal/metabolismo , Composição Corporal/fisiologia , Obesidade/metabolismo , Circunferência da Cintura/fisiologia , Adulto , Índice de Massa Corporal , Peso Corporal , Impedância Elétrica , Feminino , Humanos , Pessoa de Meia-Idade , Adulto Jovem
5.
Orv Hetil ; 160(44): 1727-1734, 2019 Nov.
Artigo em Húngaro | MEDLINE | ID: mdl-31657254

RESUMO

Authors discuss the musculoskeletal aspects of obesity by applying a novel approach. Biochemical changes associated with obesity and especially metabolic syndrome, may have a great impact on the function of bones, joints and muscles. Therefore we need a new view and new strategies in rheumatic diseases. Obesity-associated metabolic changes should be considered during the progress of as well as the selection of treatment in inflammatory rheumatic diseases. Individualised treatment is necessary due to associated comorbidities as well. Orv Hetil. 2019; 160(44): 1727-1734.


Assuntos
Artropatias/etiologia , Artropatias/fisiopatologia , Síndrome Metabólica , Doenças Musculoesqueléticas/etiologia , Doenças Musculoesqueléticas/fisiopatologia , Obesidade/complicações , Obesidade/fisiopatologia , Doenças Reumáticas , Adipocinas/metabolismo , Artrite , Humanos , Artropatias/metabolismo , Leptina/metabolismo , Doenças Musculoesqueléticas/metabolismo , Obesidade/metabolismo , Osteoartrite/etiologia , Osteoartrite/metabolismo , Osteoartrite/fisiopatologia , Doenças Reumáticas/etiologia , Doenças Reumáticas/metabolismo , Doenças Reumáticas/fisiopatologia
6.
DNA Cell Biol ; 38(11): 1303-1312, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31553232

RESUMO

Growth differentiation factor 5 (GDF5) was reported to regulate brown adipogenesis; however, its effects on insulin sensitivity, full metabolic syndrome spectrum, and the thermogenesis in subcutaneous white adipose tissue (sWAT) have not been elucidated yet. We thus generated fatty acid-binding protein 4 (Fabp4)-GDF5 transgenic (TG) mice and showed that GDF5 TG mice developed a relative lean phenotype on a high-fat diet (HFD) and showed increased insulin sensitivity. Over expression of GDF5 in adipose tissues greatly promoted the thermogenic process in sWAT after cold or ß3-agonist treatment. In TG mice, sWAT showed an important thermogenic effect as the thermogenic gene expression was markedly increased, which was consistent with the typical features of beige adipocytes. Moreover, knockdown of the protein GDF5 impaired browning program in sWAT after thermogenic stimuli. Enhanced mitogen-activated protein kinase (MAPK)/activating transcription factor 2 (ATF2) signaling was also identified in sWAT of HFD-fed GDF5 mice, and thermogenesis in mature adipocytes induced by GDF5 protein could be partly blocked by a p38 MAPK inhibitor. Taken together, our data suggest that GDF5 could improve insulin sensitivity and prevent metabolic syndrome, the adaptive thermogenesis in sWAT could mediate the obesity resistance effects of GDF5 in mice and partially resulted in the activation of the p38 MAPK signaling pathway.


Assuntos
Tecido Adiposo Branco/fisiologia , Fator 5 de Diferenciação de Crescimento/fisiologia , Termogênese/genética , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adipogenia/fisiologia , Tecido Adiposo Branco/metabolismo , Animais , Células Cultivadas , Fator 5 de Diferenciação de Crescimento/genética , Resistência à Insulina/genética , Sistema de Sinalização das MAP Quinases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Transdução de Sinais/genética
7.
Nature ; 574(7776): 63-68, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554967

RESUMO

The gp130 receptor cytokines IL-6 and CNTF improve metabolic homeostasis but have limited therapeutic use for the treatment of type 2 diabetes. Accordingly, we engineered the gp130 ligand IC7Fc, in which one gp130-binding site is removed from IL-6 and replaced with the LIF-receptor-binding site from CNTF, fused with the Fc domain of immunoglobulin G, creating a cytokine with CNTF-like, but IL-6-receptor-dependent, signalling. Here we show that IC7Fc improves glucose tolerance and hyperglycaemia and prevents weight gain and liver steatosis in mice. In addition, IC7Fc either increases, or prevents the loss of, skeletal muscle mass by activation of the transcriptional regulator YAP1. In human-cell-based assays, and in non-human primates, IC7Fc treatment results in no signs of inflammation or immunogenicity. Thus, IC7Fc is a realistic next-generation biological agent for the treatment of type 2 diabetes and muscle atrophy, disorders that are currently pandemic.


Assuntos
Receptor gp130 de Citocina/metabolismo , Citocinas/síntese química , Citocinas/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Ligação Competitiva , Citocinas/química , Diabetes Mellitus Tipo 2/metabolismo , Desenho de Drogas , Fígado Gorduroso/prevenção & controle , Teste de Tolerância a Glucose , Humanos , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Incretinas/metabolismo , Interleucina-6/antagonistas & inibidores , Interleucina-6/metabolismo , Masculino , Camundongos , Músculo Esquelético/efeitos dos fármacos , Obesidade/metabolismo , Pâncreas/metabolismo , Fosfoproteínas/metabolismo , Engenharia de Proteínas , Receptores de Interleucina-6/metabolismo , Transdução de Sinais , Fatores de Transcrição , Ganho de Peso/efeitos dos fármacos
8.
Life Sci ; 235: 116834, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31493478

RESUMO

Obesity has a positive relation to non-alcoholic fatty liver disease (NAFLD) and studies have demonstrated that strength training can regulate lipid accumulation in the hepatocytes of obese rats. AIMS: Our aim is to evaluate the effects of high fat diet and strength training on markers of oxidation and lipogenesis in the liver of Wistar rats. MAIN METHODS: Forty Wistar rats were divided into four groups (n = 10): control (CTL), strength training (TR), high fat diet consumption (HF) and high fat diet consumption with strength training (HFT). Animals were subjected to physical strength training and high fat diet consumption for 12 weeks, 3 session per week. Then, the animals were euthanized, and liver markers were evaluated via immunolabeling. KEY FINDINGS: Our results indicated that strength training reduced the expression of adiposity as well as the accumulation of glycogen and lipids in the liver. This reduction of fatty acid (FA) stored in hepatocytes is related to reduction of proteins linked to ß-oxidation such as Fas/CD95, LIMP-II and CD36, as well as other proteins linked to lipogeneses such as SREBP-1. SIGNIFICANCE: Finally, we observed that high fat diet can alter lipogenesis and reduce ß-oxidation promoted hepatic fat accumulation. In conclusion, there was a reduction of obesity-related hepatic lipogenesis after 12 weeks of strength training.


Assuntos
Metabolismo dos Lipídeos , Fígado/metabolismo , Obesidade/metabolismo , Condicionamento Físico Animal/fisiologia , Animais , Biomarcadores/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glicogênio/metabolismo , Lipogênese , Masculino , Oxirredução , Proteínas/metabolismo , Ratos
9.
J Agric Food Chem ; 67(40): 11099-11107, 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31496244

RESUMO

Urolithins are bioactive gut microbiota metabolites of ellagic acid. Here, we have identified four unknown urolithins in human feces after the intake of a pomegranate extract. The new metabolites occurred only in 19% of the subjects. 4,8,9,10-Tetrahydroxy urolithin, (urolithin M6R), was unambiguously identified by 1H NMR, UV, and HRMS. Three metabolites were tentatively identified by the UV, HRMS, and chromatographic behavior, as 4,8,10-trihydroxy (urolithin M7R), 4,8,9-trihydroxy (urolithin CR), and 4,8-dihydroxy (urolithin AR) urolithins. Phase II conjugates of the novel urolithins were detected in urine and confirmed their absorption, circulation, and urinary excretion. The production of the new urolithins was not specific of any of the known urolithin metabotypes A and B. The new metabolites needed a bacterial 3-dehydroxylase activity for their production, and this is a novel feature as all the previously known urolithins maintained the hydroxyl at 3 position. The ability of production of these "R" urolithins can be considered an additional metabolic feature for volunteer stratification.


Assuntos
Cumarínicos/metabolismo , Fezes/química , Lythraceae/metabolismo , Obesidade/dietoterapia , Extratos Vegetais/metabolismo , Urina/química , Adulto , Idoso , Cumarínicos/química , Ácido Elágico/química , Ácido Elágico/metabolismo , Feminino , Humanos , Lythraceae/química , Masculino , Pessoa de Meia-Idade , Obesidade/metabolismo , Obesidade/urina , Extratos Vegetais/química
10.
Nat Med ; 25(9): 1390-1395, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501611

RESUMO

Visceral adipose tissue (VAT)-fat stored around the internal organs-has been suggested as an independent risk factor for cardiovascular and metabolic disease1-3, as well as all-cause, cardiovascular-specific and cancer-specific mortality4,5. Yet, the contribution of genetics to VAT, as well as its disease-related effects, are largely unexplored due to the requirement for advanced imaging technologies to accurately measure VAT. Here, we develop sex-stratified, nonlinear prediction models (coefficient of determination = 0.76; typical 95% confidence interval (CI) = 0.74-0.78) for VAT mass using the UK Biobank cohort. We performed a genome-wide association study for predicted VAT mass and identified 102 novel visceral adiposity loci. Predicted VAT mass was associated with increased risk of hypertension, heart attack/angina, type 2 diabetes and hyperlipidemia, and Mendelian randomization analysis showed visceral fat to be a causal risk factor for all four diseases. In particular, a large difference in causal effect between the sexes was found for type 2 diabetes, with an odds ratio of 7.34 (95% CI = 4.48-12.0) in females and an odds ratio of 2.50 (95% CI = 1.98-3.14) in males. Our findings bolster the role of visceral adiposity as a potentially independent risk factor, in particular for type 2 diabetes in Caucasian females. Independent validation in other cohorts is necessary to determine whether the findings can translate to other ethnicities, or outside the UK.


Assuntos
Adiposidade/genética , Doenças Cardiovasculares/genética , Gordura Intra-Abdominal/metabolismo , Doenças Metabólicas/genética , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/patologia , Gordura Intra-Abdominal/patologia , Masculino , Análise da Randomização Mendeliana , Doenças Metabólicas/epidemiologia , Doenças Metabólicas/patologia , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Caracteres Sexuais
11.
Nat Med ; 25(9): 1385-1389, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31501613

RESUMO

The worldwide obesity epidemic1 makes it important to understand how lipid turnover (the capacity to store and remove lipids) regulates adipose tissue mass. Cross-sectional studies have shown that excess body fat is associated with decreased adipose lipid removal rates2,3. Whether lipid turnover is constant over the life span or changes during long-term weight increase or loss is unknown. We determined the turnover of fat cell lipids in adults followed for up to 16 years, by measuring the incorporation of nuclear bomb test-derived 14C in adipose tissue triglycerides. Lipid removal rate decreases during aging, with a failure to reciprocally adjust the rate of lipid uptake resulting in weight gain. Substantial weight loss is not driven by changes in lipid removal but by the rate of lipid uptake in adipose tissue. Furthermore, individuals with a low baseline lipid removal rate are more likely to remain weight-stable after weight loss. Therefore, lipid turnover adaptation might be important for maintaining pronounced weight loss. Together these findings identify adipose lipid turnover as an important factor for the long-term development of overweight/obesity and weight loss maintenance in humans.


Assuntos
Envelhecimento/metabolismo , Peso Corporal/genética , Obesidade/metabolismo , Ganho de Peso/genética , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Adolescente , Adulto , Envelhecimento/genética , Envelhecimento/patologia , Peso Corporal/fisiologia , Radioisótopos de Carbono/química , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Masculino , Obesidade/genética , Obesidade/patologia , Sobrepeso/genética , Sobrepeso/metabolismo , Sobrepeso/patologia , Triglicerídeos/metabolismo , Perda de Peso/genética
12.
J Agric Food Chem ; 67(37): 10352-10360, 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31503479

RESUMO

The potential for apple peels to mitigate the deleterious effects of a high-fat diet in mice was investigated here. Mice were fed a high-fat diet supplemented with apple powders from three apple varieties or a commercial apple polyphenol. Polyphenols were characterized using colorimetric assays and high-performance liquid chromatography. Mice were tested for standard metabolic parameters. There was a dose response to dietary apple peels, with the higher intake leading to reduced weight gain and adipose tissue mass relative to the lower intake, but none of the treatments were statistically different from the control. The gene expression of liver enzyme stearoyl-CoA desaturase (Scd-1) was correlated with adipose weight, and liver enzyme cytochrome P51 (Cyp51) was downregulated by the apple diets. The feces from a subset of mice were analyzed for polyphenols and for bacteria taxa by next-generation sequencing. The results revealed that the makeup of the fecal microbiota was related to the metabolism of dietary polyphenols.


Assuntos
Biflavonoides/análise , Catequina/análise , Fezes/química , Frutas/metabolismo , Microbioma Gastrointestinal , Malus/metabolismo , Obesidade/dietoterapia , Proantocianidinas/análise , Animais , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Biflavonoides/metabolismo , Catequina/metabolismo , Dieta Hiperlipídica/efeitos adversos , Frutas/química , Humanos , Masculino , Malus/química , Camundongos , Obesidade/genética , Obesidade/metabolismo , Obesidade/microbiologia , Polifenóis/análise , Polifenóis/metabolismo , Proantocianidinas/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Esterol 14-Desmetilase/genética , Esterol 14-Desmetilase/metabolismo
13.
Eur J Endocrinol ; 181(5): 525-537, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31536965

RESUMO

Objective: To evaluate the effect of insulin resistance in obesity on the expression in whole blood of mRNA and miRNA affecting bone homeostasis as well as to estimate the influence of oral glucose load (OGTT) on serum osteocalcin concentration in obese individuals with and without insulin resistance. Design: Cross-sectional study. Methods: Carboxylated (cOC), undercarboxylated (ucOC) and total osteocalcin were measured by ELISA in the serum of obese subjects with insulin resistance (n = 41) and obese subjects without insulin resistance (n = 41) (control group) during OGTT. Analysis of gene expression (microarray) and miRNAs (real-time PCR) was performed in venous blood (representating samples) collected before OGTT from obese with insulin resistance and controls. Results: Obese subjects with insulin resistance (higher HOMA-IR and lower oral glucose insulin sensitivity index) presented significantly increased expression of WNT signalling inhibitors (DKK1, DKK2, SOST, SFRP1) and downregulation of the key factor in WNT signalling - ß catenin participating in osteoblasts differentiation. Expression of miRNA involved in osteoblastogenesis was also inhibited (miR-29b, miR-181a, miR-210, miR-324-3p). During OGTT, contrary to the control group, subjects with insulin resistance presented suppression of cOC and total OC decrease after 1 and 2 h of oral glucose load. Conclusions: Obese subjects with insulin resistance may have defects in osteoblastogenesis that was demonstrated via key signalling molecules mRNA downregulation, and increased expression of WNT antagonists as well as inhibition of expression of miRNA participating in the regulation of osteoblast differentiation. Disturbed osteoblastogenesis in insulin-resistant subjects results in the suppression of blood carboxylated and total osteocalcin decrease during OGTT.


Assuntos
Remodelação Óssea/fisiologia , Resistência à Insulina/fisiologia , MicroRNAs/sangue , RNA Mensageiro/sangue , Adulto , Estudos Transversais , Ensaio de Imunoadsorção Enzimática , Feminino , Teste de Tolerância a Glucose , Humanos , Masculino , Análise em Microsséries , Pessoa de Meia-Idade , Obesidade/etiologia , Obesidade/metabolismo , Osteoblastos/metabolismo , Osteoclastos/metabolismo , Via de Sinalização Wnt/fisiologia
14.
J Agric Food Chem ; 67(38): 10595-10603, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31475817

RESUMO

While ß-cryptoxanthin is hypothesized to have a preventive effect on lifestyle-related diseases, its underlying mechanisms are unknown. We investigated the effect of ß-cryptoxanthin on energy metabolism in adipose tissues and its underlying mechanism. C57BL/6J mice were fed a high-fat diet (60% kcal fat) containing 0 or 0.05% ß-cryptoxanthin for 12 weeks. ß-cryptoxanthin treatment was found to reduce body fat gain and plasma glucose level, while increasing energy expenditure. The expression of uncoupling protein (UCP) 1 was elevated in adipose tissues in the treatment group. Furthermore, the in vivo assays showed that the Ucp1 mRNA expression was higher in the ß-cryptoxanthin treatment group, an effect that disappeared upon cotreatment with a retinoic acid receptor (RAR) antagonist. In conclusion, we report that ß-cryptoxanthin reduces body fat and body weight gain and that ß-cryptoxanthin increases the expression of UCP1 via the RAR pathway.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , beta-Criptoxantina/administração & dosagem , Obesidade/tratamento farmacológico , Receptores do Ácido Retinoico/metabolismo , Proteína Desacopladora 1/genética , Animais , Metabolismo Energético/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Receptores do Ácido Retinoico/genética , Transdução de Sinais/efeitos dos fármacos , Proteína Desacopladora 1/metabolismo
15.
Res Vet Sci ; 125: 374-381, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31400635

RESUMO

Adiponectin is an adipokine that exerts insulin-sensitizing and antiinflammatory properties. The aim of this study was to develop and validate a new heterologous ultrasensitive assay based on amplified luminescent technology for adiponectin determination in serum and saliva of dogs. A complete analytical validation of the assay was made in these fluids, and also this assay was applied to quantify adiponectin in serum and saliva of obese and lean dogs and dogs with leishmaniosis. These conditions were selected because in obesity there is a controversy about how adiponectin concentrations change in dogs, and in case of canine leishmaniosis, although it is described a decrease in serum adiponectin, there are not studies about how adiponectin changes after treatment. A total of 11 dogs were used in the validation and 26 dogs with different body condition and 8 with canine leishmaniosis were used for the clinical evaluation of the new assay for adiponectin quantification in serum and saliva of dogs. The analytical evaluation showed that the developed method could measure adiponectin in serum and saliva of dogs with high repeatability and sensitivity, adding a limit of quantification lower than commercially available ELISAs. In addition, significantly higher adiponectin concentrations were found in lean dogs and a correlation between serum and saliva was observed (P < .01). Moreover, dogs with leishmania presented reduced levels of adiponectin in serum. In conclusion, a new assay has been developed for adiponectin measurements which is more sensitive and faster than the traditional ELISA assays requiring less sample volume.


Assuntos
Adiponectina/metabolismo , Imunoensaio/veterinária , Leishmaniose/veterinária , Obesidade/veterinária , Adiponectina/sangue , Animais , Cães , Imunoensaio/métodos , Leishmaniose/diagnóstico , Leishmaniose/metabolismo , Masculino , Obesidade/diagnóstico , Obesidade/metabolismo , Saliva/química
16.
Eur J Med Chem ; 181: 111565, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387062

RESUMO

The human Carbonic anhydrases (hCA) VA and VB play a key role in ureagenesis, gluconeogenesis, lipogenesis and in the metabolism regulation, thus representing highly popular drug targets. Albeit several hCA inhibitors have been designed and are currently in clinical use, serious drug interactions have been reported due to their poor selectivity. In this perspective, the drug repurposing approach could be a useful tool in order to investigate the drug promiscuity/polypharmacology profile. In this study, virtual screening techniques and in vitro assays were combined to identify novel selective hCA VA inhibitors from among around 94000 compounds. The docking analysis highlighted 12 promising best hits, biologically characterized in terms of their hCA VA inhibitory activity. Interestingly, among them, the anticancer agents fludarabine and lenvatinib and the antiepileptic rufinamide were able to selectively inhibit the enzyme activity in the micromolar range, while a pyrido-indole derivative, the homovanillic acid sulfate and the desacetyl metabolite of the antibacterial cephapirin in the nanomolar range.


Assuntos
Fármacos Antiobesidade/farmacologia , Inibidores da Anidrase Carbônica/farmacologia , Reposicionamento de Medicamentos , Obesidade/tratamento farmacológico , Fármacos Antiobesidade/química , Anidrase Carbônica I/antagonistas & inibidores , Anidrase Carbônica I/metabolismo , Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/química , Projeto Auxiliado por Computador , Descoberta de Drogas , Humanos , Simulação de Acoplamento Molecular , Obesidade/metabolismo
17.
Cell Physiol Biochem ; 53(3): 465-479, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464387

RESUMO

BACKGROUND/AIMS: Cyclophilin D (CypD) mediates the mitochondrial permeability transition pore (mPTP) opening that contributes to mitochondrial dysfunction. CypD is regulated by its acetylation/deacetylation state that depends on Sirtuin-3 (SIRT3) mitochondrial deacetylase. Since obesity and metabolic syndrome decrease SIRT3 activity and expression, we tested the hypothesis that CypD hyperacetylation promotes mitochondrial dysfunction under this pathophysiological state, which is associated with ventricular dysfunction and heart failure. METHODS: Myocardial tissue samples from patients with left ventricular heart failure, with either obesity or normal weight, were processed for the expression of SIRT3 and acetylation profile by Western Blot (WB). In addition, a rat model of obesity and metabolic syndrome induced by 30% (w/v) of sucrose was conducted. The WB analysis was used to determine the levels of mitochondrial expression of SIRT3, Adenine Nucleotide Translocator (ANT), CypD and the acetylation profile, as well as immunoprecipitation to establish the acetylation levels of CypD. Mitochondrial function was assessed by oxygen consumption analysis and maximum Ca2+ retention capacity. Oxidative stress was assessed by aconitase activity, protein carbonyl and thiol groups content. RESULTS: SIRT3 expression in the biopsies of the failing human hearts showed a 46% decrease in the expression levels of obese patients in comparison to the non-obese patients (p=0.0219). Remarkably, body mass index was associated with protein acetylation (0.627; p = 0.035), suggesting that the acetylation profiles of the failing hearts of obese patients are partly mediated by a reduction in SIRT3, which is also associated with higher BNP levels, indicating a more severe ventricular dysfunction (-0.636; p = 0.043). Accordingly, obese rats demonstrated a SIRT3 mitochondrial expression decrease of 22% concomitantly with a hyperacetylated mitochondrial profile, including CypD. Cardiac mitochondria from obese animals were 2.5-fold more prone to mPTP opening than the controls. CONCLUSION: Our results indicate that obesity reduces SIRT3 expression and that CypD hyperacetylation increases mPTP opening, suggesting that the activation of SIRT3 might be a potential target to decrease ventricular dysfunction and slow the progression of heart failure.


Assuntos
Mitocôndrias Cardíacas/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Obesidade/metabolismo , Sirtuína 3/metabolismo , Acetilação , Adulto , Idoso , Animais , Índice de Massa Corporal , Cálcio/metabolismo , Ciclofilinas/metabolismo , Feminino , Insuficiência Cardíaca/metabolismo , Humanos , Imunoprecipitação , Técnicas In Vitro , Masculino , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Translocases Mitocondriais de ADP e ATP/metabolismo , Consumo de Oxigênio/fisiologia , Ratos , Ratos Wistar
18.
Life Sci ; 234: 116780, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430453

RESUMO

Bronchial asthma and obesity are common health problems. Obesity is already responsible for 300,000 deaths per year. AIMS: The aim of the present study was to assess whether apocynin, alpha lipoic acid and probiotic administration in combination with low-fat diet supplementation influences the levels of antioxidant enzymes in the pulmonary tissues of obese asthmatic mice. MAIN METHODS: The study was performed on male C57/BL6 mice divided into 10 groups: (I) control; (II) asthma; (III) obesity; (IV) asthma + obesity; (V) asthma + obesity + apocynin p.o. 15 mg/kg/day for 12 weeks; (VI) asthma + obesity + low-fat diet for 12 weeks; (VII) asthma + obesity + low-fat diet for 12 weeks with apocynin p.o. 15 mg/kg/day; (VIII) asthma + obesity + low-fat diet with probiotics for 12 weeks; (IX) asthma + obesity + low-fat diet for 12 weeks with lipoic acid p.o. 100 mg/kg/day for 12 weeks; (X) asthma + obesity + standard diet with probiotics for 12 weeks. Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) activity were examined. The administration of apocynin alone and apocynin in combination with a low-fat diet resulted in a significant increase in SOD values (respectively p < 0.001; p = 0.010). Application of probiotics resulted in a decrease in CAT activity (p = 0.037) and an increase in GPx activity (p < 0.001) compared to obese asthmatic mice. The administration of lipoic acid resulted in an increase in GR activity (p = 0.024 vs. control). KEY FINDINGS: Supplementation containing apocynin, lipoic acid and probiotics has a positive influence on the antioxidant capacity of the pulmonary tissues of obese asthmatic mice. SIGNIFICANCE: These results may contribute to the development of new therapeutic approaches.


Assuntos
Acetofenonas/uso terapêutico , Antioxidantes/uso terapêutico , Asma/tratamento farmacológico , Obesidade/tratamento farmacológico , Probióticos/uso terapêutico , Ácido Tióctico/uso terapêutico , Animais , Asma/complicações , Asma/metabolismo , Catalase/análise , Catalase/metabolismo , Glutationa Peroxidase/análise , Glutationa Peroxidase/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/complicações , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Superóxido Dismutase/análise , Superóxido Dismutase/metabolismo
19.
J Agric Food Chem ; 67(36): 10107-10115, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31434473

RESUMO

We examined the antiobesity effect of a limonoid 7-deacetoxy-7-oxogedunin, named CG-1, purified from the seeds of Carapa guianensis, Meliaceae, known as andiroba in high-fat-diet (HFD)-fed mice. C57BL/6 mice were fed a low-fat diet or an HFD and orally administered CG-1 (20 mg/kg) for 7 weeks. CG-1 lowered the body weight gain and improved the serum triglyceride level and insulin sensitivity in HFD-fed mice. The expression level of the adipogenesis-related genes was lowered by CG-1 in the visceral white adipose tissue (vWAT). The mRNA expression level of the macrophage-related genes decreased in vWAT following the administration of CG-1 to HFD-fed mice. It is noteworthy that CG-1 activated the brown adipose tissue (BAT) with enhanced expression of uncoupling protein 1 and increased the rectal temperature in HFD-fed mice. These results indicate that the limonoid CG-1 decreased body weight gain and ameliorated hypertriglyceridemia and insulin resistance with the activation of BAT in HFD-fed mice.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Fármacos Antiobesidade/administração & dosagem , Resistência à Insulina , Limoninas/administração & dosagem , Meliaceae/química , Obesidade/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Tecido Adiposo Marrom/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Sementes/química , Triglicerídeos/sangue , Proteína Desacopladora 1/genética , Proteína Desacopladora 1/metabolismo , Ganho de Peso/efeitos dos fármacos
20.
J Appl Oral Sci ; 27: e20180365, 2019 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-31365708

RESUMO

OBJECTIVES: Visfatin is an adipokine that plays an important role in immune functions as a growth factor, enzyme, and pro-inflammatory mediator. We aimed to determine the levels of visfatin, interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) in gingival crevicular fluid (GCF) in both obese/non-obese patients, with/without generalized chronic periodontitis (GCP). METHODOLOGY: Patients were categorized as obese (O) (n=31) or non-obese (nO) (n=19). Groups were divided into four subgroups according to periodontal conditions: (1) periodontally healthy without obesity (nO-Ctrl); (2) GCP without obesity (nO-CP); (3) periodontally healthy with obesity (O-Ctrl); and (4) GCP with obesity (O-CP). Demographic variables, anthropometric and laboratory data were recorded. Periodontal parameters were measured at baseline and 3rd months after either non-surgical periodontal treatment or calorie -restricted diet therapy. At the same time, GCF samples were taken from patients to analyze TNF-alpha, IL-6,and visfatin levels. RESULTS: Periodontal parameters were significantly higher in the O group than in the nO group (P<0.05). IL-6 levels were higher in the O group than in the nO group (P<0.001). The visfatin levels of the obese patients were reduceddecreased following the treatments (P<0.05). Cholesterol levels were higher in the O group than in the nO groups (P<0.05). IL-6 levels were higher in O-CP and O-Ctrl groups than in the nO-Ctrl group (P<0.05). Compared to the other groups, visfatin levels were significantly higher in the O-CP group but decreased following treatment (P<0.05). CONCLUSIONS: Our findings suggest that visfatin and IL-6 levels in GCF are associated with the pathogenesis of obesity and periodontitis. Within the limits of this study, we considered that there might be an association between the lipid profile and periodontitis on systemically healthy individuals.


Assuntos
Citocinas/análise , Líquido do Sulco Gengival/química , Interleucina-6/análise , Nicotinamida Fosforribosiltransferase/análise , Obesidade/metabolismo , Periodontite/metabolismo , Fator de Necrose Tumoral alfa/análise , Adulto , Idoso , Biomarcadores/análise , Índice de Massa Corporal , Estudos de Casos e Controles , Citocinas/fisiologia , Feminino , Humanos , Interleucina-6/fisiologia , Masculino , Pessoa de Meia-Idade , Nicotinamida Fosforribosiltransferase/fisiologia , Índice Periodontal , Periodontite/diagnóstico por imagem , Radiografia Panorâmica , Valores de Referência , Estatísticas não Paramétricas , Fator de Necrose Tumoral alfa/fisiologia
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