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1.
Nat Commun ; 12(1): 2388, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33888702

RESUMO

To unravel the pathogenesis of obesity and its complications, we investigate the interplay between circadian clocks and NF-κB pathway in human adipose tissue. The circadian clock function is impaired in omental fat from obese patients. ChIP-seq analyses reveal that the core clock activator, BMAL1 binds to several thousand target genes. NF-κB competes with BMAL1 for transcriptional control of some targets and overall, BMAL1 chromatin binding occurs in close proximity to NF-κB consensus motifs. Obesity relocalizes BMAL1 occupancy genome-wide in human omental fat, thereby altering the transcription of numerous target genes involved in metabolic inflammation and adipose tissue remodeling. Eventually, clock dysfunction appears at early stages of obesity in mice and is corrected, together with impaired metabolism, by NF-κB inhibition. Collectively, our results reveal a relationship between NF-κB and the molecular clock in adipose tissue, which may contribute to obesity-related complications.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Relógios Circadianos/imunologia , Gordura Intra-Abdominal/patologia , NF-kappa B/metabolismo , Obesidade/complicações , Adipócitos/imunologia , Adipócitos/metabolismo , Adiponectina/genética , Adulto , Animais , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Sequenciamento de Cromatina por Imunoprecipitação , Relógios Circadianos/genética , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/imunologia , Inflamação/patologia , Gordura Intra-Abdominal/imunologia , Masculino , Células-Tronco Mesenquimais , Camundongos Transgênicos , Pessoa de Meia-Idade , Obesidade/imunologia , Obesidade/metabolismo , Obesidade/patologia , Omento/imunologia , Omento/patologia , Proteínas Circadianas Period/genética , Cultura Primária de Células , Transcrição Genética
2.
Int J Mol Sci ; 22(6)2021 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-33801130

RESUMO

It was suggested that the epigenetic alterations of the placenta are associated with obesity, as well as the delivery mode. This study aimed to assess the effect of maternal outcome and delivery procedure on global placental DNA methylation status, as well as selected 5'-Cytosine-phosphate-Guanine-3' (CpG) sites in ADIPOQ and LEP genes. Global DNA methylation profile in the placenta was assessed using the 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) ratio evaluated with the ELISA, followed by target gene methylation patterns at selected gene regions which were determined using methylation-specific qPCR in 70 placentas from healthy, pregnant women with single pregnancy. We found no statistically significant differences in 5-mC/5-hmC ratio between intrapartum cesarean sections (CS) and vaginal deliveries (p = 0.214), as well as between elective cesarean sections and vaginal deliveries (p = 0.221). In intrapartum cesarean sections, the ADIPOQ demethylation index was significantly higher (the average: 1.75) compared to elective cesarean section (the average: 1.23, p = 0.010) and vaginal deliveries (the average: 1.23, p = 0.011). The LEP demethylation index did not significantly differ among elective CS, intrapartum CS, and vaginal delivery groups. The demethylation index of ADIPOQ correlated negatively with LEP in the placenta in the vaginal delivery group (r = -0.456, p = 0.017), but not with the global methylation. The methylation of a singular locus might be different depending on the mode of delivery and uterine contractions. Further studies should be conducted with locus-specific analysis of the whole genome to detect the methylation index of specific genes involved in metabolism.


Assuntos
5-Metilcitosina/análogos & derivados , 5-Metilcitosina/metabolismo , Adiponectina/genética , Metilação de DNA , Leptina/genética , Placenta/metabolismo , Adiponectina/metabolismo , Parto Obstétrico , Epigênese Genética , Feminino , Regulação da Expressão Gênica , Loci Gênicos , Humanos , Leptina/metabolismo , Gravidez
3.
Int J Mol Sci ; 22(6)2021 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-33803685

RESUMO

Cachexia is a multifactorial syndrome characterized by muscle loss that cannot be reversed by conventional nutritional support. To uncover the molecular basis underlying the onset of cancer cachectic muscle wasting and establish an effective intervention against muscle loss, we used a cancer cachectic mouse model and examined the effects of aerobic exercise. Aerobic exercise successfully suppressed muscle atrophy and activated adiponectin signaling. Next, a cellular model for cancer cachectic muscle atrophy using C2C12 myotubes was prepared by treating myotubes with a conditioned medium from a culture of colon-26 cancer cells. Treatment of the atrophic myotubes with recombinant adiponectin was protective against the thinning of cells through the increased production of p-mTOR and suppression of LC3-II. Altogether, these findings suggest that the activation of adiponectin signaling could be part of the molecular mechanisms by which aerobic exercise ameliorates cancer cachexia-induced muscle wasting.


Assuntos
Adiponectina/metabolismo , Caquexia/complicações , Caquexia/metabolismo , Atrofia Muscular/complicações , Atrofia Muscular/metabolismo , Condicionamento Físico Animal , Transdução de Sinais , Adiponectina/genética , Animais , Linhagem Celular Tumoral , Meios de Cultivo Condicionados/farmacologia , Modelos Animais de Doenças , Feminino , Camundongos Endogâmicos BALB C , Proteínas Associadas aos Microtúbulos/metabolismo , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Fosforilação/efeitos dos fármacos , Biossíntese de Proteínas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas Recombinantes/farmacologia
4.
Int J Mol Sci ; 22(8)2021 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-33920997

RESUMO

Deregulation of adiponectin is found in systemic autoimmune rheumatic diseases (SARDs). Its expression is downregulated by various inflammatory mediators, but paradoxically, elevated serum levels are present in SARDs with high inflammatory components, such as rheumatoid arthritis and systemic lupus erythematosus. Circulating adiponectin is positively associated with radiographic progression in rheumatoid arthritis as well as with cardiovascular risks and lupus nephritis in systemic lupus erythematosus. However, in SARDs with less prominent inflammation, such as systemic sclerosis, adiponectin levels are low and correlate negatively with disease activity. Regulators of adiponectin gene expression (PPAR-γ, Id3, ATF3, and SIRT1) and inflammatory cytokines (interleukin 6 and tumor necrosis factor α) are differentially expressed in SARDs and could therefore influence total adiponectin levels. In addition, anti-inflammatory therapy could also have an impact, as tocilizumab treatment is associated with increased serum adiponectin. However, anti-tumor necrosis factor α treatment does not seem to affect its levels. Our review provides an overview of studies on adiponectin levels in the bloodstream and other biological samples from SARD patients and presents some possible explanations why adiponectin is deregulated in the context of therapy and gene regulation.


Assuntos
Adiponectina/metabolismo , Doenças Autoimunes/metabolismo , Doenças Reumáticas/metabolismo , Adiponectina/sangue , Adiponectina/química , Adiponectina/genética , Animais , Doenças Autoimunes/sangue , Doenças Autoimunes/terapia , Citocinas/metabolismo , Humanos , Modelos Biológicos , Doenças Reumáticas/sangue , Doenças Reumáticas/terapia , Fatores de Transcrição/metabolismo
5.
Medicine (Baltimore) ; 100(9): e24672, 2021 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-33655931

RESUMO

ABSTRACT: This study aimed at assessing the association of maternal diabetes mellitus (DM), the adiponectin gene (APM1) gene polymorphisms, and their interactions with risk of congenital heart disease (CHD) in offspring.A case-control study of 464 mothers of CHD patients and 504 mothers of healthy children was conducted.After adjusting for potential confounding factors, our study suggested that mothers with gestational DM (GDM) during this pregnancy (adjusted odds ratio [aOR = 2.96]), GDM in previous pregnancy experiences (aOR = 3.16), and pregestational DM in the 3 months before this pregnancy (aOR = 4.52) were at a significantly higher risk of CHD in offspring, when compared with those without any diabetes. The polymorphisms of maternal APM1 gene at rs1501299 (T/T vs G/G: aOR = 3.45; T/G vs G/G: aOR = 1.73) and rs2241766 (G/G vs T/T, aOR = 3.36; G/T vs T/T, aOR = 1.93) were significantly associated with risk of CHD in offspring. In addition, significant interactions between maternal DM and the APM1 genetic variants on the development of CHD were found.Our findings indicate that maternal DM, APM1 gene genetic variants, and their interactions are significantly associated with risk of CHD in offspring. However, more studies in different ethnic populations and with a larger sample and prospective design are required to confirm our findings.


Assuntos
Adiponectina/genética , Diabetes Mellitus , Diabetes Gestacional , Cardiopatias Congênitas/genética , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Razão de Chances , Polimorfismo Genético , Gravidez , Fatores de Risco
6.
Gene ; 784: 145593, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-33766710

RESUMO

BACKGROUND: Obesity and metabolic syndrome frequently co-exist and define obese individuals into different obesity phenotypes, such as metabolically healthy obese (MHO), metabolically unhealthy obese (MUO) and metabolically unhealthy normal weight (MUNW). Growing evidence suggests that genetic predisposition and environmental factors can explain the heterogeneity among these phenotypes. METHODS: We conducted a case-control study including 130 MHO, 251 MUNW, 208 MUO and 336 health controls by genotyping 2 SNPs (rs2241766, rs1501299) in ADIPOQ to investigate possible associations between SNPs in the ADIPOQ gene with susceptibility to three obese phenotypes respectively in Chinese Han population. Unconditional logistic regressions were used to detect the association between ADIPOQ SNPs and MHO/MUNW/MUO risks. RESULTS: Variant G allele of rs2241766 was associated with a reduced odds of MUO (additive model: Adjusted OR = 0.55; 95% CI = 0.40-0.75; P < 0.001) and no evidence of any significant association between rs2241766 and MHO phenotype (additive model: Adjusted OR = 0.84; 95% CI = 0.61-1.16; P = 0.306) or MUNW phenotype (additive model: Adjusted OR = 0.95; 95% CI = 0.73-1.24; P = 0.720) was found. Minor allele T of rs1501299 were significantly associated with decreased risk of MHO (Adjusted OR = 0.53; 95% CI = 0.37-0.76; P < 0.001) and MUNW (Adjusted OR = 0.63; 95% CI = 0.48-0.83; P = 0.001) in additive genetic model after correction for multiple testing. CONCLUSIONS: The variant G allele of rs2241766 was negatively associated with risk of MUO and variant T allele of rs1501299 exhibited reduced odds for MHO and MUNW. Beyond that, future studies are warranted to validate and extend our findings.


Assuntos
Adiponectina/genética , Grupo com Ancestrais do Continente Asiático/genética , Síndrome Metabólica/genética , Obesidade/genética , Polimorfismo de Nucleotídeo Único , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , China/etnologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Fenótipo
7.
Nat Cell Biol ; 23(3): 268-277, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664495

RESUMO

The sympathetic nervous system-catecholamine-uncoupling protein 1 (UCP1) axis plays an essential role in non-shivering adaptive thermogenesis. However, whether there exists a direct effector that physically connects catecholamine signalling to UCP1 in response to acute cold is unknown. Here we report that outer mitochondrial membrane-located AIDA is phosphorylated at S161 by the catecholamine-activated protein kinase A (PKA). Phosphorylated AIDA translocates to the intermembrane space, where it binds to and activates the uncoupling activity of UCP1 by promoting cysteine oxidation of UCP1. Adipocyte-specific depletion of AIDA abrogates UCP1-dependent thermogenesis, resulting in hypothermia during acute cold exposure. Re-expression of S161A-AIDA, unlike wild-type AIDA, fails to restore the acute cold response in Aida-knockout mice. The PKA-AIDA-UCP1 axis is highly conserved in mammals, including hibernators. Denervation of the sympathetic postganglionic fibres abolishes cold-induced AIDA-dependent thermogenesis. These findings uncover a direct mechanistic link between sympathetic input and UCP1-mediated adaptive thermogenesis.


Assuntos
Adipócitos Marrons/metabolismo , Tecido Adiposo Marrom/inervação , Proteínas de Transferência de Fosfolipídeos/metabolismo , Sistema Nervoso Simpático/fisiologia , Termogênese , Proteína Desacopladora 1/metabolismo , Adiponectina/genética , Adiponectina/metabolismo , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Metabolismo Energético , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxirredução , Proteínas de Transferência de Fosfolipídeos/deficiência , Proteínas de Transferência de Fosfolipídeos/genética , Fosforilação , Transdução de Sinais , Proteína Desacopladora 1/deficiência , Proteína Desacopladora 1/genética
8.
J Int Med Res ; 49(3): 300060521994925, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33729859

RESUMO

OBJECTIVE: To investigate the relationship between peroxisome proliferator-activated receptor gamma (PPARγ) mRNA, serum adiponectin (ADP) and lipids in paediatric patients with Kawasaki disease (KD). METHODS: This prospective study enrolled paediatric patients with KD and grouped them according to the presence or absence of coronary artery lesions (CAL). A group of healthy age-matched children were recruited as the control group. The levels of PPARγ mRNA, serum ADP and lipids were compared between the groups. Receiver operating characteristic (ROC) curve analysis was undertaken to determine if the PPARγ mRNA level could be used as a predictive biomarker of CAL prognosis. RESULTS: The study enrolled 42 patients with KD (18 with CAL [CAL group] and 24 without CAL [NCAL group]) and 20 age-matched controls. PPARγ mRNA levels in patients with KD were significantly higher than those in the controls; but significantly lower in the CAL group than the NCAL group. ROC curve analysis demonstrated that the PPARγ mRNA level provided good predictive accuracy for the prognosis of CAL. There was no association between PPARγ, ADP and lipid levels. CONCLUSION: There was dyslipidaemia in children with KD, but there was no correlation with PPARγ and ADP. PPARγ may be a predictor of CAL in patients with KD with good predictive accuracy.


Assuntos
Síndrome de Linfonodos Mucocutâneos , PPAR gama , Adiponectina/genética , Criança , Vasos Coronários , Humanos , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/genética , PPAR gama/genética , Estudos Prospectivos
9.
Int J Mol Sci ; 22(4)2021 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-33557390

RESUMO

Adiponectin, an adipose tissue-derived hormone, plays integral roles in lipid and glucose metabolism in peripheral tissues, such as the skeletal muscle, adipose tissue, and liver. Moreover, it has also been shown to have an impact on metabolic processes in the central nervous system. Astrocytes comprise the most abundant cell type in the central nervous system and actively participate in metabolic processes between blood vessels and neurons. However, the ability of adiponectin to control nutrient metabolism in astrocytes has not yet been fully elucidated. In this study, we investigated the effects of adiponectin on multiple metabolic processes in hypothalamic astrocytes. Adiponectin enhanced glucose uptake, glycolytic processes and fatty acid oxidation in cultured primary hypothalamic astrocytes. In line with these findings, we also found that adiponectin treatment effectively enhanced synthesis and release of monocarboxylates. Overall, these data suggested that adiponectin triggers catabolic processes in astrocytes, thereby enhancing nutrient availability in the hypothalamus.


Assuntos
Adiponectina/metabolismo , Astrócitos/metabolismo , Glucose/metabolismo , Hipotálamo/metabolismo , Nutrientes/metabolismo , Adiponectina/genética , Animais , Astrócitos/citologia , Metabolismo Energético , Feminino , Glicólise , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Oxirredução
10.
Gene ; 781: 145540, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33631239

RESUMO

BACKGROUND: Asthma and atopy are considered condition associated with obesity, being affected by genetic and environmental factors. The LEP and ADIPOQ genes, responsible for the expression and secretion of leptin and adiponectin, respectively, and polymorphisms in such genes have been linked to both diseases, independently, and also with the obesity-associated asthma phenotype in populations with high European ancestry and high-income countries. However, in mixed populations, there are few studies evaluating the impact of these variants in genes associated with the phenotype of asthma and obesity. Thus, the aim of this study was to investigate variants in LEP and ADIPOQ associated with asthma and atopy, and whether overweight modifies that effect. METHODS: The study involved 203 asthmatics children and 813 control subjects (between 5 and 11 years old), with or without overweight, from the SCAALA (Asthma and Allergy Social Changes in Latin America) program. Among them, 831 had data for allergy markers, being 258 atopic and 573 non-atopic. Genotyping was performed using a commercial panel Omnium Illumina 2.5. Logistic regression was performed to identify associations expected by using PLINK 1.09 and three genetic models: additive, dominant and recessive adjusted for sex, age, helminth infection, BMI and Principal Components (PC) 1 and 2, for ancestry, in order to control the confounding factor by population structure. RESULTS: For asthma, G allele of rs822396, in ADIPOQ, was positively associated in additive model (OR 1.4, 95% CI 1.08-1.83) and T allele of rs1063537 in dominant model (OR 1.52, 95% CI 1.01-2.30). In LEP, rs11763517 (C allele) and rs11760956 (A allele) were both negatively associated with asthma in the additive model (OR 0.70, 95% CI 0.54-0.91; OR 0.66, 95% CI 0.50-0.89) respectively, and the A allele of rs2167270 in dominant model (OR 0.71, 95% CI 0.51-0.98). The G allele of rs12706832 showed a positive association with asthma in the recessive model (OR 1.66, 95% CI 1.06-2.61). When the population was stratified by the BMI / Age Z-Score, the protection observed for asthma between the variants rs11760956, rs11763517 and rs2167270 was lost overweight individuals; The protection observed for atopy was lost in all variants (rs16861205, rs2167270 and rs17151919) in the overweight group. CONCLUSION: These results suggest that SNPs on the LEP and ADIPOQ genes may have an impact on atopy and asthma. Furthermore, we also show that the asthma and atopy protection attributed to variants on LEP and ADIPOQ genes is lost in individuals exposed to overweight.


Assuntos
Adiponectina/genética , Asma/genética , Hipersensibilidade Imediata/genética , Leptina/genética , Sobrepeso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos
11.
Nutr. hosp ; 38(1): 67-72, ene.-feb. 2021. tab
Artigo em Inglês | IBECS | ID: ibc-198842

RESUMO

INTRODUCTION: obesity often leads to deregulation and disrupting of the function of adipokines, which leads to various altered conditions, including metabolic syndrome (MetS). Adiponectin is one of the main adipokines secreted by adipocytes. The ADIPQ gene polymorphism rs266729 (-11377 C>G) is significantly associated with metabolic alterations related to obesity in different populations. Mexico has a high prevalence of obesity and risk factors associated with MetS. We investigated the association of the ADIPQ gene polymorphism rs266729 (-11377 C>G) with MetS in a Mexican population of western Mexico. METHODS: a total of 101 MetS patients and 70 unrelated healthy subjects were genotyped for ADIPQ polymorphism rs266729 using the restriction fragment length polymorphism method. RESULTS: we found a higher frequency of the minor allele G in MetS patients, as compared to that observed in the control group (OR = 2.17; 95 % CI, 1.26-3.70; p = 0.003). Also, the GG genotype was significantly associated with MetS risk under codominant (OR = 4.0; 95 % CI, 1.32-11.71; p = 0.014), dominant (OR = 2.16; 95 % CI, 1.12-4.03; p = 0.018), and recessive (OR = 3.33; 95 % CI, 1.14-9.45; p = 0.033) genetic models. CONCLUSION: our findings suggest that the minor allele G in the ADIPQ gene polymorphism rs266729 constitutes a risk factor for the development of MetS in a Mexican population of western Mexico


INTRODUCCIÓN: la obesidad frecuentemente tiene como consecuencia una desregulación y disrupción de la función de las adipocinas, que dan lugar a varias alteraciones, incluyendo el síndrome metabólico (SM). La adiponectina es una de las principales adipocinas secretadas por los adipocitos. El polimorfismo rs266729 (-11377 C>G) del gen ADIPOQ se ha asociado significativamente con alteraciones metabólicas relacionadas con la obesidad en diferentes poblaciones. México tiene una alta prevalencia de obesidad y de factores de riesgo asociados al SM. En el presente estudio investigamos la asociación del polimorfismo rs266729 (-11377 C>G) del gen ADIPOQ con el SM en una población mexicana del occidente de México. Metodos: a un total de 101 pacientes con SM y 70 sujetos sanos no relacionados se les identificó el polimorfismo rs266729 por el método de la PCR-RFLP. RESULTADOS: encontramos una mayor frecuencia del alelo menor G en los pacientes con SM, en comparación con la frecuencia observada en el grupo de control (OR = 2,17; IC 95 %: 1,26-3,70; p = 0,003). Asimismo, el genotipo GG se asoció significativamente con el SM bajo los modelos genéticos codominante (OR = 4,0; IC 95 %: 1,32-11,71; p = 0,014), dominante (OR = 2,16; IC 95 %: 1,12-4,03; p = 0,018) y recesivo (OR = 3,33; IC 95 %: 1,14-9,45; p = 0,033). CONCLUSIÓN: nuestros resultados sugieren que el alelo menor G del polimorfismo rs266729 (-11377 C>G) del gen ADIPOQ representa un factor de riesgo para el desarrollo de SM en la población mexicana del occidente de México


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Polimorfismo Genético , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Obesidade/epidemiologia , Protocolos Clínicos , Adipocinas/sangue , Adiponectina/sangue , México/epidemiologia , Adipocinas/análise , Adipocinas/genética , Adiponectina/genética , Estudos Transversais , Antropometria
12.
PLoS One ; 16(1): e0243745, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33507936

RESUMO

BACKGROUND: It has been reported that genetic factors are associated with risk factors and onset of lifestyle-related diseases, but this finding is still the subject of much debate. OBJECTIVE: The aim of the present study was to investigate the correlation of genetic factors, including salivary telomere length and three single nucleotide polymorphisms (SNPs) that may influence lifestyle-related diseases, with lifestyle-related diseases themselves. METHODS: In one year at a single facility, relative telomere length and SNPs were determined by using monochrome multiplex quantitative polymerase chain reaction and TaqMan SNP Genotyping Assays, respectively, and were compared with lifestyle-related diseases in 120 Japanese individuals near our university. RESULTS: In men and all participants, age was inversely correlated with relative telomere length with respective p values of 0.049 and 0.034. In men, the frequency of hypertension was significantly higher in the short relative telomere length group than in the long group with unadjusted p value of 0.039, and the difference in the frequency of hypertension between the two groups was of borderline statistical significance after adjustment for age (p = 0.057). Furthermore, in men and all participants, the sum of the number of affected lifestyle-related diseases, including hypertension, was significantly higher in the short relative telomere length group than in the long group, with p values of 0.004 and 0.029, respectively. For ADIPOQ rs1501299, men's ankle brachial index was higher in the T/T genotype than in the G/G and G/T genotypes, with p values of 0.001 and 0.000, respectively. For SIRT1 rs7895833, men's body mass index and waist circumference and all participants' brachial-ankle pulse wave velocity were higher in the A/G genotype than in the G/G genotype, with respective p values of 0.048, 0.032 and 0.035. For FOXO3A rs2802292, women's body temperature and all participants' saturation of peripheral oxygen were lower in the G/T genotype than in the T/T genotype, with respective p values of 0.039 and 0.032. However, relative telomere length was not associated with physiological or anthropometric measurements except for height in men (p = 0.016). ADIPOQ rs1501299 in men, but not the other two SNPs, was significantly associated with the sum of the number of affected lifestyle-related diseases (p = 0.013), by genotype. For each SNPs, there was no significant difference in the frequency of hypertension or relative telomere length by genotype. CONCLUSION: Relative telomere length and the three types of SNPs determined using saliva have been shown to be differentially associated with onset of and measured risk factors for lifestyle-related diseases consisting mainly of cardiovascular diseases and cancer.


Assuntos
Adiponectina/genética , Proteína Forkhead Box O3/genética , Hipertensão/genética , Neoplasias , Polimorfismo de Nucleotídeo Único , Sirtuína 1/genética , Telômero/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Hipertensão/epidemiologia , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Saliva
13.
Int J Gynaecol Obstet ; 153(1): 33-44, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33314055

RESUMO

Polycystic ovary syndrome (PCOS) involves abnormalities in ovarian, reproductive, and metabolic systems. Genetic polymorphisms associated with individual differences and variations might be related to complex disorders with unknown causes, including PCOS. Several leading genetic markers with known cellular functions have been identified among Iranian women presenting with PCOS. In particular, the existing evidence shows a significant relationship between PCOS and the following genetic polymorphisms: rs2275913 (interleukin-17A), rs9927163 (interleukin-32), Pro12Ala (peroxisome proliferator-activated receptor-γ), rs17173608 (chemerin), rs2236242 (vaspin), ApaI (vitamin D receptor), and rs7895833 (sirtuin 1). In addition, a higher risk of PCOS is associated with the rs2910164 (microRNA 146a), rs2241766 (adiponectin), -34 T/C (cytochrome 17), and rs1800682 (Fas) polymorphisms. Furthermore, protective effects against PCOS have been reported for the A4223C polymorphism of adenosine deaminase 1. Overall, the available data indicate that Iranian women with PCOS have a higher prevalence of polymorphisms in inflammation- and metabolism-related genes, but not in insulin-related genes. More extensive studies are needed to identify the ethnicity-related genetic associations in PCOS.


Assuntos
Síndrome do Ovário Policístico/genética , Polimorfismo Genético , Adiponectina/genética , Quimiocinas/genética , Feminino , Humanos , Interleucina-17/genética , Interleucinas/genética , Irã (Geográfico) , PPAR gama/genética
14.
Artigo em Inglês | MEDLINE | ID: mdl-33075494

RESUMO

MicroRNA-221-3p (miR-221-3p) is associated with both metabolic diseases and cancers. However, its role in terminal adipocyte differentiation and lipid metabolism are uncharacterized. miR-221-3p or its inhibitor was transfected into differentiating or mature human adipocytes. Triglyceride (TG) content and adipogenic gene expression were monitored, global lipidome analysis was carried out, and mechanisms underlying the effects of miR-221-3p were investigated. Finally, cross-talk between miR-221-3p expressing adipocytes and MCF-7 breast carcinoma (BC) cells was studied, and miR-221-3p expression in tumor-proximal adipose biopsies from BC patients analyzed. miR-221-3p overexpression inhibited terminal differentiation of adipocytes, as judged from reduced TG storage and gene expression of the adipogenic markers SCD1, GLUT4, FAS, DGAT1/2, AP2, ATGL and AdipoQ, whereas the miR-221-3p inhibitor increased TG storage. Knockdown of the predicted miR-221-3p target, 14-3-3γ, had similar antiadipogenic effects as miR-221-3p overexpression, indicating it as a potential mediator of mir-221-3p function. Importantly, miR-221-3p overexpression inhibited de novo lipogenesis but increased the concentrations of ceramides and sphingomyelins, while reducing diacylglycerols, concomitant with suppression of sphingomyelin phosphodiesterase, ATP citrate lyase, and acid ceramidase. miR-221-3p expression was elevated in tumor proximal adipose tissue from patients with invasive BC. Conditioned medium of miR-221-3p overexpressing adipocytes stimulated the invasion and proliferation of BC cells, while medium of the BC cells enhanced miR-221-3p expression in adipocytes. Elevated miR-221-3p impairs adipocyte lipid storage and differentiation, and modifies their ceramide, sphingomyelin, and diacylglycerol content. These alterations are relevant for metabolic diseases but may also affect cancer progression.


Assuntos
Adipócitos/metabolismo , Adipogenia/genética , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Gotículas Lipídicas/metabolismo , MicroRNAs/genética , Proteínas 14-3-3/genética , Proteínas 14-3-3/metabolismo , Adipócitos/patologia , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Diferenciação Celular , Proliferação de Células , Ceramidas/classificação , Ceramidas/metabolismo , Diacilglicerol O-Aciltransferase/genética , Diacilglicerol O-Aciltransferase/metabolismo , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Lipase/genética , Lipase/metabolismo , Células MCF-7 , Glândulas Mamárias Humanas/metabolismo , Glândulas Mamárias Humanas/patologia , MicroRNAs/agonistas , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Transdução de Sinais , Esfingolipídeos/classificação , Esfingolipídeos/metabolismo , Estearoil-CoA Dessaturase/genética , Estearoil-CoA Dessaturase/metabolismo , Triglicerídeos/classificação , Triglicerídeos/metabolismo , Receptor fas/genética , Receptor fas/metabolismo
15.
Biochim Biophys Acta Gen Subj ; 1865(3): 129836, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33370564

RESUMO

BACKGROUND: Emerging evidence revealed peptides within breast milk may be an abundant source of potential candidates for metabolism regulation. Our previous work identified numerous peptides existed in breast milk, but its function has not been validated. Thus, our study aims to screen for novel peptides that have the potential to antagonize obesity and diabetes. METHODS: A function screen was designed to identify the candidate peptide and then the peptide effect was validated by assessing lipid storage. Afterwards, the in vivo study was performed in two obese models: high-fat diet (HFD)-induced obese mice and obese ob/ob mice. For mechanism study, a RNA-seq analysis was conducted to explore the pathway that account for the biological function of peptide. RESULTS: By performing a small scale screening, a peptide (AVPVQALLLNQ) termed AOPDM1 (anti-obesity peptide derived from breast milk 1) was identified to reduce lipid storage in adipocytes. Further study showed AOPDM1 suppressed adipocyte differentiation by sustaining ERK activity at later stage of differentiation which down-regulated PPARγ expression. In vivo, AOPDM1 effectively reduced fat mass and improved glucose metabolism in high-fat diet (HFD)-induced obese mice and obese ob/ob mice. CONCLUSIONS: We identified a novel peptide AOPDM1 derived from breast milk could restrict adipocyte differentiation and ameliorate obesity through regulating MAPK pathway. GENERAL SIGNIFICANCE: Our findings may provide a potential candidate for the discovery of therapeutic drugs for obesity and type 2 diabetes.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Leite Humano/química , Obesidade/prevenção & controle , Peptídeos/farmacologia , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Fármacos Antiobesidade/síntese química , Diferenciação Celular/efeitos dos fármacos , Dieta Hiperlipídica , Feminino , Regulação da Expressão Gênica , Humanos , Leptina/genética , Leptina/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Peptídeos/síntese química , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
16.
J Cancer Res Ther ; 16(6): 1269-1273, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33342783

RESUMO

Context: Obesity has been strongly associated with risks and is a common factor in the risk of postmenopausal women with breast cancer (BC). Various single-nucleotide polymorphisms have been identified in the adiponectin gene. Aims: We aimed in this study to access the diagnostic value of adiponectin gene polymorphism rs 1501299 (G267T) in BC and its association with serum adiponectin level in obese and overweight postmenopausal BC female patients. Settings and Design: This study was conducted on 90 BC patients divided into two groups according to body mass index (BMI), and 60 apparently healthy females as a control group with matched BMI. Both groups were with BMI >25 (obese or overweight). Subjects and Methods: All participants were subjected to laboratory investigations (CA 15-3, serum adiponectin) and molecular study of adiponectin gene rs 1501299 (G276T) by polymerase chain reaction-restriction fragment length polymorphism technique. Results: A statistically significant difference was observed in the polymorphic genotypes (GT and TT) compared to (GG) wild genotype when compared BC patients to control group (P = 0.001). Also on measuring the risk estimate, a significant difference (odd's ratio was 3.76, 95% confidence interval was 1.68-8.4, P = 0.001). While no statistical significant difference in genotype frequency was found between the obese and overweight patients (P > 0.05). Median serum adiponectin level was decreased in BC patients compared to the control group (8.9 vs. 14.6 with P = 0.004). Conclusions: This study supported the association between adiponectin gene polymorphism, serum level, and BC risk among a group of obese and overweight postmenopausal Egyptian patients.


Assuntos
Adiponectina/sangue , Adiponectina/genética , Biomarcadores Tumorais/análise , Neoplasias da Mama/sangue , Neoplasias da Mama/genética , Índice de Massa Corporal , Neoplasias da Mama/diagnóstico , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/sangue , Pós-Menopausa/genética , Curva ROC , Fatores de Risco
17.
BMC Med Genet ; 21(1): 187, 2020 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-32977760

RESUMO

BACKGROUND: Adiponectin gene (ADIPOQ) polymorphisms have been shown to affect adiponectin serum concentration and some have been associated with breast cancer (BC) risk. The aims of this study were to describe the frequency of single nucleotide polymorphisms (SNPs) of ADIPOQ in Mexican women with BC and to determine if they show an association with it. METHODS: DNA samples from 397 patients and 355 controls were tested for the ADIPOQ gene SNPs: rs2241766 (GT) and rs1501299 (GT) by TaqMan allelic discrimination assay. Hardy-Weinberg equilibrium (HWE) was tested. Multiple SNP inheritance models adjusted by age and body mass index (BMI) were examined for the SNP rs1501299. RESULTS: We found that in the frequency analysis of rs1501299 without adjusting the BMI and age, the genotype distribution had a statistically significant difference (P = 0.003). The T allele was associated with a BC risk (OR, 1.99; 95% CI 1.13-3.51, TT vs. GG; OR, 1.53; 95% CI 1.12-2.09, GT vs. GG). The SNP rs2241766 was in HW disequilibrium in controls. In conclusion, the rs1501299 polymorphism is associated with a BC risk. CONCLUSIONS: Identification of the genotype of these polymorphisms in patients with BC can contribute to integrate the risk profile in both patients and their relatives as part of a comprehensive approach and increasingly more personalized medicine.


Assuntos
Adiponectina/genética , Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Polimorfismo de Nucleotídeo Único , Adulto , Alelos , Índice de Massa Corporal , Neoplasias da Mama/diagnóstico , Feminino , Frequência do Gene , Genótipo , Humanos , Desequilíbrio de Ligação , México , Pessoa de Meia-Idade
18.
PLoS Genet ; 16(9): e1009019, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32915782

RESUMO

Loci identified in genome-wide association studies (GWAS) can include multiple distinct association signals. We sought to identify the molecular basis of multiple association signals for adiponectin, a hormone involved in glucose regulation secreted almost exclusively from adipose tissue, identified in the Metabolic Syndrome in Men (METSIM) study. With GWAS data for 9,262 men, four loci were significantly associated with adiponectin: ADIPOQ, CDH13, IRS1, and PBRM1. We performed stepwise conditional analyses to identify distinct association signals, a subset of which are also nearly independent (lead variant pairwise r2<0.01). Two loci exhibited allelic heterogeneity, ADIPOQ and CDH13. Of seven association signals at the ADIPOQ locus, two signals colocalized with adipose tissue expression quantitative trait loci (eQTLs) for three transcripts: trait-increasing alleles at one signal were associated with increased ADIPOQ and LINC02043, while trait-increasing alleles at the other signal were associated with decreased ADIPOQ-AS1. In reporter assays, adiponectin-increasing alleles at two signals showed corresponding directions of effect on transcriptional activity. Putative mechanisms for the seven ADIPOQ signals include a missense variant (ADIPOQ G90S), a splice variant, a promoter variant, and four enhancer variants. Of two association signals at the CDH13 locus, the first signal consisted of promoter variants, including the lead adipose tissue eQTL variant for CDH13, while a second signal included a distal intron 1 enhancer variant that showed ~2-fold allelic differences in transcriptional reporter activity. Fine-mapping and experimental validation demonstrated that multiple, distinct association signals at these loci can influence multiple transcripts through multiple molecular mechanisms.


Assuntos
Adiponectina/genética , Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Alelos , Caderinas/genética , Caderinas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Frequência do Gene/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/métodos , Humanos , Proteínas Substratos do Receptor de Insulina/genética , Proteínas Substratos do Receptor de Insulina/metabolismo , Masculino , Síndrome Metabólica/genética , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
19.
Am J Physiol Renal Physiol ; 319(3): F469-F475, 2020 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-32744085

RESUMO

A lower 24-h urine pH (24h-pH), i.e., a higher renal excretion of free protons, at a given acid load to the body, denotes a reduction in the kidney's capacity for net acid excretion (NAE). There is increasing evidence, not only for patients with type 2 diabetes but also for healthy individuals, that higher body fatness or waist circumference (WC) has a negative impact on renal function to excrete acids (NAE). We hypothesized that adiposity-related inflammation molecules might mediate this relation between adiposity and renal acid excretion function. Twelve biomarkers of inflammation were measured in fasting blood samples from 162 adult participants (18-25 yr old) of the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study who had undergone anthropometric measurements and collected 24-h urine samples. Both Baron and Kenny's (B&K's) steps to test mediation and causal mediation analysis were conducted to examine the potential mediatory roles of biomarkers of inflammation in the WC-24-h pH relationship after strictly controlling for laboratory-measured NAE. In B&K's mediation analysis, leptin, soluble intercellular adhesion molecule 1 (sICAM-1), and adiponectin significantly associated with the outcome 24-h pH and attenuated the WC-pH relation. In agreement herewith, causal mediation analysis estimated the "natural indirect effects" of WC on 24-h pH via leptin (P = 0.01) and adiponectin (P = 0.03) to be significant, with a trend for sICAM-1 (P = 0.09). The calculated proportions mediated by leptin, adiponectin, and sICAM-1 were 64%, 23%, and 12%, respectively. Both mediation analyses identified an inflammatory cytokine (leptin) and an anti-inflammatory cytokine (adiponectin) along with sICAM-1 as being potentially involved in mediating adiposity-related influences on renal acid excretion capacity.


Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Inflamação/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Rim/metabolismo , Leptina/metabolismo , Adiponectina/sangue , Adiponectina/genética , Adolescente , Adulto , Biomarcadores/sangue , Feminino , Humanos , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão Intercelular/genética , Leptina/sangue , Leptina/genética , Masculino , Urinálise , Adulto Jovem
20.
Proc Natl Acad Sci U S A ; 117(29): 17381-17388, 2020 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-32632018

RESUMO

Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.


Assuntos
Adiponectina/metabolismo , Complemento C1q/metabolismo , Fosfolipídeos/metabolismo , Esfingolipídeos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Adipocinas/metabolismo , Adiponectina/genética , Animais , Ânions , Membrana Celular , LDL-Colesterol , Humanos , Metabolismo dos Lipídeos , Lipidômica , Lipoproteínas/metabolismo , Lipossomos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Opsonizantes/metabolismo , Plasma
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