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1.
Nutrients ; 13(8)2021 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-34445011

RESUMO

White blood cell (WBC) counts represent overall immunity. However, a few studies have been conducted to explore the genetic impacts of immunity and their interaction with lifestyles. We aimed to identify genetic variants associated with a low-WBC risk and document interactions between polygenetic risk scores (PRS), lifestyle factors, and nutrient intakes that influence low-WBC risk in a large hospital-based cohort. Single nucleotide polymorphisms (SNPs) were selected by genome-wide association study of participants with a low-WBC count (<4 × 109/L, n = 4176; low-WBC group) or with a normal WBC count (≥4 × 109/L, n = 36,551; control group). The best model for gene-gene interactions was selected by generalized multifactor dimensionality reduction. PRS was generated by summing selected SNP risk alleles of the best genetic model. Adjusted odds ratio (ORs) of the low-WBC group were 1.467 (1.219-1.765) for cancer incidence risk and 0.458 (0.385-0.545) for metabolic syndrome risk. Vitamin D intake, plant-based diet, and regular exercise were positively related to the low-WBC group, but smoking and alcohol intake showed an inverse association. The 7 SNPs included in the best genetic model were PSMD3_rs9898547, LCT_rs80157389, HLA-DRB1_rs532162239 and rs3097649, HLA-C rs2308575, CDKN1A_rs3176337 and THRA_rs7502539. PRS with 7 SNP model were positively associated with the low-WBC risk by 2.123-fold (1.741 to 2.589). PRS interacted with fat intake and regular exercise but not with other nutrient intakes or lifestyles. The proportion with the low WBC in the participants with high-PRS was lower among those with moderate-fat intake and regular exercise than those with low-fat intake and no exercise. In conclusion, adults with high-PRS had a higher risk of a low WBC count, and they needed to be advised to have moderate fat intake (20-25 energy percent) and regular exercise.


Assuntos
Gorduras na Dieta/administração & dosagem , Imunidade/genética , Leucócitos/imunologia , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Adulto , Fatores Etários , Idoso , Fatores de Risco Cardiometabólico , Estudos de Casos e Controles , Doenças Transmissíveis/epidemiologia , Doenças Transmissíveis/genética , Doenças Transmissíveis/imunologia , Estudos Transversais , Dieta com Restrição de Gorduras , Exercício Físico , Feminino , Estudos de Associação Genética , Humanos , Contagem de Leucócitos , Masculino , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Síndrome Metabólica/imunologia , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/genética , Neoplasias/imunologia , Recomendações Nutricionais , República da Coreia/epidemiologia , Medição de Risco
2.
Nutrients ; 13(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34371946

RESUMO

Nutrient sensing plays important roles in promoting satiety and maintaining good homeostatic control. Taste receptors (TAS) are located through the gastrointestinal tract, and recent studies have shown they have a relationship with metabolic disorders. The aim of this study was to analyze the jejunal expression of TAS1R2, TAS1R3, TAS2R14 and TAS2R38 in women with morbid obesity, first classified according to metabolic syndrome presence (MetS; n = 24) or absence (non-MetS; n = 45) and then classified according to hepatic histology as normal liver (n = 28) or nonalcoholic fatty liver disease (n = 41). Regarding MetS, we found decreased expression of TAS2R14 in MetS patients. However, when we subclassified patients according to liver histology, we did not find differences between groups. We found negative correlations between glucose levels, triglycerides and MetS with TAS1R3 expression. Moreover, TAS2R14 jejunal expression correlated negatively with the presence of MetS and ghrelin levels and positively with the jejunal Toll-like receptor (TLR)4, peroxisome proliferator-activated receptor (PPAR)-γ, and interleukin (IL)-10 levels. Furthermore, TAS2R38 expression correlated negatively with TLR9 jejunal expression and IL-6 levels and positively with TLR4 levels. Our findings suggest that metabolic dysfunctions such as MetS trigger downregulation of the intestinal TASs. Therefore, taste receptors modulation could be a possible therapeutic target for metabolic disorders.


Assuntos
Jejuno/metabolismo , Obesidade Mórbida/genética , Receptores Acoplados a Proteínas G/genética , Paladar , Regulação para Baixo , Feminino , Expressão Gênica , Humanos , Metabolismo dos Lipídeos/genética , Fígado/patologia , Síndrome Metabólica/complicações , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade Mórbida/complicações , Obesidade Mórbida/metabolismo , Obesidade Mórbida/patologia , Receptores Acoplados a Proteínas G/metabolismo
3.
Nutrients ; 13(7)2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34371949

RESUMO

Homocysteine (Hcy) is well known to be increased in the metabolic syndrome (MetS) incidence. However, it remains unclear whether the relationship is causal or not. Recently, Mendelian Randomization (MR) has been popularly used to assess the causal influence. In this study, we adopted MR to investigate the causal influence of Hcy on MetS in adults using three independent cohorts. We considered one-sample MR and two-sample MR. We analyzed one-sample MR in 5902 individuals (2090 MetS cases and 3812 controls) from the KARE and two-sample MR from the HEXA (676 cases and 3017 controls) and CAVAS (1052 cases and 764 controls) datasets to evaluate whether genetically increased Hcy level influences the risk of MetS. In observation studies, the odds of MetS increased with higher Hcy concentrations (odds ratio (OR) 1.17, 95%CI 1.12-1.22, p < 0.01). One-sample MR was performed using two-stage least-squares regression, with an MTHFR C677T and weighted Hcy generic risk score as an instrument. Two-sample MR was performed with five genetic variants (rs12567136, rs1801133, rs2336377, rs1624230, and rs1836883) by GWAS data as the instrumental variables. For sensitivity analysis, weighted median and MR-Egger regression were used. Using one-sample MR, we found an increased risk of MetS (OR 2.07 per 1-SD Hcy increase). Two-sample MR supported that increased Hcy was significantly associated with increased MetS risk by using the inverse variance weighted (IVW) method (beta 0.723, SE 0.119, and p < 0.001), the weighted median regression method (beta 0.734, SE 0.097, and p < 0.001), and the MR-Egger method (beta 2.073, SE 0.843, and p = 0.014) in meta-analysis. The MR-Egger slope showed no evidence of pleiotropic effects (intercept -0.097, p = 0.107). In conclusion, this study represented the MR approach and elucidates the significant relationship between Hcy and the risk of MetS in the Korean population.


Assuntos
Predisposição Genética para Doença , Homocisteína/sangue , Síndrome Metabólica/genética , Idoso , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana , Síndrome Metabólica/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único
4.
Nutrients ; 13(7)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34371836

RESUMO

Cardiometabolic disorders are among the leading causes of mortality in the human population. Dietary polyphenols exert beneficial effects on cardiometabolic health in humans. Molecular mechanisms, however, are not completely understood. Aiming to conduct in-depth integrative bioinformatic analyses to elucidate molecular mechanisms underlying the protective effects of polyphenols on cardiometabolic health, we first conducted a systematic literature search to identify human intervention studies with polyphenols that demonstrate improvement of cardiometabolic risk factors in parallel with significant nutrigenomic effects. Applying the predefined inclusion criteria, we identified 58 differentially expressed genes at mRNA level and 5 miRNAs, analyzed in peripheral blood cells with RT-PCR methods. Subsequent integrative bioinformatic analyses demonstrated that polyphenols modulate genes that are mainly involved in the processes such as inflammation, lipid metabolism, and endothelial function. We also identified 37 transcription factors that are involved in the regulation of polyphenol modulated genes, including RELA/NFKB1, STAT1, JUN, or SIRT1. Integrative bioinformatic analysis of mRNA and miRNA-target pathways demonstrated several common enriched pathways that include MAPK signaling pathway, TNF signaling pathway, PI3K-Akt signaling pathway, focal adhesion, or PPAR signaling pathway. These bioinformatic analyses represent a valuable source of information for the identification of molecular mechanisms underlying the beneficial health effects of polyphenols and potential target genes for future nutrigenetic studies.


Assuntos
Síndrome Metabólica/prevenção & controle , Fenômenos Fisiológicos da Nutrição/genética , Polifenóis/farmacologia , Substâncias Protetoras/farmacologia , Adulto , Fatores de Risco Cardiometabólico , Biologia Computacional , Feminino , Humanos , Masculino , Síndrome Metabólica/genética , MicroRNAs/sangue , Pessoa de Meia-Idade , Nutrigenômica , RNA Mensageiro/sangue , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais/genética
5.
J Pak Med Assoc ; 71(7): 1832-1837, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34410257

RESUMO

OBJECTIVE: To find the association of single nucleotide polymorphism of hypoxia-inducible factor-1 alpha, rs11549465 (1772 Cytosine > Thymine) with metabolic syndrome, and to compare the anthropometric and biochemical variables in different genotypes of hypoxia-inducible factor-1 alpha. METHODS: The cross-sectional comparative study was conducted at the University of Health Sciences, Lahore, Pakistan, from July 2016 to April 2019, and comprised patients of metabolic syndrome selected from the Sheikh Zayed Hospital, Lahore. Healthy controls were also enrolled. Fasting venous sample was taken for the determination of study parameters. The genetic variant of hypoxia-inducible factor-1 alpha was analysed by restriction fragment length polymorphism polymerase chain reaction. Data was analysed using SPSS 22. RESULTS: Out of 400 subjects, 200(50%) each were patients and controls. The frequency of CC genotype of hypoxia-inducible factor-1 alpha Cytosine > Thymine in patients was 166(83%) and in controls 147(73.5%); CT genotype was 34(17%) and 53(26.5%) respectively, while TT genotype was not observed. There was a significant association of the C allele and CC genotype (p=0.03) with the increased risk of metabolic syndrome (p=0.02). On comparison of study variables in the two genotypes, systolic blood pressure, anthropometric and lipid parameters were significantly higher in the wild CC genotype compared to CT in the control group (p<0.05), but there was no significant difference in the patients (p>0.05). CONCLUSIONS: Major allele C of hypoxia-inducible factor-1 alpha 1772 Cytosine > Thymine was found to be associated with increased risk of metabolic syndrome.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndrome Metabólica , Estudos de Casos e Controles , Estudos Transversais , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Hipóxia , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único
6.
Genes (Basel) ; 12(6)2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205732

RESUMO

MC4R, LEP, and LEPR genes are involved in the hypothalamic leptin-melanocortin regulation pathway, which is important for energy homeostasis. Our study aimed to evaluate the associations between the MC4R rs17782313, LEP rs7799039, and LEPR rs1137101 polymorphisms with obesity-related parameters in childhood and adulthood. The data were obtained from the Kaunas Cardiovascular Risk Cohort study, which started in 1977 with 1082 participants aged 12-13 years. In 2012-2014, the follow-up survey was carried out. Genotype analysis of all respondents (n = 509) aged 48-49 years was performed for the gene polymorphisms using Real-Time Polymerase Chain Reaction. Anthropometric measurements were performed in childhood and adulthood. In childhood, only skinfold thicknesses were associated with gene variants being the lowest in children with MC4R TT genotype and LEP AG genotype. In adulthood, odds of obesity and metabolic syndrome was higher in MC4R CT/CC genotype than TT genotype carriers (OR 1.8; 95% CI 1.2-2.8 and OR 1.6; 95% CI 1.1-2.4, respectively). In men, physical activity attenuated the effect of the MC4R rs17782313 on obesity. The LEP GG genotype was associated with higher BMI, waist circumference, and visceral fat level only in men. No associations of the LEPR rs1137101 polymorphisms with anthropometric measurements and leptin level were found. In conclusion, the associations of the MC4R and LEP gene polymorphisms with obesity-related parameters strengthened with age.


Assuntos
Leptina/genética , Síndrome Metabólica/genética , Obesidade Pediátrica/genética , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética , Adiposidade , Adulto , Fatores Etários , Criança , Exercício Físico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores Sexuais
7.
Int J Mol Sci ; 22(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198942

RESUMO

Empagliflozin (EMPA) is a sodium-glucose transporter 2 (SGLT2) inhibitor that functions as a new-generation glucose-lowering agent and has been proven to be beneficial for patients with cardiovascular diseases. However, the possible benefits and mechanisms of its antiarrhythmic effects in cardiac tissue have not yet been reported. In this study, we elucidated the possible antiarrhythmic effects and mechanisms of EMPA treatment in cardiac tissues of metabolic syndrome (MS) mice. A total of 20 C57BL/6J mice (age: 8 weeks) were divided into four groups: (1) control group, mice fed a standard chow for 16 weeks; (2) MS group, mice fed a high-fat diet for 16 weeks; (3) EMPA group, mice fed a high-fat diet for 12 weeks and administered EMPA at 10 mg/kg daily for the following 4 weeks; and (4) glibenclamide (GLI) group, mice fed a high-fat diet for 12 weeks and administered GLI at 0.6 mg/kg daily for the following 4 weeks. All mice were sacrificed after 16 weeks of feeding. The parameters of electrocardiography (ECG), echocardiography, and the effective refractory period (ERP) of the left ventricle were recorded. The histological characteristics of cardiac tissue, including connexin (Cx) expression and fibrotic areas, were also evaluated. Compared with the MS group, the ECG QT interval in the EMPA group was significantly shorter (57.06 ± 3.43 ms vs. 50.00 ± 2.62 ms, p = 0.011). The ERP of the left ventricle was also significantly shorter in the EMPA group than that in the GLI group (20.00 ± 10.00 ms vs. 60.00 ± 10.00 ms, p = 0.001). The expression of Cx40 and Cx43 in ventricular tissue was significantly lower in the MS group than in the control group. However, the downregulation of Cx40 and Cx43 was significantly attenuated in the EMPA group compared with the MS and GLI groups. The fibrotic areas of ventricular tissue were also fewer in the EMPA group than that in the MS group. In this study, the ECG QT interval in the EMPA group was shorter than that in the MS group. Compared with the MS group, the EMPA group exhibited significant attenuation of downregulated connexin expression and significantly fewer fibrotic areas in ventricles. These results may provide evidence of possible antiarrhythmic effects of EMPA.


Assuntos
Compostos Benzidrílicos/farmacologia , Doenças Cardiovasculares/tratamento farmacológico , Conexina 43/genética , Conexinas/genética , Glucosídeos/farmacologia , Transportador 2 de Glucose-Sódio/genética , Animais , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Dieta Hiperlipídica/efeitos adversos , Modelos Animais de Doenças , Ecocardiografia , Eletrocardiografia , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Glibureto/farmacologia , Humanos , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/genética , Camundongos , Transportador 2 de Glucose-Sódio/efeitos dos fármacos
8.
Int J Mol Sci ; 22(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199293

RESUMO

Metabolic syndrome (MetS) represents a cluster of disorders that increase the risk of a plethora of conditions, in particular type two diabetes, cardiovascular diseases, and certain types of cancers. MetS is a complex entity characterized by a chronic inflammatory state that implies dysregulations of adipokins and proinflammatory cytokins together with hormonal and growth factors imbalances. Of great interest is the implication of microRNA (miRNA, miR), non-coding RNA, in cancer genesis, progression, and metastasis. The adipose tissue serves as an important source of miRs, which represent a novel class of adipokines, that play a crucial role in carcinogenesis. Altered miRs secretion in the adipose tissue, in the context of MetS, might explain their implication in the oncogenesis. The interplay between miRs expressed in adipose tissue, their dysregulation and cancer pathogenesis are still intriguing, taking into consideration the fact that miRNAs show both carcinogenic and tumor suppressor effects. The aim of our review was to discuss the latest publications concerning the implication of miRs dysregulation in MetS and their significance in tumoral signaling pathways. Furthermore, we emphasized the role of miRNAs as potential target therapies and their implication in cancer progression and metastasis.


Assuntos
Carcinogênese/genética , Síndrome Metabólica/genética , MicroRNAs/metabolismo , Animais , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , MicroRNAs/genética , Transdução de Sinais/genética
9.
Int J Mol Sci ; 22(13)2021 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-34209784

RESUMO

Prenatal malnutrition is known to affect the phenotype of the offspring through changes in epigenetic regulation. Growing evidence suggests that epigenetics is one of the mechanisms by which nutrients and minerals affect metabolic traits. Although the perinatal period is the time of highest phenotypic plasticity, which contributes largely to developmental programming, there is evidence of nutritional influence on epigenetic regulation during adulthood. Calcium (Ca) plays an important role in the pathogenesis of insulin resistance syndrome. Cortisol, the most important glucocorticoid, is considered to lead to insulin resistance and metabolic syndrome. 11ß-hydroxysteroid dehydrogenase-1 is a key enzyme that catalyzes the intracellular conversion of cortisone to physiologically active cortisol. This brief review aims to identify the effects of Ca deficiency during pregnancy and/or lactation on insulin resistance in the offspring. Those findings demonstrate that maternal Ca deficiency during pregnancy may affect the epigenetic regulation of gene expression and thereby induce different metabolic phenotypes. We aim to address the need for Ca during pregnancy and propose the scaling-up of clinical and public health approaches that improved pregnancy outcomes.


Assuntos
Cálcio/deficiência , Resistência à Insulina , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Animais , Cálcio/farmacologia , Epigênese Genética/fisiologia , Feminino , Humanos , Resistência à Insulina/genética , Troca Materno-Fetal/fisiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/genética , Gravidez , Complicações na Gravidez/metabolismo , Efeitos Tardios da Exposição Pré-Natal/genética
10.
Hautarzt ; 72(8): 658-665, 2021 Aug.
Artigo em Alemão | MEDLINE | ID: mdl-34228138

RESUMO

Hidradenitis suppurativa/acne inversa (HS) has a multifactorial pathogenesis. In addition to a sporadic form, a familial form is reported in around 40% of patients, for whom an autosomal dominant (AD) inheritance with reduced gene penetrance is assumed. The phenotype of the disease with inflammatory nodules, abscesses and secreting sinus tracts suggests an infectious origin, but the exact role of the bacteria detected in HS pathogenesis remains unclear. Smoking and metabolic syndrome are regarded as important trigger factors in HS, with obesity and hormonal changes playing a pathogenic role in the latter. Ultimately, Toll-like receptors, antimicrobial peptides, immune cells and key cytokines are involved in the excessive inflammatory reaction of HS and are also the targets of future therapies.


Assuntos
Hidradenite Supurativa , Síndrome Metabólica , Citocinas , Hidradenite Supurativa/diagnóstico , Hidradenite Supurativa/genética , Humanos , Inflamação , Síndrome Metabólica/genética , Fumar
11.
Molecules ; 26(11)2021 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-34199898

RESUMO

In both humans and animal models, consumption of a high-saturated-fat diet has been linked to vascular dysfunction and cognitive impairments. Laboratory animals provide excellent models for more invasive high-fat-diet-related research. However, the physiological differences between humans and common animal models in terms of how they react metabolically to high-fat diets need to be considered. Here, we review the factors that may affect the translatability of mechanistic research in animal models, paying special attention to the effects of a high-fat diet on vascular outcomes. We draw attention to the dissociation between metabolic syndrome and dyslipidemia in rodents, unlike the state in humans, where the two commonly occur. We also discuss the differential vulnerability between species to the metabolic and vascular effects of macronutrients in the diet. Findings from animal studies are better interpreted as modeling specific aspects of dysfunction. We conclude that the differences between species provide an opportunity to explore why some species are protected from the detrimental aspects of high-fat-diet-induced dysfunction, and to translate these findings into benefits for human health.


Assuntos
Transtornos Cerebrovasculares/patologia , Dieta Hiperlipídica/efeitos adversos , Dislipidemias/patologia , Síndrome Metabólica/patologia , Animais , Transtornos Cerebrovasculares/etiologia , Modelos Animais de Doenças , Dislipidemias/induzido quimicamente , Dislipidemias/complicações , Humanos , Síndrome Metabólica/genética , Roedores , Especificidade da Espécie , Pesquisa Médica Translacional
12.
Nutrients ; 13(6)2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-34208143

RESUMO

BACKGROUND: The increasing prevalence of obesity in children has raised the incidence of Metabolic Syndrome (MetS) in this age group. Given the short- and long-term health impact of MetS, it is essential to prevent its onset by detecting its main triggers. Besides, genetic factors play an essential role in influencing which individuals within a population are most likely to develop obesity in response to a particular environment. In this regard, a common variation in the FTO gene is reproducibly associated with BMI and obesity from childhood and the genetic load has been linked to several cardiovascular risk factors, highlighting the FTO single nucleotide polymorphism (SNP) rs9939609. Therefore, this study aimed to establish the relationship between the FTO SNP rs9939609 and MetS. METHODS: A cross-sectional study was carried out on 220 children from the Biobío region (Chile). MetS diagnosis was established through the modified Cook criteria, using prevalence ratios, COR curves, and linear regressions to determine its association with MetS and its components. RESULTS: The prevalence of MetS was significantly increased among carriers of the risk allele (A): TT, 20.2%; TA, 25.4%; AA, 44.7% (p = 0.006). Also, the presence of A was associated with altered MetS-related variables. CONCLUSIONS: The FTO SNP rs9939609 was associated with a raised prevalence of MetS among A allele carriers, and was higher in the homozygous genotype (AA).


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Síndrome Metabólica/genética , Polimorfismo de Nucleotídeo Único , Índice de Massa Corporal , Criança , Chile/epidemiologia , Estudos Transversais , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Síndrome Metabólica/epidemiologia
13.
J Biol Chem ; 297(1): 100881, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34144038

RESUMO

GPR17 is a G-protein-coupled receptor (GPCR) implicated in the regulation of glucose metabolism and energy homeostasis. Such evidence is primarily drawn from mouse knockout studies and suggests GPR17 as a potential novel therapeutic target for the treatment of metabolic diseases. However, links between human GPR17 genetic variants, downstream cellular signaling, and metabolic diseases have yet to be reported. Here, we analyzed GPR17 coding sequences from control and disease cohorts consisting of individuals with adverse clinical metabolic deficits including severe insulin resistance, hypercholesterolemia, and obesity. We identified 18 nonsynonymous GPR17 variants, including eight variants that were exclusive to the disease cohort. We characterized the protein expression levels, membrane localization, and downstream signaling profiles of nine GPR17 variants (F43L, V96M, V103M, D105N, A131T, G136S, R248Q, R301H, and G354V). These nine GPR17 variants had similar protein expression and subcellular localization as wild-type GPR17; however, they showed diverse downstream signaling profiles. GPR17-G136S lost the capacity for agonist-mediated cAMP, Ca2+, and ß-arrestin signaling. GPR17-V96M retained cAMP inhibition similar to GPR17-WT, but showed impaired Ca2+ and ß-arrestin signaling. GPR17-D105N displayed impaired cAMP and Ca2+ signaling, but unaffected agonist-stimulated ß-arrestin recruitment. The identification and functional profiling of naturally occurring human GPR17 variants from individuals with metabolic diseases revealed receptor variants with diverse signaling profiles, including differential signaling perturbations that resulted in GPCR signaling bias. Our findings provide a framework for structure-function relationship studies of GPR17 signaling and metabolic disease.


Assuntos
Síndrome Metabólica/genética , Mutação de Sentido Incorreto , Receptores Acoplados a Proteínas G/genética , Transdução de Sinais , Cálcio/metabolismo , AMP Cíclico/metabolismo , Células HEK293 , Humanos , Transporte Proteico , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , beta-Arrestinas/metabolismo
14.
EMBO Rep ; 22(7): e52036, 2021 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-34114325

RESUMO

Dysregulation of lipid metabolism could lead to the development of metabolic disorders. We report here that the F-box protein JFK promotes excessive lipid accumulation in adipose tissue and contributes to the development of metabolic syndrome. JFK transgenic mice develop spontaneous obesity, accompanied by dyslipidemia, hyperglycemia, and insulin resistance, phenotypes that are further exacerbated under high-fat diets. In contrast, Jfk knockout mice are lean and resistant to diet-induced metabolic malfunctions. Liver-specific reconstitution of JFK expression in Jfk knockout mice leads to hepatic lipid accumulation resembling human hepatic steatosis and nonalcoholic fatty liver disease. We show that JFK interacts with and destabilizes ING5 through assembly of the SCF complex. Integrative transcriptomic and genomic analysis reveals that the SCFJFK -ING5 axis interferes with AMPK activity and fatty acid ß-oxidation, leading to the suppression of hepatic lipid catabolism. Significantly, JFK is upregulated and AMPKα1 is down-regulated in liver tissues from NAFLD patients. These results reveal that SCFJFK is a bona fide E3 ligase for ING5 and link the SCFJFK -ING5 axis to the development of obesity and metabolic syndrome.


Assuntos
Resistência à Insulina , Síndrome Metabólica , Hepatopatia Gordurosa não Alcoólica , Animais , Dieta Hiperlipídica/efeitos adversos , Humanos , Metabolismo dos Lipídeos/genética , Fígado/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/genética , Obesidade/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo
15.
BMC Geriatr ; 21(1): 391, 2021 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-34187381

RESUMO

BACKGROUND: Vitamin D deficiency has been associated with type 2 diabetes (T2D) and metabolic syndrome (MS) and its components. However, it is unclear whether a low concentration of vitamin D is the cause or consequence of these health conditions. Thus, this study aimed to evaluate the association of vitamin D concentrations and its genetic risk scores (GRSs) with MS and its component diseases, such as T2D, in middle-aged and elderly participants from rural eastern China. METHODS: A subset of 2393 middle-aged and elderly individuals were selected from 70,458 participants of the Nantong Chronic Diseases Study of 2017-2018 in China. We used two 25-hydroxyvitamin D (25[OH]D) synthesis single-nucleotide polymorphisms (SNPs) (DHCR7-rs12785878 and CYP2R1-rs10741657) and two 25(OH) D metabolism SNPs (GC-rs2282679 and CYP24A1-rs6013897) for creating GRSs, which were used as instrumental variables to assess the effect of genetically lowered 25(OH) D concentrations on MS and T2D based on the Wald ratio. F statistics were used to validate that the four SNPs genetically determined 25(OH) D concentrations. RESULTS: Compared to vitamin D sufficient individuals, individuals with vitamin D insufficiency had an odds ratio (OR [95% confidence interval {CI}]) of MS of 1.30 (1.06-1.61) and of T2D of 1.32 (1.08-1.64), individuals with vitamin D deficiency had an ORs (95% CI) of MS of 1.50 (1.24-1.79) and of T2D of 1.47 (1.12-1.80), and those with vitamin D severe deficiency had an ORs (95% CI) of MS of 1.52 (1.29-1.85) and of T2D of 1.54 (1.27-1.85). Mendelian randomization analysis showed a 25-nmol/L decrease in genetically instrumented serum 25(OH) D concentrations using the two synthesis SNPs (DHCR7 and CYP2R1 genes) associated with the risk of T2D and abnormal diastolic blood pressure (DBP) with ORs of 1.10 (95%CI: 1.02-1.45) for T2D and 1.14 (95%CI: 1.03-1.43) for DBP. CONCLUSIONS: This one sample Mendelian randomization analysis shows genetic evidence for a causal role of lower 25(OH) D concentrations in promoting of T2D and abnormal DBP in middle-aged and elderly participants from rural China.


Assuntos
Diabetes Mellitus Tipo 2 , Síndrome Metabólica , Deficiência de Vitamina D , Idoso , China/epidemiologia , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Humanos , Análise da Randomização Mendeliana , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Vitamina D/análogos & derivados , Deficiência de Vitamina D/diagnóstico , Deficiência de Vitamina D/epidemiologia , Deficiência de Vitamina D/genética
16.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068765

RESUMO

Epigenetics refers to the DNA chemistry changes that result in the modification of gene transcription and translation independently of the underlying DNA coding sequence. Epigenetic modifications are reported to involve various molecular mechanisms, including classical epigenetic changes affecting DNA methylation and histone modifications and small RNA-mediated processes, particularly that of microRNAs. Epigenetic changes are reversible and are closely interconnected. They are recognised to play a critical role as mediators of gene regulation, and any alteration in these mechanisms has been identified to mediate various pathophysiological conditions. Moreover, genetic predisposition and environmental factors, including dietary alterations, lifestyle or metabolic status, are identified to interact with the human epigenome, highlighting the importance of epigenetic factors as underlying processes in the aetiology of various diseases such as MetS. This review will reflect on how both the classical and microRNA-regulated epigenetic changes are associated with the pathophysiology of metabolic syndrome. We will then focus on the various aspects of epigenetic-based strategies used to modify MetS outcomes, including epigenetic diet, epigenetic drugs, epigenome editing tools and miRNA-based therapies.


Assuntos
Epigênese Genética , Código das Histonas/genética , Síndrome Metabólica/genética , Metilação de DNA , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Histonas/genética , Humanos , Síndrome Metabólica/patologia , MicroRNAs/genética
17.
Biomed Res Int ; 2021: 5570827, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33997011

RESUMO

Backgrounds: Adiponectin (apM1) may affect insulin sensitivity, and tumor necrosis factor (TNF-α) can inhibit the binding of insulin and insulin receptors. However, whether apM1 and TNF-α genes influence the development of metabolic syndrome (MetS) preceded by insulin resistance is unclear. The current study examines the interactions between the apM1 +45 genotypes, TNF-α -308 genotypes, and insulin resistance on the occurrence of MetS. Methods: A total of 329 community residents were recruited, and their personal characteristics were collected. Waist circumference and biochemical markers were examined for determining MetS. Genotypes were identified by the polymerase chain reaction. Results: After adjusting for the confounding effects, compared to apM1 +45 GG and GT genotypes carriers with HOMR-IR less than 2.0, those carriers with HOMA-IR greater than 2.0 had an increased MetS risk (OR = 4.35, 95% CI 2.14-8.85). Further, apM1 +45 TT carriers with HOMA-IR greater than 2.0 experienced a higher MetS risk (OR = 5.91, 95% CI 2.78-12.54). A significant interaction of the apM1 +45 genotype and insulin resistance on the MetS development was observed (P = 0.04). Conclusion: Our data suggested that apM1 +45 genotypes might modify the effect of insulin resistance on the development of Taiwanese MetS.


Assuntos
Adiponectina/genética , Resistência à Insulina/genética , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/genética , Grupo com Ancestrais do Continente Asiático , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taiwan
18.
Diabetes ; 70(8): 1843-1856, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33980691

RESUMO

To understand the causal role of adiposity and ectopic fat in type 2 diabetes and cardiometabolic diseases, we aimed to identify two clusters of adiposity genetic variants: one with "adverse" metabolic effects (UFA) and the other with, paradoxically, "favorable" metabolic effects (FA). We performed a multivariate genome-wide association study using body fat percentage and metabolic biomarkers from UK Biobank and identified 38 UFA and 36 FA variants. Adiposity-increasing alleles were associated with an adverse metabolic profile, higher risk of disease, higher CRP, and higher fat in subcutaneous and visceral adipose tissue, liver, and pancreas for UFA and a favorable metabolic profile, lower risk of disease, higher CRP and higher subcutaneous adipose tissue but lower liver fat for FA. We detected no sexual dimorphism. The Mendelian randomization studies provided evidence for a risk-increasing effect of UFA and protective effect of FA for type 2 diabetes, heart disease, hypertension, stroke, nonalcoholic fatty liver disease, and polycystic ovary syndrome. FA is distinct from UFA by its association with lower liver fat and protection from cardiometabolic diseases; it was not associated with visceral or pancreatic fat. Understanding the difference in FA and UFA may lead to new insights in preventing, predicting, and treating cardiometabolic diseases.


Assuntos
Adiposidade/genética , Gordura Intra-Abdominal/metabolismo , Fígado/metabolismo , Síndrome Metabólica/genética , Pâncreas/metabolismo , Adulto , Idoso , Fatores de Risco Cardiometabólico , Feminino , Humanos , Masculino , Síndrome Metabólica/metabolismo , Pessoa de Meia-Idade , Fenótipo
19.
FEBS Lett ; 595(13): 1768-1781, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33977527

RESUMO

Transient receptor potential vanilloid subfamily 1 (TRPV1) is a non-selective cation channel protein expressed in neuronal and non-neuronal cells. Although TRPV1 is implicated in thermogenesis and diet-induced obesity (DIO), its precise role remains controversial. TRPV1-/- mice are protected from DIO, while TRPV1 activation enhances thermogenesis to prevent obesity. To reconcile this, we fed wild-type and TRPV1-/- mice for 32 weeks with normal chow or a high-fat diet and analyzed the weight gain, metabolic activities, and thermogenic protein expression in white and brown fats. TRPV1-/- mice became obese, exhibited reduced locomotor activity, reduced energy expenditure, enhanced hepatic steatosis, and decreased thermogenic protein expression in adipose tissues. Our data reveal that lack of TRPV1 does not prevent obesity, but rather enhances metabolic dysfunction.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Redes Reguladoras de Genes/efeitos dos fármacos , Síndrome Metabólica/genética , Obesidade/genética , Canais de Cátion TRPV/genética , Tecido Adiposo Marrom/efeitos dos fármacos , Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Tecido Adiposo Branco/metabolismo , Animais , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Masculino , Síndrome Metabólica/induzido quimicamente , Síndrome Metabólica/metabolismo , Camundongos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Termogênese
20.
Wei Sheng Yan Jiu ; 50(2): 261-273, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33985634

RESUMO

OBJECTIVE: To investigate the associations between the polymorphisms and interaction of the interleukin 6(IL-6) genes at-634 C/G, -174 G/C, -1363 G/T loci, as well as the interactions between the three loci and tumor necrosis factor(TNF-α), and peripheral blood leukocytes(white blood cell, WBC) with metabolic syndrome(MS). METHODS: Using the case-control research method, according to the inclusion and exclusion criteria, from March 2015 to March 2016 from the General Hospital of Ningxia Medical University and Wuzhong City People's Hospital, 376 unrelated cases and 408 control groups were selected. We conducted questionnaire surveys(including general conditions, disease and medication history, family history, etc. ), physical examinations(including height, weight and calculation of body mass index(BMI), waist circumference, hip circumference and calculation of waist-to-hip ratio(WHR), SBP, DBP, etc. ), blood collection and testing(including WBC count, serum TNF-α level and biochemical indicators TG, TC, HDL-C, LDL-C, FPG, UA, AST, ALT, etc. ), and the polymorphism detection of IL-6 gene at-634 C/G, -174 G/C, -1363 G/T sites. The SNPstats online software was used to analyze the relationship between the polymorphisms of IL-6 gene and MS. The SHEsis online software was used to analyze the linkage disequilibrium(LD) of the IL-6 three-site and the relationship between haplotype and MS. GMDR 0. 7 software was used to analyze the interactions among the three sites of IL-6 gene, and one between the three sites and TNF-α and WBC, respectively. RESULTS: Before and after adjustment of sex, age and nationality, the polymorphism at the 3 position of IL-6 gene was not related to the onset of MS in different genetic models(both P> 0. 05). There was a linkage disequilibrium between the three loci of IL-6 gene, but the haploids formed by these three loci were not associated with MS susceptibility(all P> 0. 05). There was no interaction among the three sites, but the two-factor, three-factor, and four-factor interaction models consisting of the three sites and TNF-α were all statistically significant(all P<0. 001) and the replacement tests were all P<0. 001, and were all associated with MS occurrence. The two-factor, three-factor, and four-factor interaction models consisting of the three sites and WBC were all P<0. 01, and the replacement tests were all P<0. 05. The differences were statistically significant, which was related to the onset of MS. CONCLUSION: The IL-6 gene-634 C/G, -174 G/C, and-1363 G/T loci polymorphism may not be significantly associated with the prevalence of MS. Interactions between the three sites and TNF-α and WBC levels can significantly increase the risk of MS.


Assuntos
Síndrome Metabólica , Humanos , Interleucina-6/genética , Leucócitos , Síndrome Metabólica/genética , Fator de Necrose Tumoral alfa/genética , Circunferência da Cintura
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