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2.
Nat Med ; 24(7): 1070-1080, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29942096

RESUMO

Hepatic steatosis is a multifactorial condition that is often observed in obese patients and is a prelude to non-alcoholic fatty liver disease. Here, we combine shotgun sequencing of fecal metagenomes with molecular phenomics (hepatic transcriptome and plasma and urine metabolomes) in two well-characterized cohorts of morbidly obese women recruited to the FLORINASH study. We reveal molecular networks linking the gut microbiome and the host phenome to hepatic steatosis. Patients with steatosis have low microbial gene richness and increased genetic potential for the processing of dietary lipids and endotoxin biosynthesis (notably from Proteobacteria), hepatic inflammation and dysregulation of aromatic and branched-chain amino acid metabolism. We demonstrated that fecal microbiota transplants and chronic treatment with phenylacetic acid, a microbial product of aromatic amino acid metabolism, successfully trigger steatosis and branched-chain amino acid metabolism. Molecular phenomic signatures were predictive (area under the curve = 87%) and consistent with the gut microbiome having an effect on the steatosis phenome (>75% shared variation) and, therefore, actionable via microbiome-based therapies.


Assuntos
Diabetes Mellitus/genética , Metagenômica , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Animais , Células Cultivadas , Estudos de Coortes , Transplante de Microbiota Fecal , Feminino , Hepatócitos/metabolismo , Humanos , Metaboloma , Metabolômica , Camundongos , Microbiota , Fenótipo , Transcriptoma/genética
3.
Mol Nutr Food Res ; 62(10): e1800060, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29536615

RESUMO

SCOPE: Angiopoietin-like protein 4 (ANGPTL-4) regulates plasma lipoprotein levels, but its relevance in human obesity and type 2 diabetes (T2D) is largely unknown. We aim to investigate the regulation of circulating ANGPTL-4 levels in obesity, T2D, and after changes in body weight. METHODS AND RESULTS: Circulating ANGPTL-4 levels were measured in two different cohorts. First, in a cross-sectional study, we evaluated ANGPTL-4 levels in lean and obese patients with normoglycemia or with altered glucose tolerance (AGT; n = 282). Second, in a longitudinal intervention study, 51 obese participants were evaluated. A hypocaloric diet was prescribed, with follow-up 2 years later. ANGPTL-4 levels were significantly increased in obese patients with AGT compared to lean participants. Moreover, ANGPTL-4 was positively correlated with BMI, waist circumference, fat mass, HbA1c, HOMA-IR, fasting triglycerides, and with inflammatory markers. Participants gaining weight after the follow-up showed increased ANGPTL-4 levels in parallel to increased BMI, fat mass, and fasting glucose, while ANGPTL-4 levels were reduced in participants losing weight. CONCLUSION: Our data support a relevant role of ANGPTL-4 in human obesity and its involvement in long-term body weight changes.


Assuntos
Proteína 4 Semelhante a Angiopoietina/sangue , Diabetes Mellitus Tipo 2/sangue , Obesidade/sangue , Adulto , Peso Corporal , Estudos Transversais , Feminino , Intolerância à Glucose , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/dietoterapia , Circunferência da Cintura , Perda de Peso
4.
Clin Nutr ; 37(6 Pt A): 2091-2096, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29050649

RESUMO

BACKGROUND & AIMS: Increased iron stores significantly influence the clinical course of several chronic metabolic diseases. Recent studies have shown that iron overload decreases osteocalcin. We aimed to explore the relationship among osteocalcin, iron stores and insulin sensitivity. METHODS: Extensive clinical and laboratory measurements, including serum ferritin, cross-linked C-telopeptide of type I collagen (CTX) and osteocalcin (OC) concentrations, were analyzed in 250 adult consecutive Caucasian men. Insulin sensitivity was evaluated through frequently sampled intravenous glucose tolerance tests with minimal model analysis. RESULTS: Circulating serum ferritin were negatively associated with serum OC and CTX (p = 0.004 and p = 0.045 respectively). In all subjects as a whole, BMI and ferritin contributed to explain 5.2% of OC variance after controlling for age and smoking status. However, the association between OC and insulin sensitivity remained significant only in lean subjects (BMI < 25 kg/m2, r = 0.468; p = 0.006) whereas the link between serum ferritin concentration and OC and CTX were significant only in overweight/obese subjects (BMI ≥ 25 kg/m2, r = -0.229; p = 0.002 and r = -0.196; p = 0.008, respectively). CONCLUSIONS: The association of circulating osteocalcin with parameters of insulin sensitivity and iron stores were dependent on obesity status. Increased iron stores could contribute to the detrimental metabolic effects of overweight and obesity on bone.


Assuntos
Ferritinas/sangue , Resistência à Insulina/fisiologia , Obesidade , Osteocalcina/sangue , Adulto , Estudos Transversais , Humanos , Ferro/sangue , Sobrecarga de Ferro , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/epidemiologia , Espanha/epidemiologia
5.
FASEB J ; 31(10): 4482-4491, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28646016

RESUMO

Subclinical hypothyroidism is known to be associated with increased serum cholesterol. Since thyroid-stimulating hormone (TSH) exerts an inductor effect on cholesterol biosynthesis, we aimed to investigate the relationship between TSH mRNA and cholesterol metabolism in human adipose tissue (AT). Cross-sectionally, AT TSH-ß (TSHB) mRNA was evaluated in 4 independent cohorts in association with serum total and LDL cholesterol, and AT lipidomics. Longitudinally, the effects of statins and of diet and exercise on AT TSHB mRNA were also examined. The bidirectional relationship between cholesterol and TSHB were studied in isolated human adipocytes. TSHB mRNA was consistently detected in AT from euthyroid subjects, and positively associated with serum total- and LDL-cholesterol, and with AT-specific cholesterol metabolism-associated lipids [arachidonoyl cholesteryl ester, C8-dihydroceramide, N-stearoyl-d-sphingosine, and GlcCer(18:0, 24:1)]. Reduction of cholesterol with statins and with diet and exercise interventions led to decreased TSHB mRNA in human AT, whereas excess cholesterol up-regulated TSHB mRNA in human adipocytes. In addition, recombinant human TSH α/ß administration resulted in increased HMGCR mRNA levels in human adipocytes. In mice, subcutaneous AT Tshb expression levels correlated directly with circulating cholesterol levels. In summary, current results provide novel evidence of TSHB as a paracrine factor that is modulated in parallel with cholesterol metabolism in human AT.-Moreno-Navarrete, J. M., Moreno, M., Ortega, F., Xifra, G., Hong, S., Asara, J. M., Serrano, J. C. E., Jové, M., Pissios, P., Blüher, M., Ricart, W., Portero-Otin, M., Fernández-Real, J. M. TSHB mRNA is linked to cholesterol metabolism in adipose tissue.


Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Metabolismo dos Lipídeos/fisiologia , Lipídeos/sangue , Tireotropina Subunidade beta/genética , Tireotropina/metabolismo , Animais , Colesterol/metabolismo , Humanos , Hipotireoidismo/metabolismo , Camundongos
6.
Nat Med ; 23(7): 850-858, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530702

RESUMO

Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4 months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla, and many of the metformin-regulated genes in these species encoded metalloproteins or metal transporters. Our findings provide support for the notion that altered gut microbiota mediates some of metformin's antidiabetic effects.


Assuntos
DNA Bacteriano/análise , Diabetes Mellitus Tipo 2/tratamento farmacológico , Microbioma Gastrointestinal/genética , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Animais , Ácidos e Sais Biliares/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Método Duplo-Cego , Ácidos Graxos Voláteis/metabolismo , Transplante de Microbiota Fecal , Fezes/química , Fezes/microbiologia , Feminino , Vida Livre de Germes , Teste de Tolerância a Glucose , Humanos , Técnicas In Vitro , Masculino , Metagenômica , Camundongos , Pessoa de Meia-Idade
7.
Clin Nutr ; 36(5): 1434-1439, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-27745814

RESUMO

BACKGROUND & AIMS: Serum hepcidin concentration is known to increase in parallel to circulating markers of iron stores. We aimed to investigate whether this is reflected at the tissue level in subjects with obesity. METHODS: Serum hepcidin and ferritin levels (ELISA) and hepatic iron content (using magnetic resonance imaging) were analyzed longitudinally in 44 participants (19 without obesity and 25 with obesity). In a subgroup of 16 participants with obesity, a weight loss intervention was performed. RESULTS: Serum hepcidin, ferritin and hepatic iron content (HIC) were significantly increased in participants with obesity. Age- and gender-adjusted serum hepcidin was positively correlated with BMI, hsCRP, ferritin and HIC. In addition, age- and gender-adjusted serum hepcidin was positively correlated with ferritin and HIC in both non-obese and obese participants. In multivariate regression analysis, hepatic iron content (p < 0.01) and serum ferritin (p < 0.001) contributed independently to circulating hepcidin concentration variation after controlling for age, gender, BMI and hsCRP. Diet intervention-induced weight loss led to decreased serum hepcidin (p = 0.01), serum ferritin concentration (p = 0.01) and HIC (p = 0.002). Of note, the percent change of serum hepcidin strongly correlated with the percent change of serum ferritin (r = 0.69, p = 0.01) and HIC (r = 0.61, p = 0.03) even after controlling for age and gender. CONCLUSIONS: Serum hepcidin is a reliable marker of the hepatic iron content in subjects with obesity.


Assuntos
Hepcidinas/sangue , Ferro/química , Fígado/química , Obesidade/sangue , Adulto , Biomarcadores/sangue , Índice de Massa Corporal , Proteína C-Reativa/química , Estudos Transversais , Dieta Redutora/efeitos adversos , Feminino , Ferritinas/sangue , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Perda de Peso
8.
Mol Nutr Food Res ; 60(7): 1673-83, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27059147

RESUMO

SCOPE: Changes in genetic variations affecting the taste receptor, type 2, member 38 (TAS2R38) may identify the interacting mechanism leading to obesity and potential associations with proteins partaking in innate immunity, such as surfactant protein D (SPD) and mannan-binding lectin (MBL). METHODS AND RESULTS: We evaluated haplotypes of the bitter-taste receptor TAS2R38 in an identification sample of 210 women in different weight conditions, including anorexia nervosa and obesity. The association with SPD and MBL was tested in an independent sample picturing general population (n = 534). The relationship with obesity was validated in an extended final sample of 1319 participants. In the sample comprised of women in extreme weight conditions, increased obesity was identified in AVI/AVI subjects (OR = 2.5 [1.06-6.11], p = 0.035). In the sample picturing general population, increased SPD and MBL concentrations were found in nonsmoking AVI carriers. In this cohort, smoking and obesity blunted associations between TAS2R38 haplotypes and SPD and MBL. In the extended sample, the association of AVI/AVI haplotypes with increased obesity was also identified (OR = 1.4 [0.99/1.85], p = 0.049), being more robust in subjects aged <40 years (OR = 1.9 [1.06/3.42], p = 0.031). CONCLUSION: Current data reinforce the impact of TAS2R38 gene on phenotypic and clinical outputs affecting obesity, showing significant associations with extreme weight conditions (i.e., obesity and anorexia nervosa), and changes in both olfactory capacity and immune traits.


Assuntos
Imunidade Inata/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas-G/genética , Adolescente , Adulto , Idoso , Índice de Massa Corporal , Peso Corporal , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Haplótipos , Humanos , Masculino , Lectina de Ligação a Manose/genética , Pessoa de Meia-Idade , Proteína D Associada a Surfactante Pulmonar/genética , Fumar , Paladar , Adulto Jovem
9.
Diabetologia ; 59(4): 822-32, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26831303

RESUMO

AIMS/HYPOTHESIS: We aimed to investigate the potential mechanisms involved in the compromised adipogenesis of visceral (VAT) vs subcutaneous adipose tissue (SAT) using comparative metabolomics. Based on the differentially identified metabolites, we focused on the relationship between the active form of vitamin B6 (pyridoxal 5-phosphate [PLP]), known to be generated through pyridoxal kinase (PDXK), and adipogenesis. METHODS: Non-targeted metabolomics analyses were performed in paired VAT and SAT (n = 14, discovery cohort). PDXK gene expression was evaluated in two validation cohorts of paired SAT and VAT samples in relation to obesity status and insulin sensitivity, and mechanistically after weight loss in vivo and in 3T3-L1 cells in vitro. RESULTS: Comparative metabolomics showed that PLP was significantly decreased in VAT vs SAT. Concordantly, PDXK mRNA levels were significantly decreased in VAT vs SAT, specifically in adipocytes. The decrease was specially marked in obese individuals. PDXK mRNA levels showed a strong association with adipogenic, lipid-droplet-related and lipogenic genes. At a functional level, systemic insulin sensitivity positively associated with PDXK expression, and surgically-induced weight loss (improving insulin sensitivity) led to increased SAT PDXK mRNA levels in parallel with adipogenic genes. In human pre-adipocytes, PDXK mRNA levels increased during adipocyte differentiation and after administration of peroxisome proliferator-activated receptor-γ agonists, and decreased under inflammatory stimuli. Mechanistic studies in 3T3-L1 cells showed that PLP administration resulted in increased adipogenic mRNA markers during early adipogenesis, whereas the PLP antagonist 4-deoxypyridoxine exerted opposite effects. CONCLUSIONS/INTERPRETATION: Overall, these results support the notion that in situ production of PLP is required for physiological adipogenesis.


Assuntos
Tecido Adiposo/metabolismo , Metabolômica/métodos , Piridoxal Quinase/metabolismo , Células 3T3-L1 , Adipócitos/metabolismo , Adipogenia/genética , Adipogenia/fisiologia , Adulto , Animais , Feminino , Humanos , Resistência à Insulina , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/metabolismo , Gordura Subcutânea/metabolismo , Vitamina B 6/metabolismo
11.
J Breath Res ; 10(1): 016001, 2016 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-26824193

RESUMO

Anaesthetic gases and disinfectants are a primary source of air contamination in hospitals. A highly sensitive sorbent-trap methodology has been used to analyse exhaled breath samples with detection limits in the pptv range, which allows volatile organic compounds (VOCs) to be detected at significantly lower levels (5-6 orders of magnitude below) than the recommended exposure limits by different organizations. Two common VOCs used in hospital environments, isopropyl alcohol (IPA) and sevoflurane, have been evaluated. Forced-expiratory breath samples were obtained from 100 volunteers (24 hospital staff, 45 hospital visitors and 31 external controls). Significant differences for IPA were found between samples from volunteers who had not been in contact with hospital environments (mean value of 8.032 ppbv) and people staying (20.981 ppbv, p = 0.0002) or working (19.457 ppbv, p = 0.000 09) in such an environment. Sevoflurane, an anaesthetic gas routinely used as an inhaled anaesthetic, was detected in all samples from volunteers in the hospital environment but not in volunteers who had not been in recent contact with a hospital environment. The levels of sevoflurane were significantly higher (p = 0.000 24) among staff members (0.522 ppbv) than among visitors to the hospital (0.196 ppbv). We conclude that highly sensitive methods are required to detect anaesthetic gas contamination in hospital environments.


Assuntos
2-Propanol/análise , Poluentes Ocupacionais do Ar/análise , Anestésicos Inalatórios/análise , Éteres Metílicos/análise , Compostos Orgânicos Voláteis/análise , Adulto , Líquidos Corporais/química , Testes Respiratórios/métodos , Expiração , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sevoflurano
12.
J Clin Endocrinol Metab ; 101(3): 1282-9, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26765579

RESUMO

CONTEXT: Different genetic and imaging iron markers are known to be increased in the liver, adipose tissue, and brain of obese subjects. OBJECTIVE: We aimed to investigate these markers in human skeletal muscle. DESIGN, SETTING, PATIENTS, AND OUTCOME MEASURES: Markers of iron accumulation were measured in three different territories: Iron gene markers (TFRC1, TF, SLC11A2, FTL, FTH1, and SLC40A1) were studied in abdominal rectus abdominis (Cohort 1, n = 26) and quadriceps (Cohort 2, n = 13) muscle using real-time PCR, whereas paravertebral muscle R2* signal (as surrogate of iron content) (Cohort 3, n = 43) was evaluated by means of magnetic resonance imaging. INTERVENTION: In a subgroup of 14 obese participants from Cohort 3, a diet-induced weight loss was performed. RESULTS: Rectus abdominis muscle age-adjusted gene expression of SLC40A1 (ferroportin) (r = 0.47; P = .04), SLC11A2 (r = 0.50; P = .03) and CYBA (r = 0.62; P = .006) increased with body fatness. In obese participants from Cohort 1, muscle CYBA gene expression was positively correlated with serum ferritin. This association was replicated in quadriceps from obese participants (Cohort 2). Paravertebral muscle R2* was positively associated with body mass index, waist circumference, and fat mass (measured by dual-energy x-ray absorptiometry) in parallel with hepatic iron content, serum ferritin, and hepcidin. In multivariate regression analyses, obesity parameters (P < .0001) and hsCRP concentration (P < .05) contributed independently to the variance of sex-, serum hepcidin- and age-adjusted muscle R2*. Of note, weight loss intervention resulted in decreased muscle R2* (P = .02) in correlation with the change of serum ferritin (r = 0.69; P = .01). CONCLUSIONS: These findings emphasize a significant iron accumulation in human skeletal muscle in association with obesity. The mechanisms implicated in these observations should be studied further.


Assuntos
Biomarcadores/metabolismo , Ferro/metabolismo , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/metabolismo , Adiposidade/genética , Adulto , Idoso , Estudos de Casos e Controles , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Estudos Transversais , Diagnóstico por Imagem , Dieta Redutora , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Obesidade/dietoterapia
13.
Obesity (Silver Spring) ; 24(2): 352-8, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26813526

RESUMO

OBJECTIVE: Circulating and adipose tissue markers of iron overload are increased in subjects with obesity. The aim is to study iron signals in adipose tissue. METHODS: Adipose tissue R2* values and hepatic iron concentration (HIC) were evaluated using magnetic resonance imaging (MRI) in 23 middle-aged subjects with obesity and 20 subjects without obesity. RESULTS: Subcutaneous (SAT) and visceral adipose tissue (VAT) R2* were increased in subjects with obesity (P = 0.004 and P = 0.008) and correlated significantly and positively with HIC in all subjects. Strikingly, most of the associations of liver iron with metabolic parameters were replicated with SAT and VAT R2*. BMI, waist circumference, fat mass, HOMA value, and C-reactive protein positively correlated with HIC and SAT and VAT R2*. BMI or percent fat mass (but not insulin resistance) contributed independently to 26.8-34.8% of the variance in sex- and age-adjusted SAT or VAT R2* (ß > 0.40, P < 0.005). Within subjects with obesity, total cholesterol independently contributed to 14.8% of sex- and age-adjusted VAT iron variance (ß = 0.50, P = 0.025). CONCLUSIONS: Increased R2* in adipose tissue, which might indicate iron content, runs in parallel to liver iron stores of subjects with obesity. VAT iron seems also associated with serum cholesterol within subjects with obesity.


Assuntos
Tecido Adiposo/metabolismo , Ferritinas/metabolismo , Resistência à Insulina , Sobrecarga de Ferro/metabolismo , Obesidade/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Biomarcadores/metabolismo , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade
14.
Surg Obes Relat Dis ; 12(2): 357-62, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26525371

RESUMO

BACKGROUND: Adipose tissue of obese subjects is known to exhibit increased inflammatory activity linked to altered expression of factors involved in glucose and lipid metabolism. The surgical procedure constitutes an injury per se, evoking a systemic inflammatory response. OBJECTIVE: To evaluate changes in the expression of key-genes in adipose tissue after common surgical procedures performed in obese patients. SETTING: A tertiary hospital. METHODS: Paired subcutaneous (SAT) and visceral (VAT) adipose tissue samples were collected at the beginning and the end of surgery in 33 obese patients that underwent laparoscopic Roux-en-Y gastric bypass (RYGB, n = 17) or laparoscopic vertical sleeve gastrectomy (SG, n = 16). The expression of genes involved in inflammation, glucose and lipid metabolism was assessed. RESULTS: The surgical procedure led to increased expression of interleukin 6, interleukin 8 (P<.0001 in both depots), tumor necrosis factor α (P = .001 in SAT), and lipopolysaccharide binding protein (P = .0004 in VAT). Surgery also induced concomitant decreased expression of GLUT4, IRS1 (P = .046 in VAT), and adiponectin, whereas the messenger RNA of lipogenic genes [fatty acid synthase (P = .024); sterol regulatory element binding transcription factor 1 (P = .011) and aquaporin 9 (P<.0001) in SAT; and PPARγ (P = .018) and solute carrier family 27 (fatty acid transporter), member 2 (P = .028) in VAT] increased in parallel to inflammation. Changes in gene expression during surgery were enhanced in patients following RYGB, when compared with SG. CONCLUSIONS: Bariatric surgery acutely changes the expression of inflammatory and lipogenic genes in adipose tissue. This information should be considered cautiously when designing studies to assess adipose tissue gene expression in morbidly obese patients. The same timing of sampling is mandatory.


Assuntos
Cirurgia Bariátrica , Citocinas/genética , Regulação da Expressão Gênica , Inflamação/genética , Obesidade Mórbida/cirurgia , RNA Mensageiro/genética , Gordura Subcutânea/metabolismo , Citocinas/biossíntese , Feminino , Humanos , Inflamação/metabolismo , Metabolismo dos Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/genética , Obesidade Mórbida/metabolismo , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real
15.
Clin Endocrinol (Oxf) ; 84(5): 756-63, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26406918

RESUMO

OBJECTIVE: Rodent models have found that osteocalcin crosses the blood-brain barrier and regulates behaviour. No data are available on osteocalcin's effects on brain microstructure and cognitive performance in humans. We evaluated the association between serum osteocalcin concentrations and (i) brain microstructural changes on magnetic resonance imaging (MRI) and (ii) neuropsychological performance. DESIGN, PATIENTS AND MEASUREMENTS: We studied 24 consecutive obese subjects (13 women; age, 49·8 ± 8·1 years; body mass index [BMI], 43·9 ± 4·54 kg/m(2) ) and 20 healthy volunteers (10 women; age, 48·8 ± 9·5 years; BMI, 24·3 ± 3·54 kg/m(2) ) in a cross-sectional study within the multicentre FLORINASH Project. FLAIR signal intensity and DTI-metrics (primary (λ1 ), secondary (λ2 ) and tertiary (λ3 ) eigenvalues; fractional anisotropy (FA); and mean diffusivity) in the caudate, hypothalamus, thalamus and putamen, and in subcortical white matter were assessed. Cognitive performance evaluated by neuropsychological test battery. RESULTS: Lower osteocalcin concentrations were associated with BMI, higher λ1, λ2 and λ3 values at the caudate and lower FLAIR signal intensity at the caudate and putamen. Obese patients with lower osteocalcin concentrations had higher FA at putamen and thalamus. Lower osteocalcin concentrations were associated with higher Iowa Gambling Task (IGT) scores. FLAIR signal intensity at the caudate <601·832 yielded 85·7% sensitivity, 64·3% specificity, 70·6% negative predictive value and 81·8% positive predictive value for IGT score. Lower osteocalcin was an independent predictor of worse cognitive performance on multivariate analysis (F = 3·551, P = 0·01343; R(2) = 0·103). Bayesian information criterion demonstrated that osteocalcin had the predominant role in predicting IGT score. CONCLUSIONS: Lower serum osteocalcin concentrations are associated with brain microstructural changes and worse cognitive performance.


Assuntos
Encéfalo/fisiopatologia , Cognição/fisiologia , Obesidade/sangue , Osteocalcina/sangue , Adulto , Anisotropia , Teorema de Bayes , Índice de Massa Corporal , Encéfalo/patologia , Estudos Transversais , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Testes Neuropsicológicos , Obesidade/fisiopatologia , Obesidade/psicologia , Valor Preditivo dos Testes
16.
Obesity (Silver Spring) ; 24(1): 139-47, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26692580

RESUMO

OBJECTIVE: To investigate CISD1 mRNA and protein in human adipose tissue in association with obesity and adipogenesis. METHODS: Subcutaneous (SAT) and visceral (VAT) adipose tissue CISD1 gene expression (real-time PCR) and protein (Western blot) levels were investigated in human adipose tissue and during human adipocyte differentiation. RESULTS: SAT and VAT CISD1 mRNA and protein levels were significantly decreased in subjects with obesity and negatively correlated with BMI after controlling for age and sex. In participants with morbid obesity, VAT CISD1 gene expression was positively correlated with insulin sensitivity (r = 0.47, P = 0.01), and bariatric surgery-induced weight loss led to increased SAT CISD1 mRNA levels. In both VAT and SAT, CISD1 gene expression was significantly associated with SIRT1, ISCA2, and mitochondrial biogenesis-related (PPARGC1A, TFAM, and MT-CO3) and browning-related (PRDM16 and UCP1) gene expression. In addition, VAT CISD1 gene expression was significantly associated with adipogenic and iron metabolism-related genes. Importantly, these correlations were replicated in a second cohort. At the cellular level, CISD1 gene expression increased during human adipocyte differentiation in correlation with adipogenic genes (r > 0.60, P < 0.005). CONCLUSIONS: These data suggest a possible role of CISD1 in obesity-associated dysfunctional adipogenesis in human VAT.


Assuntos
Adipogenia/genética , Gordura Intra-Abdominal/metabolismo , Proteínas Mitocondriais/genética , Obesidade/genética , Tecido Adiposo/metabolismo , Adulto , Idoso , Cirurgia Bariátrica , Índice de Massa Corporal , Diferenciação Celular/genética , Células Cultivadas , Estudos de Coortes , Feminino , Expressão Gênica , Humanos , Resistência à Insulina/genética , Gordura Intra-Abdominal/patologia , Masculino , Pessoa de Meia-Idade , Proteínas Mitocondriais/metabolismo , Obesidade/metabolismo , Obesidade/patologia , Obesidade/cirurgia
17.
Atherosclerosis ; 243(2): 493-8, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26520905

RESUMO

BACKGROUND AND AIMS: Obesity is an important determinant of increased cardiovascular risk. Increased fat mass has been assumed to constitute the main prominent contributor to changes in carotid intima-media thickness (c-IMT). METHODS: In 421 consecutive subjects (301 women), c-IMT was evaluated ultrasonographically in 6 independent territories and body composition was assessed by dual-energy X-ray absorptiometry. RESULTS: c-IMT was positively associated with lean body mass in both men (r = 0.328, p = <0.0001) and women (r = 0.268 p = <0.0001) and increased across lean mass quartiles (p = <0.0001 for linear-trend ANOVA). Stepwise linear regression analysis showed that age and lean mass (but not fat mass or traditional cardiovascular risk factors) contributed to 46.2% of c-IMT variance in men (p = <0.0001). Even within obese men, lean mass was an independent contributor to c-IMT variance. Among women, age, lean mass and ultrasensitive CRP levels contributed independently to 47.7% of c-IMT variance (p < 0.0001). CONCLUSIONS: Lean mass, and not fat mass, might contribute to increase c-IMT in obese patients independently of classical atherosclerotic risk factors. These data reinforce the concept that the increase in metabolically fat-free mass that accompanies the body weight enlargement is closely related to the raise in blood pressure.


Assuntos
Composição Corporal , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/etiologia , Espessura Intima-Media Carotídea , Obesidade/complicações , Absorciometria de Fóton , Adiposidade , Adulto , Fatores Etários , Doenças das Artérias Carótidas/diagnóstico por imagem , Estudos Transversais , Feminino , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/fisiopatologia , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Fatores Sexuais
18.
Sci Rep ; 5: 14600, 2015 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-26455903

RESUMO

The human intestine is home to a diverse range of bacterial and fungal species, forming an ecological community that contributes to normal physiology and disease susceptibility. Here, the fungal microbiota (mycobiome) in obese and non-obese subjects was characterized using Internal Transcribed Spacer (ITS)-based sequencing. The results demonstrate that obese patients could be discriminated by their specific fungal composition, which also distinguished metabolically "healthy" from "unhealthy" obesity. Clusters according to genus abundance co-segregated with body fatness, fasting triglycerides and HDL-cholesterol. A preliminary link to metabolites such as hexadecanedioic acid, caproic acid and N-acetyl-L-glutamic acid was also found. Mucor racemosus and M. fuscus were the species more represented in non-obese subjects compared to obese counterparts. Interestingly, the decreased relative abundance of the Mucor genus in obese subjects was reversible upon weight loss. Collectively, these findings suggest that manipulation of gut mycobiome communities might be a novel target in the treatment of obesity.


Assuntos
Microbioma Gastrointestinal/genética , Intestinos/microbiologia , Mucor/crescimento & desenvolvimento , Obesidade/microbiologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Aspergillus/classificação , Aspergillus/genética , Aspergillus/crescimento & desenvolvimento , Glicemia/metabolismo , Candida/classificação , Candida/genética , Candida/crescimento & desenvolvimento , Caproatos/sangue , Estudos de Casos e Controles , HDL-Colesterol/sangue , DNA Intergênico/genética , Jejum , Feminino , Glutamatos/sangue , Humanos , Intestinos/patologia , Masculino , Pessoa de Meia-Idade , Mucor/classificação , Mucor/genética , Técnicas de Tipagem Micológica , Obesidade/patologia , Ácidos Palmíticos/sangue , Penicillium/classificação , Penicillium/genética , Penicillium/crescimento & desenvolvimento , Saccharomyces/classificação , Saccharomyces/genética , Saccharomyces/crescimento & desenvolvimento , Análise de Sequência de DNA , Triglicerídeos/sangue
19.
Mol Nutr Food Res ; 59(12): 2460-70, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26394887

RESUMO

SCOPE: Very few studies have evaluated serum hepcidin in patients with type 2 diabetes and they have reported conflicting results. In addition, the effect of antidiabetic drugs on circulating hepcidin has not been explored so far. The aims of the study were to evaluate hepcidin concentrations and hepcidin/ferritin ratio in type 2 diabetes subjects and healthy non-diabetic controls and to evaluate the effect of metformin on hepcidin concentrations. METHODS AND RESULTS: Study 1: Cross-sectional multivariate study of 239 non-diabetic individuals and 65 people with type 2 diabetes. The multivariate analysis included covariates of chronic inflammation, BMI, pharmacological treatment, menopausal status and insulin resistance. Study 2: Randomized, double-blinded, placebo-controlled 4-month trial metformin compared to placebo among 36 type 2 diabetic patients. In both groups diet was controlled by maintaining a hypocaloric intake across the trial. Hepcidin levels were significantly lower in patients with type 2 diabetes than in non-diabetic individuals either in crude or adjusted regression models (P<0.05). Hepcidin decreased in both arms of the trial (Placebo, p = 0.004; metformin, p = 0.022). CONCLUSION: Circulating hepcidin was significantly and independently lower in type 2 diabetes. Metformin treatment is not associated with reductions in hepcidin but hypocaloric diet could be involved.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hepcidinas/sangue , Hipoglicemiantes/uso terapêutico , Metformina/uso terapêutico , Adulto , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Feminino , Ferritinas/sangue , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Análise Multivariada
20.
J Clin Endocrinol Metab ; 100(11): E1467-76, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26252355

RESUMO

CONTEXT: Molecular mechanisms associated with physiological variations in adipose tissue (AT) are not fully recognized. The most recent reports highlight the critical relevance of microRNAs (miRNAs) found in AT. OBJECTIVE: To identify changes in messenger RNA (mRNA) and miRNA expressions and their interaction in human AT before and after surgery-induced weight loss. Research Design and Setting: Genome-wide mRNA and miRNA expressions were assessed by microarrays in abdominal subcutaneous AT of 16 morbidly obese women before and 2 years after laparoscopic Roux-en-Y gastric bypass. The association of changes in miRNAs with their respective mRNA targets was studied. The results were replicated in publicly available microarray datasets. Validation was made by real-time polymerase chain reaction in additional fat samples from 26 age-matched lean women and in isolated human adipocytes. RESULTS: A total of 5018 different mRNA probe sets and 15 miRNAs were differentially expressed after surgery-induced weight loss. The clustering of similar expression patterns for gene products with related functions revealed molecular footprints that elucidate significant changes in cell cycle, development, lipid metabolism, and the inflammatory response. The participation of inflammation was demonstrated by results assessed in isolated adipocytes. Interestingly, when transcriptomes were analyzed taking into account the presence of miRNA target sites, miRNA target mRNAs were upregulated in obese AT (P value = 2 × 10(-181)) and inflamed adipocytes (P value = 4 × 10(-61)), according to the number of target sites harbored by each transcript. CONCLUSIONS: Current findings suggest impaired miRNA target gene expression in obese AT in close association with inflammation, both improving after weight loss.


Assuntos
Regulação para Baixo , Derivação Gástrica , MicroRNAs/metabolismo , Obesidade Mórbida/cirurgia , Gordura Subcutânea Abdominal/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/imunologia , Adipócitos Brancos/metabolismo , Adulto , Índice de Massa Corporal , Linhagem Celular , Células Cultivadas , Estudos de Coortes , Estudos Transversais , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Estudos Longitudinais , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Obesidade Mórbida/genética , Obesidade Mórbida/imunologia , Obesidade Mórbida/metabolismo , RNA Mensageiro/metabolismo , Gordura Subcutânea Abdominal/imunologia , Perda de Peso
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