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1.
PLoS One ; 16(9): e0256988, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34478452

RESUMO

Epidemiological studies suggest that individuals with comorbid conditions including diabetes, chronic lung, inflammatory and vascular disease, are at higher risk of adverse COVID-19 outcomes. Genome-wide association studies have identified several loci associated with increased susceptibility and severity for COVID-19. However, it is not clear whether these associations are genetically determined or not. We used a Phenome-Wide Association (PheWAS) approach to investigate the role of genetically determined COVID-19 susceptibility on disease related outcomes. PheWAS analyses were performed in order to identify traits and diseases related to COVID-19 susceptibility and severity, evaluated through a predictive COVID-19 risk score. We utilised phenotypic data in up to 400,000 individuals from the UK Biobank, including Hospital Episode Statistics and General Practice data. We identified a spectrum of associations between both genetically determined COVID-19 susceptibility and severity with a number of traits. COVID-19 risk was associated with increased risk for phlebitis and thrombophlebitis (OR = 1.11, p = 5.36e-08). We also identified significant signals between COVID-19 susceptibility with blood clots in the leg (OR = 1.1, p = 1.66e-16) and with increased risk for blood clots in the lung (OR = 1.12, p = 1.45 e-10). Our study identifies significant association of genetically determined COVID-19 with increased blood clot events in leg and lungs. The reported associations between both COVID-19 susceptibility and severity and other diseases adds to the identification and stratification of individuals at increased risk, adverse outcomes and long-term effects.


Assuntos
COVID-19/genética , Obesidade/genética , Tromboflebite/genética , Trombose/genética , COVID-19/epidemiologia , COVID-19/virologia , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/virologia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Análise da Randomização Mendeliana , Obesidade/epidemiologia , Obesidade/virologia , Fenômica , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , SARS-CoV-2/patogenicidade , Tromboflebite/epidemiologia , Tromboflebite/virologia , Trombose/epidemiologia , Trombose/virologia
2.
Nat Commun ; 12(1): 5253, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489471

RESUMO

Genome-wide association studies (GWAS) have identified many disease-associated variants, yet mechanisms underlying these associations remain unclear. To understand obesity-associated variants, we generate gene regulatory annotations in adipocytes and hypothalamic neurons across cellular differentiation stages. We then test variants in 97 obesity-associated loci using a massively parallel reporter assay and identify putatively causal variants that display cell type specific or cross-tissue enhancer-modulating properties. Integrating these variants with gene regulatory information suggests genes that underlie obesity GWAS associations. We also investigate a complex genomic interval on 16p11.2 where two independent loci exhibit megabase-range, cross-locus chromatin interactions. We demonstrate that variants within these two loci regulate a shared gene set. Together, our data support a model where GWAS loci contain variants that alter enhancer activity across tissues, potentially with temporally restricted effects, to impact the expression of multiple genes. This complex model has broad implications for ongoing efforts to understand GWAS.


Assuntos
Adipócitos/fisiologia , Elementos Facilitadores Genéticos , Pleiotropia Genética , Obesidade/genética , Adipócitos/citologia , Arritmias Cardíacas/genética , Arritmias Cardíacas/patologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Estudo de Associação Genômica Ampla , Gigantismo/genética , Gigantismo/patologia , Cardiopatias Congênitas/genética , Cardiopatias Congênitas/patologia , Humanos , Hipotálamo/fisiologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , MAP Quinase Quinase 5/genética , Neurônios/citologia , Neurônios/fisiologia , Polimorfismo de Nucleotídeo Único , Proteínas Quinases/genética , Locos de Características Quantitativas , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Fatores de Transcrição/genética , Transcriptoma
3.
Zhen Ci Yan Jiu ; 46(8): 642-8, 2021 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-34472748

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) at "Zusanli"(ST36)-"Sanyinjiao"(SP6) on glucose and lipid metabolism and insulin resistance (IR) in obese diabetic rats, so as to explore its mechanism underlying improvement of obesity diabetes. METHODS: SPF male rats were randomly divided into normal control, model, meridian-acupoint EA (acupoint), non-meridian non-acupoint EA (non-acupoint), and medication (metformin) groups, with 10 rats in each group. The diabetes model was established by feeding the rats with high-fat diet for 8 weeks. EA (1.5 mA, 10 Hz/100 Hz) was applied to unilateral ST36 and SP6 for 20 min, once daily (except Sundays) for 4 weeks. Rats of the medication group were treated by gavage of metformin (300 mg/kg) once daily for 4 weeks (except Sundays). The body weight and length were measured and the Lee's index was calculated. The contents of total cholesterol (TC), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C) in the plasma were detected by using a full-automatic biochemical analyzer. The content of fasting serum insulin (FINS) was assayed by using radioimmunoassay, the fasting blood glucose (FBG) was measured, and serum superoxide dismutase (SOD) activity by using xanthine oxidase method, serum malondialdehyde (MDA) by color method, serum glutathione peroxidase (GSH-Px) activity by indirect method, reactive oxygen species (ROS) by Dithio-bis-nitrobenzoic acid (DTNB) direct method, and the homeostasis model assessment of IR (HOMA-IR) and insulin sensitive index (ISI) were calculated. The expression levels of pancreatic tissue P66shc mRNA and PKCß mRNA were detected by using RT-PCR, and the histopathological changes of the liver and adipose tissues were observed after H.E. staining. RESULTS: Compared with the normal control group, the Lee's index, levels of FBG, FINS, HOMA-IR, TC, TG, LDL-C, MDA, ROS, and P66shc mRNA and PKCß mRNA expressions were significantly increased (P<0.05,P<0.01), and ISI, HDL-C, SOD, GSH-Px significantly decreased (P<0.05, P<0.01) in the model group. After the interventions, the levels of Lee's index,levels of FBG, FINS, HOMA-IR, TC, TG, LDL-C, MDA, ROS, and expressions of P66shc mRNA and PKCß mRNA were remarkably down-regulated (P<0.05, P<0.01), and those of ISI, HDL-C, SOD, and GSH-Px up-regulated (P<0.05, P<0.01) in both EA and medication groups. H.E. staining showed many white adipocytes in the adipose tissue, radial and cord-like arrangement of liver cells, and many of them with vacuoles in the cytoplasm of small vesicular lipid droplets in the model group; and relative reduction of white adipocytes in number, smaller in cell body, and no obvious abnormal changes of structure and arrangement of liver cells in the EA and medication groups. CONCLUSION: EA of ST36 and SP6 can improve glucose and lipid metabolism and IR in obese diabetic rats, which may be related to its function in suppressing PKCß/P66shc signaling and oxidative stress.


Assuntos
Terapia por Acupuntura , Diabetes Mellitus Experimental , Eletroacupuntura , Pontos de Acupuntura , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/terapia , Masculino , Obesidade/genética , Obesidade/terapia , Estresse Oxidativo , Ratos , Ratos Sprague-Dawley , Proteína 1 de Transformação que Contém Domínio 2 de Homologia de Src
4.
BMC Genomics ; 22(1): 668, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34525971

RESUMO

OBJECTIVE: From genome-wide association studies, brain-derived neurotrophic factor (BDNF) locus on chromosome 11 was the only SNP associated with both smoking and body mass index (BMI) in European, African and Asian population. This study aims to explore the unique genetic predisposition to obesity in former smokers by examining the effects of BDNF on BMI and waist circumference (WC). METHODS: The study design is case-control study with a cohort validation in supplementary. We included 15,072 ethnic Chinese participants in the Guangzhou Biobank Cohort Study (GBCS) with data of four BDNF SNPs related to both BMI and smoking behavior. We used baseline smoke exposure data in 2003-2007 and follow-up outcomes of general obesity (by BMI) and central obesity (WC) in 2008-2012. Odds ratios (ORs) and 95% confidence intervals (CIs) for general obesity and central obesity associated with these SNPs were derived from logistic regression. RESULTS: Of 15,072 participants (3169 men and 11,903 women), 1664 (11.0%) had general and 7868 (52.2%) had central obesity. In 1233 former smokers, the rs6265 GG, versus AA, genotype was associated with higher risks of general obesity (OR = 1.79, 95% CI = 1.06-3.01) and central obesity (OR = 2.08, 95% CI = 1.47-2.92) after adjustment. These associations were not significant in never or current smokers. In former heavy (≥20 cigarettes/day) smokers, the rs6265 GG genotype showed a higher odds for general obesity (OR = 2.15, 95% CI = 1.05-4.40), while no association was found in former light (1-9 cigarettes/day) smokers. Similar results were found for the association of rs6265 with central obesity and for the associations of other two BDNF SNPs (rs4923457 and rs11030104) with both general and central obesity. CONCLUSIONS: We firstly identified the genetic predisposition (BDNF SNPs) to general and central obesity in former smokers, particularly in former heavy smokers. The different associations of the SNPs for general/central obesity in different smoke exposure groups may be related to the competitive performance of the sites and epigenetic modification, which needs further study.


Assuntos
Fator Neurotrófico Derivado do Encéfalo , Estudo de Associação Genômica Ampla , Índice de Massa Corporal , Fator Neurotrófico Derivado do Encéfalo/genética , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Obesidade/genética , Fumantes
5.
Nat Commun ; 12(1): 5175, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462445

RESUMO

Calcitonin receptor (Calcr)-expressing neurons of the nucleus tractus solitarius (NTS; CalcrNTS cells) contribute to the long-term control of food intake and body weight. Here, we show that Prlh-expressing NTS (PrlhNTS) neurons represent a subset of CalcrNTS cells and that Prlh expression in these cells restrains body weight gain in the face of high fat diet challenge in mice. To understand the relationship of PrlhNTS cells to hypothalamic feeding circuits, we determined the ability of PrlhNTS-mediated signals to overcome enforced activation of AgRP neurons. We found that PrlhNTS neuron activation and Prlh overexpression in PrlhNTS cells abrogates AgRP neuron-driven hyperphagia and ameliorates the obesity of mice deficient in melanocortin signaling or leptin. Thus, enhancing Prlh-mediated neurotransmission from the NTS dampens hypothalamically-driven hyperphagia and obesity, demonstrating that NTS-mediated signals can override the effects of orexigenic hypothalamic signals on long-term energy balance.


Assuntos
Obesidade/metabolismo , Hormônio Liberador de Prolactina/metabolismo , Núcleo Solitário/metabolismo , Animais , Apetite , Dieta , Ingestão de Alimentos , Metabolismo Energético , Feminino , Humanos , Hipotálamo/metabolismo , Leptina/metabolismo , Masculino , Melanocortinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/psicologia , Hormônio Liberador de Prolactina/genética , Receptores da Calcitonina/genética , Receptores da Calcitonina/metabolismo
6.
Adv Exp Med Biol ; 1331: 233-248, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34453302

RESUMO

The scarcity of the results obtained for the treatment of obesity leads us to consider new strategies, contemplating all the factors involved in the development of the disease. One of the key molecules for controlling body weight and energy homeostasis is the brain-derived neurotrophic factor (BDNF). This work summarizes the mechanisms in which BDNF gene regulates this multifactorial disease. In addition, we discuss the role of other BDNF polymorphisms as genetic determinants of obesity. In this context, a total of 14 SNPs near or inside BDNF/BDNF-AS related to BMI were identified in various GWASs. Finally, we assess gene-diet interaction as a novel tool to prevent obesity and formulate solid and personalized nutritional management. Our research group has performed the first study on the association of BDNF-AS rs925946 polymorphism and calcium intake as potential modulators of the nutritional status. Although these results should be confirmed in future studies, they open the path for new prevention opportunities.


Assuntos
Manejo da Obesidade , Peso Corporal , Fator Neurotrófico Derivado do Encéfalo/genética , Genótipo , Humanos , Obesidade/genética , Obesidade/prevenção & controle , Polimorfismo de Nucleotídeo Único
7.
FASEB J ; 35(9): e21752, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34369602

RESUMO

Aging, obesity, and insulin resistance are associated with low levels of PGC1α and PGC1ß coactivators and defective mitochondrial function. We studied mice deficient for PGC1α and PGC1ß [double heterozygous (DH)] to investigate their combined pathogenic contribution. Contrary to our hypothesis, DH mice were leaner, had increased energy dissipation, a pro-thermogenic profile in BAT and WAT, and improved carbohydrate metabolism compared to wild types. WAT showed upregulation of mitochondriogenesis/oxphos machinery upon allelic compensation of PGC1α4 from the remaining allele. However, DH mice had decreased mitochondrial OXPHOS and biogenesis transcriptomes in mitochondria-rich organs. Despite being metabolically healthy, mitochondrial defects in DH mice impaired muscle fiber remodeling and caused qualitative changes in the hepatic lipidome. Our data evidence first the existence of organ-specific compensatory allostatic mechanisms are robust enough to drive an unexpected phenotype. Second, optimization of adipose tissue bioenergetics is sufficient to maintain a healthy metabolic phenotype despite a broad severe mitochondrial dysfunction in other relevant metabolic organs. Third, the decrease in PGC1s in adipose tissue of obese and diabetic patients is in contrast with the robustness of the compensatory upregulation in the adipose of the DH mice.


Assuntos
Tecido Adiposo/metabolismo , Mitocôndrias/genética , Proteínas Nucleares/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Fatores de Transcrição/genética , Envelhecimento/genética , Animais , Modelos Animais de Doenças , Metabolismo Energético/genética , Heterozigoto , Resistência à Insulina/genética , Masculino , Camundongos , Obesidade/genética , Termogênese/genética , Transcriptoma/genética
8.
Int J Mol Sci ; 22(16)2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34445208

RESUMO

The transient receptor potential melastatin subtype 8 (TRPM8) is a cold sensor in humans, activated by low temperatures (>10, <28 °C), but also a polymodal ion channel, stimulated by voltage, pressure, cooling compounds (menthol, icilin), and hyperosmolarity. An increased number of experimental results indicate the implication of TRPM8 channels in cold thermal transduction and pain detection, transmission, and maintenance in different tissues and organs. These channels also have a repercussion on different kinds of life-threatening tumors and other pathologies, which include urinary and respiratory tract dysfunctions, dry eye disease, and obesity. This compendium firstly covers newly described papers on the expression of TRPM8 channels and their correlation with pathological states. An overview on the structural knowledge, after cryo-electron microscopy success in solving different TRPM8 structures, as well as some insights obtained from mutagenesis studies, will follow. Most recently described families of TRPM8 modulators are also covered, along with a section of molecules that have reached clinical trials. To finalize, authors provide an outline of the potential prospects in the TRPM8 field.


Assuntos
Temperatura Baixa , Canais de Cátion TRPM , Sensação Térmica , Síndromes do Olho Seco/tratamento farmacológico , Síndromes do Olho Seco/genética , Síndromes do Olho Seco/metabolismo , Humanos , Obesidade/tratamento farmacológico , Obesidade/genética , Obesidade/metabolismo , Doenças Respiratórias/tratamento farmacológico , Doenças Respiratórias/genética , Doenças Respiratórias/metabolismo , Canais de Cátion TRPM/química , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Doenças Urológicas/tratamento farmacológico , Doenças Urológicas/genética , Doenças Urológicas/metabolismo
9.
Nat Immunol ; 22(9): 1175-1185, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34429546

RESUMO

Systematic characterizations of adipose regulatory T (Treg) cell subsets and their phenotypes remain uncommon. Using single-cell ATAC-sequencing and paired single-cell RNA and T cell receptor (TCR) sequencing to map mouse adipose Treg cells, we identified CD73hiST2lo and CD73loST2hi subsets with distinct clonal expansion patterns. Analysis of TCR-sharing data implied a state transition between CD73hiST2lo and CD73loST2hi subsets. Mechanistically, we revealed that insulin signaling occurs through a HIF-1α-Med23-PPAR-γ axis to drive the transition of CD73hiST2lo into a CD73loST2hi adipose Treg cell subset. Treg cells deficient in insulin receptor, HIF-1α or Med23 have decreased PPAR-γ expression that in turn promotes accumulation of CD73hiST2lo adipose Treg cells and physiological adenosine production to activate beige fat biogenesis. We therefore unveiled a developmental trajectory of adipose Treg cells and its dependence on insulin signaling. Our findings have implications for understanding the dynamics of adipose Treg cell subsets in aged and obese contexts.


Assuntos
Tecido Adiposo/imunologia , Resistência à Insulina/imunologia , Insulina/metabolismo , Receptor de Insulina/metabolismo , Linfócitos T Reguladores/imunologia , 5'-Nucleotidase/genética , 5'-Nucleotidase/metabolismo , Tecido Adiposo/citologia , Envelhecimento/imunologia , Animais , Células Cultivadas , Sequenciamento de Nucleotídeos em Larga Escala , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Masculino , Complexo Mediador/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/genética , Obesidade/imunologia , PPAR gama/metabolismo , Receptores de Antígenos de Linfócitos T/genética , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Linfócitos T Reguladores/citologia
10.
Wiad Lek ; 74(7): 1617-1621, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34459761

RESUMO

OBJECTIVE: The aim: To study the association between the effectiveness of treatment with pioglitazone non-alcoholic fatty liver disease (NAFLD) in patients with obesity and PPARG rs1801282 (Pro12Ala)-polymorphism in Ukrainians. PATIENTS AND METHODS: Materials and methods: 123 patients with NAFLD in combination with obesity 1, 2, 3 classes were included in comprehensive weight loss program (5 visits, 12-weeks). The case group was treated with pioglitazone 15 mg / day, while the control group received only program. Ultrasound (US) steatometry and genetic testing rs1801282 polymorphism in PPARG gene were performed. RESULTS: Results: Pioglitazone, PPARG rs1801282 genotype, CAP before treatment, previous weight loss attempts, and duration of obesity were associated with the change in controlled attenuation parameter (CAP) during treatment. There was a significant association between the target CAP reduction achievement and pioglitazone treatment (adjusted odds ratio 0.23, 95% CI 0.07-0.73; p = 0.01) with the CC genotype of PPARG gene (adjusted odds ratio 92.9, 95% CI 7.4-1159; p < 0.001) compared to patients with the CG genotype. CONCLUSION: Conclusions: Pioglitazone and PPARG rs1801282 polymorphism could influence on dynamics of CAP reduction during treatment.


Assuntos
Hepatopatia Gordurosa não Alcoólica , PPAR gama , Predisposição Genética para Doença , Genótipo , Humanos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/complicações , Obesidade/genética , PPAR gama/genética , Pioglitazona/uso terapêutico , Polimorfismo de Nucleotídeo Único
11.
Nutrients ; 13(7)2021 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-34371977

RESUMO

The effectiveness of weight loss treatment displays dramatic inter-individual variabilities, even with well-controlled energy intake/expenditure. This study aimed to determine the association between daily rhythms of cardiac autonomic control and weight loss efficiency and to explore the potential relevance to weight loss resistance in humans carrying the genetic variant C at CLOCK 3111T/C. A total of 39 overweight/obese Caucasian women (20 CLOCK 3111C carriers and 19 non-carriers) completed a behaviour-dietary obesity treatment of ~20 weeks, during which body weight was assessed weekly. Ambulatory electrocardiographic data were continuously collected for up to 3.5 days and used to quantify the daily rhythm of fractal cardiac dynamics (FCD), a non-linear measure of autonomic function. FCD showed a 24 h rhythm (p < 0.001). Independent of energy intake and physical activity level, faster weight loss was observed in individuals with the phase (peak) of the rhythm between ~2-8 p.m. and with a larger amplitude. Interestingly, the phase effect was significant only in C carriers (p = 0.008), while the amplitude effect was only significant in TT carriers (p < 0.0001). The daily rhythm of FCD and CLOCK 3111T/C genotype is linked to weight loss response interactively, suggesting complex interactions between the genetics of the circadian clock, the daily rhythm of autonomic control, and energy balance control.


Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Proteínas CLOCK/genética , Ritmo Circadiano/genética , Coração/inervação , Sobrepeso/terapia , Perda de Peso/genética , Adulto , Estudos de Casos e Controles , Ritmo Circadiano/fisiologia , Eletrocardiografia Ambulatorial , Ingestão de Energia , Exercício Físico , Feminino , Fractais , Genótipo , Coração/fisiopatologia , Humanos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/fisiopatologia , Obesidade/terapia , Sobrepeso/genética , Sobrepeso/fisiopatologia , Polimorfismo de Nucleotídeo Único/genética
12.
Eur J Endocrinol ; 185(4): R93-R101, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34370694

RESUMO

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.


Assuntos
Hormônios Peptídicos/fisiologia , Animais , Regulação do Apetite/efeitos dos fármacos , Regulação do Apetite/genética , Diabetes Mellitus/genética , Diabetes Mellitus/terapia , Esvaziamento Gástrico/efeitos dos fármacos , Esvaziamento Gástrico/genética , Humanos , Hipertensão/genética , Hipertensão/terapia , Contração Muscular/efeitos dos fármacos , Contração Muscular/genética , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Obesidade/genética , Obesidade/terapia , Hormônios Peptídicos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Somatostatina/química , Somatostatina/farmacologia , Somatostatina/fisiologia
13.
Int J Mol Sci ; 22(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34445304

RESUMO

Dysfunctional islets of Langerhans are a hallmark of type 2 diabetes (T2D). We hypothesize that differences in islet gene expression alternative splicing which can contribute to altered protein function also participate in islet dysfunction. RNA sequencing (RNAseq) data from islets of obese diabetes-resistant and diabetes-susceptible mice were analyzed for alternative splicing and its putative genetic and epigenetic modulators. We focused on the expression levels of chromatin modifiers and SNPs in regulatory sequences. We identified alternative splicing events in islets of diabetes-susceptible mice amongst others in genes linked to insulin secretion, endocytosis or ubiquitin-mediated proteolysis pathways. The expression pattern of 54 histones and chromatin modifiers, which may modulate splicing, were markedly downregulated in islets of diabetic animals. Furthermore, diabetes-susceptible mice carry SNPs in RNA-binding protein motifs and in splice sites potentially responsible for alternative splicing events. They also exhibit a larger exon skipping rate, e.g., in the diabetes gene Abcc8, which might affect protein function. Expression of the neuronal splicing factor Srrm4 which mediates inclusion of microexons in mRNA transcripts was markedly lower in islets of diabetes-prone compared to diabetes-resistant mice, correlating with a preferential skipping of SRRM4 target exons. The repression of Srrm4 expression is presumably mediated via a higher expression of miR-326-3p and miR-3547-3p in islets of diabetic mice. Thus, our study suggests that an altered splicing pattern in islets of diabetes-susceptible mice may contribute to an elevated T2D risk.


Assuntos
Processamento Alternativo/fisiologia , Diabetes Mellitus Tipo 2/genética , Ilhotas Pancreáticas/metabolismo , Processamento Alternativo/genética , Animais , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Suscetibilidade a Doenças , Secreção de Insulina/genética , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ilhotas Pancreáticas/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regulação para Cima/genética
14.
J Agric Food Chem ; 69(32): 9299-9312, 2021 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-34342980

RESUMO

Ginsenoside F2 (GF2) is a protopanaxdiol saponin from Panax ginseng leaves and possesses many potential pharmacological properties. GF2 may prevent obesity by directly binding to the peroxisome proliferator-activated receptor-γ (PPARγ) and inhibiting adipocyte differentiation. However, the mechanism by which GF2 alleviates obesity is unknown. We therefore explored the anti-adipogenesis and anti-obesity effects of GF2 in vitro and in vivo. GF2 inhibited differentiation and reduced the triglyceride (TG) content of 3T3-L1 preadipocytes in the early stage of adipogenesis. Administration of GF2 (50 and 100 mg/kg) to obese mice for 4 weeks reduced the body weight gain, weight of adipose tissues, adipocyte size, and total cholesterol, TG, and AST levels in serum. RNA sequencing and real-time quantitative PCR indicated that GF2 decreased the expression levels of adipokines, including PPARγ, fatty acid synthase, and adiponectin. KEGG enrichment and western blot analyses demonstrated that GF2 accelerated the phosphorylation of AMPK and ACC in vitro and in vivo. Moreover, GF2 promoted the biosynthesis of mitochondria in 3T3-L1 adipocytes and increased the expression of antioxidant enzymes such as SOD and GSH-Px in the liver of obese mice. Therefore, GF2 suppressed adipogenesis and obesity by regulating the expression of adipokines and activating the AMPK pathway. Hence, the findings suggest that GF2 may have potential therapeutic implications to treat obesity.


Assuntos
Adipogenia , Fármacos Antiobesidade , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/genética , Adipogenia/genética , Animais , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Ginsenosídeos , Camundongos , Camundongos Obesos , Obesidade/tratamento farmacológico , Obesidade/genética , PPAR gama/genética
15.
J Transl Med ; 19(1): 350, 2021 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-34399781

RESUMO

BACKGROUND: The roles of FTO gene and the level of serum 25-OH-vitamin D in obesity are frequently reported. This study aimed to investigate the interactions of serum 25-OH-vitamin D level, FTO and IRX3 genes expression, and FTO genotype in obese and overweight boys. METHODS: This study was carried out on the 120 male adolescents with overweight in Tehran, Iran. Blood samples were collected from the participants in order to evaluate the serum level of 25-OH-vitamin D, the expression level of FTO and IRX3 genes, and FTO genotype for rs9930506 at baseline and after 18 weeks of the study. RESULTS: In general, no significant association was found between serum 25-OH-vitamin D level and IRX3 and FTO genes expression. The results of linear regression on the relationship between 25-OH-vitamin D serum level and FTO and IRX3 genes expression based on FTO genotypes for rs9930506 indicated that in AA/AG genotype carriers, serum 25-OH-vitamin D level was positively associated with FTO gene expression (B = 0.07, p = 0.02) and inversely associated with IRX3 gene expression (B = - 0.07, p = 0.03). In GG carriers, serum 25-OH-vitamin D level was not associated with expression of IRX3 and FTO genes. CONCLUSION: There are significant interactions between 25-OH-vitamin D and the expression of FTO and IRX3 genes in the subset of obese patients with specific genotypes for FTO rs9930506. There was no association between serum 25-OH-vitamin D levels and the expression of FTO and IRX genes in individuals with a homozygous genotype for the risk allele of the FTO gene polymorphism.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Polimorfismo de Nucleotídeo Único , Adolescente , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Expressão Gênica , Genótipo , Proteínas de Homeodomínio/genética , Humanos , Irã (Geográfico) , Masculino , Obesidade/genética , Sobrepeso , Polimorfismo de Nucleotídeo Único/genética , Fatores de Transcrição/genética , Vitamina D
16.
Theranostics ; 11(16): 7829-7843, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34335967

RESUMO

Aims/hypothesis: MicroRNAs (miRNAs) are known to contribute to many metabolic diseases, including type 2 diabetes. This study aimed to investigate the roles and molecular mechanisms of miR-185-5p in the regulation of hepatic gluconeogenesis. Methods: MicroRNA high-throughput sequencing was performed to identify differentially expressed miRNAs. High-fat diet-induced obese C57BL/6 mice and db/db mice, a genetic mouse model for diabetes, were used for examining the regulation of hepatic gluconeogenesis. Quantitative reverse transcriptase PCR and Western blotting were performed to measure the expression levels of various genes and proteins. Luciferase reporter assays were used to determine the regulatory roles of miR-185-5p on G6Pase expression. Results: Hepatic miR-185-5p expression was significantly decreased during fasting or insulin resistance. Locked nucleic acid (LNA)-mediated suppression of miR-185-5p increased blood glucose and hepatic gluconeogenesis in healthy mice. In contrast, overexpression of miR-185-5p in db/db mice alleviated blood hyperglycemia and decreased gluconeogenesis. At the molecular level, miR-185-5p directly inhibited G6Pase expression by targeting its 3'-untranslated regions. Furthermore, metformin, an anti-diabetic drug, could upregulate miR-185-5p expression to suppress G6Pase, leading to hepatic gluconeogenesis inhibition. Conclusions/interpretation: Our findings provided a novel insight into the role of miR-185-5p that suppressed hepatic gluconeogenesis and alleviated hyperglycemia by targeting G6Pase. We further identified that the /G6Pase axis mediated the inhibitory effect of metformin on hepatic gluconeogenesis. Thus, miR-185-5p might be a therapeutic target for hepatic glucose overproduction and fasting hyperglycemia.


Assuntos
Gluconeogênese/genética , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Glicemia/análise , Diabetes Mellitus Tipo 2/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Gluconeogênese/fisiologia , Glucose/metabolismo , Glucose-6-Fosfatase/metabolismo , Hiperglicemia/metabolismo , Insulina/metabolismo , Resistência à Insulina/genética , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , MicroRNAs/metabolismo , Obesidade/genética
17.
Nat Commun ; 12(1): 4878, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-34385447

RESUMO

A postprandial increase of translation mediated by eukaryotic Initiation Factor 6 (eIF6) occurs in the liver. Its contribution to steatosis and disease is unknown. In this study we address whether eIF6-driven translation contributes to disease progression. eIF6 levels increase throughout the progression from Non-Alcoholic Fatty Liver Disease (NAFLD) to hepatocellular carcinoma. Reduction of eIF6 levels protects the liver from disease progression. eIF6 depletion blunts lipid accumulation, increases fatty acid oxidation (FAO) and reduces oncogenic transformation in vitro. In addition, eIF6 depletion delays the progression from NAFLD to hepatocellular carcinoma, in vivo. Mechanistically, eIF6 depletion reduces the translation of transcription factor C/EBPß, leading to a drop in biomarkers associated with NAFLD progression to hepatocellular carcinoma and preserves mitochondrial respiration due to the maintenance of an alternative mTORC1-eIF4F translational branch that increases the expression of transcription factor YY1. We provide proof-of-concept that in vitro pharmacological inhibition of eIF6 activity recapitulates the protective effects of eIF6 depletion. We hypothesize the existence of a targetable, evolutionarily conserved translation circuit optimized for lipid accumulation and tumor progression.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Hepatopatia Gordurosa não Alcoólica/genética , Fatores de Iniciação de Peptídeos/genética , Biossíntese de Proteínas/genética , Animais , Proteína beta Intensificadora de Ligação a CCAAT/genética , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Carcinoma Hepatocelular/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Clofazimina/farmacologia , Dieta Hiperlipídica/efeitos adversos , Progressão da Doença , Inativação Gênica , Humanos , Lipogênese/efeitos dos fármacos , Lipogênese/genética , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Hepatopatia Gordurosa não Alcoólica/metabolismo , Obesidade/etiologia , Obesidade/genética , Obesidade/metabolismo , Fatores de Iniciação de Peptídeos/antagonistas & inibidores , Fatores de Iniciação de Peptídeos/metabolismo
18.
Stem Cell Res ; 54: 102432, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34214899

RESUMO

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a basic helix-loop-helix (bHLH/PAS) transcription factor involved in the development of paraventricular nucleus of the hypothalamus (PVH) through the heterodimerization with Single-minded 1 (SIM1) (Michaud et al., 2000). Using a Sendai virus-based approach, the four reprogramming factors OCT3/4, SOX2, KLF4 and C-MYC were delivered into Peripheral Blood Mononuclear Cell (PBMCs) from a 14-year-old girl with early onset obesity carrying a de novo variant (p.P130A) in ARNT2. The resulting iPSC line CUIMCi003-A had a normal karyotype, showed pluripotency and three germ layer differentiation capacity in vitro and was heterozygous for the de novo ARNT2 variant.


Assuntos
Células-Tronco Pluripotentes Induzidas , Adolescente , Translocador Nuclear Receptor Aril Hidrocarboneto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares/metabolismo , Obesidade/genética
19.
Handb Clin Neurol ; 181: 301-310, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34238466

RESUMO

Neural circuits in the hypothalamus play a key role in the regulation of human energy homeostasis. A critical circuit involves leptin-responsive neurons in the hypothalamic arcuate nucleus (the infundibular nucleus in humans) expressing the appetite-suppressing neuropeptide proopiomelanocortin (POMC) and the appetite-stimulating Agouti-related peptide. In the fed state, the POMC-derived melanocortin peptide α-melanocyte-stimulating hormone stimulates melanocortin-4 receptors (MC4Rs) expressed on second-order neurons in the paraventricular nucleus of the hypothalamus (PVN). Agonism of MC4R leads to reduced food intake and increased energy expenditure. Disruption of this hypothalamic circuit by inherited mutations in the genes encoding leptin, the leptin receptor, POMC, and MC4R can lead to severe obesity in humans. The characterization of these and closely related genetic obesity syndromes has informed our understanding of the neural pathways by which leptin regulates energy balance, neuroendocrine function, and the autonomic nervous system. A broader understanding of these neural and molecular mechanisms has paved the way for effective mechanism-based therapies for patients whose severe obesity is driven by disruption of these pathways.


Assuntos
Obesidade , Pró-Opiomelanocortina , Metabolismo Energético/genética , Humanos , Hipotálamo/metabolismo , Leptina/genética , Leptina/metabolismo , Obesidade/genética , Pró-Opiomelanocortina/genética , Pró-Opiomelanocortina/metabolismo , Receptor Tipo 4 de Melanocortina/genética , Receptores para Leptina/genética , Síndrome
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