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1.
Orv Hetil ; 160(37): 1447-1454, 2019 Sep.
Artigo em Húngaro | MEDLINE | ID: mdl-31495190

RESUMO

Myotonic dystrophy is one of the most common, autosomal dominantly inherited adult-onset muscle disorders. Two types of the disease are known: type 1 is characterized by distal weakness and myotonia, but type 2 is associated with proximal weakness and milder clinical course. It is also called as Steinert Disease, which affects the heart conduction system, the internal secretional glands, the ocular lens as well as carbohydrate-, fat metabolism and gonadal functions. These systemic symptoms have high impact on the quality of life and might impact on patients' survival. Here we would like to emphasize these clinical conditions and the diagnostic possibilities. We hope our recommendations can help neurologists and general practitioners to achieve an optimal and individual care for patients suffering from this muscle disease. Orv Hetil. 2019; 160(37): 1447-1454.


Assuntos
Sistema de Condução Cardíaco/fisiopatologia , Distrofia Miotônica/diagnóstico , Adulto , Catarata/genética , Humanos , Resistência à Insulina/genética , Músculos/fisiopatologia , Distrofia Miotônica/complicações , Distrofia Miotônica/genética , Doenças do Sistema Nervoso , Qualidade de Vida , Expansão das Repetições de Trinucleotídeos
2.
Life Sci ; 234: 116793, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31465735

RESUMO

INTRODUCTION: Environmental factors have a key role in the control of gut microbiota and obesity. TLR2 knockout (TLR2-/-) mice in some housing conditions are protected from diet-induced insulin resistance. However, in our housing conditions these animals are not protected from diet-induced insulin-resistance. AIM: The aim of the present study was to investigate the influence of our animal housing conditions on the gut microbiota, glucose tolerance and insulin sensitivity in TLR2-/- mice. MATERIAL AND METHODS: The microbiota was investigated by metagenomics, associated with hyperinsulinemic euglycemic clamp and GTT associated with insulin signaling through immunoblotting. RESULTS: The results showed that TLR2-/- mice in our housing conditions presented a phenotype of metabolic syndrome characterized by insulin resistance, glucose intolerance and increase in body weight. This phenotype was associated with differences in microbiota in TLR2-/- mice that showed a decrease in the Proteobacteria and Bacteroidetes phyla and an increase in the Firmicutesphylum, associated with and in increase in the Oscillospira and Ruminococcus genera. Furthermore there is also an increase in circulating LPS and subclinical inflammation in TLR2-/-. The molecular mechanism that account for insulin resistance was an activation of TLR4, associated with ER stress and JNK activation. The phenotype and metabolic behavior was reversed by antibiotic treatment and reproduced in WT mice by microbiota transplantation. CONCLUSIONS: Our data show, for the first time, that the intestinal microbiota can induce insulin resistance and obesity in an animal model that is genetically protected from these processes.


Assuntos
Microbioma Gastrointestinal , Resistência à Insulina , Insulina/metabolismo , Receptor 2 Toll-Like/genética , Animais , Estresse do Retículo Endoplasmático , Deleção de Genes , Intolerância à Glucose/genética , Intolerância à Glucose/metabolismo , Intolerância à Glucose/microbiologia , Abrigo para Animais , Resistência à Insulina/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptor 2 Toll-Like/metabolismo
3.
DNA Cell Biol ; 38(8): 754-762, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31305133

RESUMO

Polycystic ovary syndrome (PCOS) is the most typical metabolic syndrome in women of reproductive age, with a high prevalence and an increased risk of long-term complications. PCOS mainly manifests as hyperandrogenism (HA), ovulatory dysfunction, and polycystic ovaries, in addition to being relevant to infertility, insulin resistance (IR), obesity, lipid abnormalities, and chronic low-grade inflammation. The etiology of this syndrome remains largely unknown. microRNAs (miRNAs), small, noncoding RNAs (nearly 22 nucleotides long), regulate gene expression at the posttranscriptional level. Abnormal miRNA levels are closely associated with the occurrence of diseases, such as diabetes, cancers, and atherosclerosis, and miRNAs can be used as predictors and diagnostic biomarkers for cancer. Interestingly, the roles of miRNAs in PCOS pathology have attracted considerable attention in recent years. Research has established that alterations in miRNA expression in women with PCOS compared with healthy women may act as noninvasive biomarkers and new therapeutic targets in PCOS. This article aims to summarize the latest research on the relationship between miRNAs and the clinical manifestations of PCOS while also providing a few mechanisms based on previous studies. Understanding the relationship between miRNAs and PCOS will provide guidance for researchers to further explore the complexity and heterogeneity of PCOS.


Assuntos
Androgênios/metabolismo , Biomarcadores/sangue , MicroRNAs , Síndrome do Ovário Policístico/genética , Androgênios/genética , Dislipidemias/genética , Feminino , Regulação da Expressão Gênica , Humanos , Resistência à Insulina/genética , MicroRNAs/sangue , Obesidade/genética , Folículo Ovariano/crescimento & desenvolvimento , Folículo Ovariano/patologia , Ovário/fisiologia , Síndrome do Ovário Policístico/etiologia
4.
Life Sci ; 232: 116603, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31254587

RESUMO

AIMS: Although anabolic steroids (AS) and trans-fatty acids overload exerts systemic toxicity and are independent risk factors for metabolic and cardiovascular disorders, their interaction remains poorly understood. Thus, we investigated the impact of a diet rich in trans-fatty acids (HFD) combined with AS on glycemic control, lipid profile, adipose tissue, skeletal muscle and pancreas microstructure and expression of genes involved in energy metabolism. MAIN METHODS: Forty-eight C57BL/6 mice were randomized into 6 groups treated for 12 weeks with a standard diet (SD) or a diet rich in C18:1 trans-fatty isomers (HFD), alone or combined with 10 or 20 mg/kg testosterone cypionate (AS). KEY FINDINGS: Our results indicated that AS improved glycemic control, upregulated gene expression of Glut-4 and CPT-1 in skeletal muscle, FAS, ACC and UCP-1 in adipose tissue. AS also reduced total and LDL cholesterol in mice fed a SD. When combined with the HFD, AS was unable to induce microstructural adaptations in adipose tissue, pancreatic islets and ß-cells, but potentiated GCK and Glut-2 (pancreas) and Glut-4 and CPT-1 (skeletal muscle) upregulation. HFD plus AS also downregulated FAS and ACC gene expression in adipose tissue. Combined with HFD, AS increased triacylglycerol circulating levels, improved insulin sensitivity and glycemic control in mice. SIGNIFICANCE: Our findings indicated that HFD and AS can interact to modulates glycemic control and lipid profile by a mechanism potentially related with a reprogramming of genes expression in organs such as the pancreas, adipose tissue and skeletal muscle.


Assuntos
Congêneres da Testosterona/genética , Congêneres da Testosterona/metabolismo , Ácidos Graxos Trans/metabolismo , Tecido Adiposo/metabolismo , Animais , Glicemia/metabolismo , Dieta Hiperlipídica/efeitos adversos , Metabolismo Energético/fisiologia , Feminino , Glucose/metabolismo , Carga Glicêmica/fisiologia , Resistência à Insulina/genética , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Pâncreas/metabolismo , Ácidos Graxos Trans/fisiologia
5.
Nat Commun ; 10(1): 2375, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31147543

RESUMO

Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins and is involved in many physiological processes. Obesity, as a worldwide healthcare problem, has attracted more and more attention. To investigate the role of adipose HuR, we generate adipose-specific HuR knockout (HuRAKO) mice. As compared with control mice, HuRAKO mice show obesity when induced with a high-fat diet, along with insulin resistance, glucose intolerance, hypercholesterolemia and increased inflammation in adipose tissue. The obesity of HuRAKO mice is attributed to adipocyte hypertrophy in white adipose tissue due to decreased expression of adipose triglyceride lipase (ATGL). HuR positively regulates ATGL expression by promoting the mRNA stability and translation of ATGL. Consistently, the expression of HuR in adipose tissue is reduced in obese humans. This study suggests that adipose HuR may be a critical regulator of ATGL expression and lipolysis and thereby controls obesity and metabolic syndrome.


Assuntos
Tecido Adiposo Branco/metabolismo , Proteína Semelhante a ELAV 1/genética , Intolerância à Glucose/genética , Hipercolesterolemia/genética , Resistência à Insulina/genética , Lipase/genética , Obesidade/genética , Adipócitos/patologia , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/imunologia , Animais , Crescimento Celular , Dieta Hiperlipídica , Proteína Semelhante a ELAV 1/metabolismo , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Intolerância à Glucose/metabolismo , Humanos , Hipercolesterolemia/metabolismo , Hipertrofia , Inflamação/imunologia , Lipase/metabolismo , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Knockout , Obesidade/metabolismo , Biossíntese de Proteínas , Estabilidade de RNA/genética , Gordura Subcutânea/metabolismo
6.
Diabetes Res Clin Pract ; 152: 79-87, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31102683

RESUMO

AIMS: The present report aimed to clarify the clinical characteristics in a girl at the age of 12 and her mother with partial lipodystrophy and Type A insulin resistance syndrome. METHODS: We examined fat distribution in the patients using dual-energy X-ray absorptiometry, magnetic resonance imaging, and computed tomography. We performed genetic analysis to examine the causal gene for lipodystrophy and insulin resistance. RESULTS: Both patients had partial lipodystrophy and a novel heterozygous missense mutation (Asn1137 → Lys1137) in the insulin receptor gene. Because Asn1137 in the catalytic loop is conserved in all protein kinases, this mutation was thought to impair insulin receptor function. By whole-exome sequencing, we found the proband had neither mutations in candidate genes known to be associated with familial partial lipodystrophy nor novel likely candidate causal genes. Taken together, we thought that fat loss in these two patients might be caused by insulin receptor dysfunction. The proband had amenorrhea due to polycystic ovary syndrome. Her menstruation improved, as fat loss was restored during adolescence. This might be caused by improving insulin resistance due to increased levels of leptin and fat mass. CONCLUSIONS: This case might help to understand the mechanisms insulin receptor dysfunction that cause lipodystrophy.


Assuntos
Antígenos CD/genética , Lipodistrofia Parcial Familiar/genética , Síndrome Metabólica/genética , Mutação de Sentido Incorreto , Receptor de Insulina/genética , Adulto , Estudos de Casos e Controles , Criança , Feminino , Testes Genéticos , Heterozigoto , Humanos , Resistência à Insulina/genética , Lipodistrofia Parcial Familiar/complicações , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Núcleo Familiar , Linhagem , Fenótipo , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/genética
7.
Genes Dev ; 33(13-14): 747-762, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31123067

RESUMO

Prolonged cold exposure stimulates the recruitment of beige adipocytes within white adipose tissue. Beige adipocytes depend on mitochondrial oxidative phosphorylation to drive thermogenesis. The transcriptional mechanisms that promote remodeling in adipose tissue during the cold are not well understood. Here we demonstrate that the transcriptional coregulator transducin-like enhancer of split 3 (TLE3) inhibits mitochondrial gene expression in beige adipocytes. Conditional deletion of TLE3 in adipocytes promotes mitochondrial oxidative metabolism and increases energy expenditure, thereby improving glucose control. Using chromatin immunoprecipitation and deep sequencing, we found that TLE3 occupies distal enhancers in proximity to nuclear-encoded mitochondrial genes and that many of these binding sites are also enriched for early B-cell factor (EBF) transcription factors. TLE3 interacts with EBF2 and blocks its ability to promote the thermogenic transcriptional program. Collectively, these studies demonstrate that TLE3 regulates thermogenic gene expression in beige adipocytes through inhibition of EBF2 transcriptional activity. Inhibition of TLE3 may provide a novel therapeutic approach for obesity and diabetes.


Assuntos
Adipócitos Bege/metabolismo , Proteínas Correpressoras/genética , Proteínas Correpressoras/metabolismo , Glucose/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Células Cultivadas , Dieta Hiperlipídica , Metabolismo Energético/genética , Deleção de Genes , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Resistência à Insulina/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/metabolismo , Termogênese/genética
8.
Biomed Res Int ; 2019: 3102414, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30984779

RESUMO

Etifoxine, an 18 kDa translocator protein (TSPO) agonist for the treatment of anxiety disorders in clinic, may be able to cause acute liver injury or cytolytic hepatitis. TSPO has been demonstrated to participate in inflammatory responses in infective diseases as well as to modulate glucose and lipid homeostasis. Hepatitis C virus (HCV) infection disrupts glucose and lipid homoeostasis, leading to insulin resistance (IR). Whether TSPO affects the HCV-induced IR remains unclear. Here, we found that the administration of etifoxine increased the TSPO protein expression and recovered the HCV-mediated lower mitochondrial membrane potential (MMP) without affecting HCV infection. Moreover, etifoxine reversed the HCV-induced lipid accumulation by modulating the expressions of sterol regulatory element-binding protein-1 and apolipoprotein J. On the other hand, in infected cells pretreated with etifoxine, the insulin-mediated insulin receptor substrate-1/Akt signals, forkhead box protein O1 translocation, and glucose uptake were blocked. Taken together, our results pointed out that etifoxine relieved the HCV-retarded MMP and reduced the lipid accumulation but deteriorated the HCV-induced IR by interfering with insulin signal molecules.


Assuntos
Hepatite C/tratamento farmacológico , Inflamação/tratamento farmacológico , Resistência à Insulina/genética , Oxazinas/administração & dosagem , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/metabolismo , Hepatite C/genética , Hepatite C/patologia , Hepatite C/virologia , Humanos , Inflamação/genética , Inflamação/patologia , Inflamação/virologia , Proteínas Substratos do Receptor de Insulina/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/genética , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Receptores de GABA/genética
9.
Med Sci Monit ; 25: 2293-3004, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31013265

RESUMO

BACKGROUND The occurrence of nonalcoholic fatty liver disease (NAFLD) is closely related to type 2 diabetes, especially in patients with insulin resistance. The purpose of this research was to elucidate the major genes and transcriptional regulation of insulin resistance in the progression of NAFLD. MATERIAL AND METHODS We downloaded the gene expression matrix of GSE89632 from Gene Expression Omnibus. Then the principal component analysis was used to identify whether the samples were clustered. Differentially expressed genes were identified by limma R package. Enrichment analysis and protein­protein interaction network was used to find potential function and screening hub genes. We further used ChIP-seq data from ENCODE to predict the transcriptional regulation of hub genes. Finally, we verified the functions of hub genes with clinical information. RESULTS These hub genes were significantly enriched in "response to insulin", "response to glucose", and "fat cell differentiation". ChIP-seq data showed that EGR1 (early growth response gene-1) may play an important role in the transcriptional regulation of SOCS1 (suppressor of cytokine signaling 1), SOCS3 (suppressor of cytokine signaling 3), and Fos gene family in the liver, as the low expression of EGR1 in patients with insulin resistance may promote the occurrence and development of NAFLD. Similarly, correlation analysis showed that EGR1 was positively correlated with the expression of SOCS1, SOCS3, and the genes of Fos gene family, and EGR1 was negatively correlated with the degree of steatosis. CONCLUSIONS Newly identified hub genes and their transcriptional regulation may promote understanding of the molecular mechanisms underlying insulin resistance related to the progression of NAFLD and provide a new therapy target and biomarkers.


Assuntos
Proteína 1 de Resposta de Crescimento Precoce/genética , Resistência à Insulina/genética , Hepatopatia Gordurosa não Alcoólica/genética , Adulto , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Progressão da Doença , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Insulina/metabolismo , Fígado/metabolismo , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Análise de Componente Principal , Mapas de Interação de Proteínas , Proteína 1 Supressora da Sinalização de Citocina/genética , Proteína 1 Supressora da Sinalização de Citocina/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo
10.
EBioMedicine ; 42: 494-503, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30948354

RESUMO

BACKGROUND: Many studies have demonstrated that microRNAs, a class of small and non-coding RNA molecules, play an important role in the regulation of glucose and lipid homeostasis. In the present study, we sought to investigate the function of miR-592 in the development of obesity-associated metabolic disorders, including hyperglycemia andinsulin resistance. METHODS: The expression levels of miR-592 were measured in the liver of obese mice and humans by quantitative reverse transcription PCR. Loss- and gain-of function experiments were employed to explore the metabolic function of miR-592 using locked nucleic acids and adenovirus in lean and obese mice, respectively. The molecular target of miR-592 was determined by western blotting and luciferase reporter assays. FINDINGS: We found a significant decreased expression of miR-592 in the liver of obese mice and humans. Inhibition of miR-592 led to elevated blood glucose levels, enhanced gluconeogenesis and reduced insulin sensitivity in lean mice. In contrast, adenovirus-mediated overexpression of hepatic miR-592 improved metabolic disorders in obese mice. Mechanistically, we found that the transcription factor forkhead box O1 (FOXO1) is a direct target gene of miR-592 to mediate its metabolic functions. miR-592 was able to inhibit the mRNA and protein expression of FOXO1 by binding to its 3'-untranslated region. INTERPRETATIONS: Our findings demonstrate that obesity-associated down-regulation of miR-592 plays an important role in the progression of metabolic diseases. Restoration of hepatic miR-592 could improve glucose and lipid metabolism in obese mice. FUND: This work is supported by the National Key Research and Development Program of China (No. 2016YFC1304805 to Dr. Chen), Natural Science Foundation of China (No. 81771574 to Dr. Wu), Shanghai Science Foundation (No. 18ZR1437800 to Dr. Li), Science and Technology Commission of Shanghai Municipality (Nos.18dz2304400 and 15,411,970,700 to Dr. Yang).


Assuntos
Hiperglicemia/sangue , Hiperglicemia/genética , Resistência à Insulina/genética , MicroRNAs/genética , Obesidade/genética , Obesidade/metabolismo , Regiões 3' não Traduzidas , Animais , Biomarcadores , Modelos Animais de Doenças , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Glucose/metabolismo , Hepatócitos/metabolismo , Metabolismo dos Lipídeos , Camundongos , Obesidade/sangue , RNA Interferente Pequeno/genética
11.
Immunity ; 50(5): 1232-1248.e14, 2019 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-31027998

RESUMO

Regulatory T cells (Treg cells) are important for preventing autoimmunity and maintaining tissue homeostasis, but whether Treg cells can adopt tissue- or immune-context-specific suppressive mechanisms is unclear. Here, we found that the enzyme hydroxyprostaglandin dehydrogenase (HPGD), which catabolizes prostaglandin E2 (PGE2) into the metabolite 15-keto PGE2, was highly expressed in Treg cells, particularly those in visceral adipose tissue (VAT). Nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ)-induced HPGD expression in VAT Treg cells, and consequential Treg-cell-mediated generation of 15-keto PGE2 suppressed conventional T cell activation and proliferation. Conditional deletion of Hpgd in mouse Treg cells resulted in the accumulation of functionally impaired Treg cells specifically in VAT, causing local inflammation and systemic insulin resistance. Consistent with this mechanism, humans with type 2 diabetes showed decreased HPGD expression in Treg cells. These data indicate that HPGD-mediated suppression is a tissue- and context-dependent suppressive mechanism used by Treg cells to maintain adipose tissue homeostasis.


Assuntos
Dinoprostona/análogos & derivados , Dinoprostona/metabolismo , Hidroxiprostaglandina Desidrogenases/metabolismo , Gordura Intra-Abdominal/imunologia , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia , Células 3T3 , Animais , Linhagem Celular , Diabetes Mellitus Tipo 2/metabolismo , Células HEK293 , Homeostase/imunologia , Humanos , Hidroxiprostaglandina Desidrogenases/genética , Resistência à Insulina/genética , Gordura Intra-Abdominal/citologia , Células Jurkat , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Knockout , Fator de Transcrição STAT5/metabolismo
12.
Reprod Biol Endocrinol ; 17(1): 36, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30982470

RESUMO

BACKGROUND: Endometriosis is an estrogen dependent, inflammatory disorder occurring in 5-10% of reproductive-aged women. Women with endometriosis have a lower body mass index (BMI) and decreased body fat compared to those without the disease, yet few studies have focused on the metabolic abnormalities in adipose tissue in women with endometriosis. Previously, we identified microRNAs that are differentially expressed in endometriosis and altered in the serum of women with the disease. Here we explore the effect of endometriosis on fat tissue and identified a role for endometriosis-related microRNAs in fat metabolism and a reduction in adipocyte stem cell number. METHODS: Primary adipocyte cells cultured from 20 patients with and without endometriosis were transfected with mimics and inhibitors of microRNAs 342-3p or Let 7b-5p to model the status of these microRNAs in endometriosis. RNA was extracted for gene expression analysis by qRT-PCR. PCNA expression was used as a marker of adipocyte proliferation. Endometriosis was induced experimentally in 9-week old female C57BL/6 mice and after 10 months fat tissue was harvested from both the subcutaneous (inguinal) and visceral (mesenteric) tissue. Adipose-derived mesenchymal stem cells in fat tissue were characterized in both endometriosis and non-endometriosis mice by FACS analysis. RESULTS: Gene expression analysis showed that endometriosis altered the expression of Cebpa, Cebpb, Ppar-γ, leptin, adiponectin, IL-6, and HSL, which are involved in driving brown adipocyte differentiation, appetite, insulin sensitivity and fat metabolism. Each gene was regulated by an alteration in microRNA expression known to occur in endometriosis. Analysis of the stem cell content of adipose tissue in a mouse model of endometriosis demonstrated a reduced number of adipocyte stem cells. CONCLUSIONS: We demonstrate that microRNAs Let-7b and miR-342-3p affected metabolic gene expression significantly in adipocytes of women with endometriosis. Similarly, there is a reduction in the adipose stem cell population in a mouse model of endometriosis. Taken together these data suggest that endometriosis alters BMI in part through an effect on adipocytes and fat metabolism.


Assuntos
Adipócitos/patologia , Endometriose/patologia , Adipócitos/metabolismo , Animais , Diferenciação Celular/genética , Proliferação de Células , Endometriose/genética , Endometriose/metabolismo , Feminino , Expressão Gênica , Humanos , Resistência à Insulina/genética , Metabolismo dos Lipídeos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Antígeno Nuclear de Célula em Proliferação/metabolismo
13.
Nat Commun ; 10(1): 1546, 2019 04 04.
Artigo em Inglês | MEDLINE | ID: mdl-30948720

RESUMO

The insulin/IGF-1 signalling pathway is a key regulator of metabolism and the rate of ageing. We previously documented that systemic inactivation of phosphoinositide 3-kinase (PI3K) p110α, the principal PI3K isoform that positively regulates insulin signalling, results in a beneficial metabolic effect in aged mice. Here we demonstrate that deletion of p110α specifically in the adipose tissue leads to less fat accumulation over a significant part of adult life and allows the maintenance of normal glucose tolerance despite insulin resistance. This effect of p110α inactivation is due to a potentiating effect on ß-adrenergic signalling, which leads to increased catecholamine-induced energy expenditure in the adipose tissue. Our findings provide a paradigm of how partial inactivation of an essential component of the insulin signalling pathway can have an overall beneficial metabolic effect and suggest that PI3K inhibition could potentiate the effect of ß-adrenergic agonists in the treatment of obesity and its associated comorbidities.


Assuntos
Tecido Adiposo/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/fisiologia , Fatores Etários , Animais , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Resistência à Insulina/genética , Camundongos Transgênicos , Obesidade/metabolismo , Transdução de Sinais
14.
Lipids Health Dis ; 18(1): 89, 2019 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-30954075

RESUMO

BACKGROUND: Elevation of exogenous free fatty acid (FFA) level leads to insulin resistance (IR) in liver, IR is manifested by elevated hepatic glucose production. We aim to study whether inhibition of endogenous fatty acid synthesis could decrease hepatic glucose production. METHODS: Low-passage HepG2 cells derived from human liver tissue were cultured in medium supplemented with FFA to induce IR, the influences of sterol regulatory element binding protein-1c (SREBP-1c) silencing on glucose production of HepG2 cells were investigated, and genes responsible for fatty acid and glucose metabolism were detected by real-time PCR. RESULTS: Compared with HepG2 cells cultured in normal growth medium, glucose production of HepG2 cells treated by FFA was significantly increased {[(0.28 ± 0.01) vs (0.83 ± 0.02)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of phosphoenolpyruvate carboxylase kinase (PEPCK) and glucose-6-phosphatase (G6PC) in HepG2 cells increased by more than 5-fold and 3-fold, respectively; the mRNA expression of fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD1) increased by approximately 4-fold and 1.1-fold, respectively; the mRNA expression of carnitine palmitoyltransferase-1 (CPT-1) changed slightly. Compared with the scrambled siRNA control, glucose production of HepG2 cells treated by FFA significantly increased after SREBP-1c silencing {[(0.018 ± 0.001) vs (0.028 ± 0.002)] umol.ug- 1 protein, n = 6 wells, P < 0.01}; the mRNA expression of PEPCK and G6PC increased by approximately 1.5-fold and 5-fold, respectively, but the mRNA expression of FAS, SCD1 and CPT-1 changed slightly. CONCLUSIONS: SREBP-1c silencing further augmented glucose production of HepG2 cells treated by FFA significantly, genes responsible for fatty acid synthesis and gluconeogenesis played an important role in this process. SREBP-1c functions not only as a lipid regulator but also plays an important role in regulation of glucose metabolism.


Assuntos
Meios de Cultura/farmacologia , Ácidos Graxos não Esterificados/farmacologia , Glucose/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Carnitina O-Palmitoiltransferase/genética , Ácido Graxo Sintases/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica/efeitos dos fármacos , Células Hep G2 , Humanos , Resistência à Insulina/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Triglicerídeos/metabolismo
15.
Free Radic Res ; 53(3): 248-268, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30843740

RESUMO

In addition to insulin, glycemic control involves thyroid hormones. However, an excess of thyroid hormone can disturb the blood glucose equilibrium, leading to alterations of carbohydrate metabolism and, eventually, diabetes. Indeed, experimental and clinical hyperthyroidism is often accompanied by abnormal glucose tolerance. A common characteristic of hyperthyroidism and type 2 diabetes is the altered mitochondrial efficiency caused by the enhanced production of reactive oxygen and nitrogen species. It is known that an excess of thyroid hormone leads to increased oxidant production and mitochondrial oxidative damage. It can be hypothesised that these species represent the link between hyperthyroidism and development of insulin resistance and diabetes, even though direct evidence of this relationship is lacking. In this review, we examine the literature concerning the effects of insulin and thyroid hormones on glucose metabolism and discuss alterations of glucose metabolism in hyperthyroid conditions and the cellular and molecular mechanisms that may underline them.


Assuntos
Diabetes Mellitus Tipo 2/genética , Hipertireoidismo/complicações , Resistência à Insulina/genética , Oxigênio/metabolismo , Espécies Reativas de Nitrogênio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Humanos , Hipertireoidismo/patologia
16.
Turk J Med Sci ; 49(2): 490-496, 2019 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-30866603

RESUMO

Background/aim: Genetic aspects play a role in insulin resistance in children. In this study, for the first time, the association of LRP5 (rs556442) polymorphism and insulin resistance in Iranian children and adolescents was investigated. Materials and methods: The study population comprises children and adolescents aged 9­18 years. Anthropometric and biochemical parameters were assessed. Insulin resistance/sensitivity was determined by the quantitative insulin sensitivity check index (QUICKI), homeostasis model assessment-insulin resistance (HOMA-IR), insulin-to-glucose ratio, McAuley index, revised McAuley index, fasting insulin resistance index (FIRI), and Bennett's index. LRP5 (rs566442) single nucleotide polymorphism (SNP) was identified using restriction fragment length polymorphism (RFLP). Linear regression analysis was used to determine the association between the LRP5 polymorphism (rs556442) and insulin sensitivity indexes. Results: Significant differences were found between GG genotype vs. AG/AA genotypes for McAuley index (P = 0.049) and revised McAuley index (P = 0.044) when adjusted for interaction factors (age, sex, and puberty) in regression models. No significant association was found between LRP5 (rs566442) and other insulin resistance indexes. Also, LRP5 (rs566442) did not show a significant impact on biochemical parameters. Conclusion: This study showed that LRP5 polymorphism (rs556442) was associated with insulin resistance in Iranian children and adolescents.


Assuntos
Resistência à Insulina/genética , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/genética , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Criança , Estudos Transversais , Feminino , Predisposição Genética para Doença , Teste de Tolerância a Glucose , Voluntários Saudáveis , Homeostase/genética , Humanos , Irã (Geográfico) , Proteína-5 Relacionada a Receptor de Lipoproteína de Baixa Densidade/fisiologia , Masculino , População Urbana
17.
Drug Metab Pers Ther ; 34(1)2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30888963

RESUMO

Background Previous studies reported conflicting results regarding association of insulin receptor substrate 1 (IRS1) gene variation with type 2 diabetes (T2D) and insulin resistance (IR) in different ethnic groups. We examined the association of rs7578326, rs2943641, and rs4675095 in the IRS1 gene with T2D and related traits in a population from Bosnia and Herzegovina, which is one of the European countries with the highest T2D prevalence of 12.5%. Methods Our study included 390 T2D patients and 252 control subjects. Biochemical parameters, including fasting glucose (FG), fasting insulin (FI), homeostasis model assessment insulin resistance index (HOMA-IR), and HbA1c were measured in all participants. Genotyping analysis was performed by Mass Array Sequenom iPlex platform. Results Our results demonstrated that rs7578326 and rs4675095 variants were associated with increased FG levels. The rs7578326 was also associated with higher FI, HOMA-IR (B = 0.08, 95% CI [0.01, 0.15], padd = 0.025; B = 0.079, 95% CI [0.006, 0.150], padd = 0.033, respectively) in T2D, and with HbA1c (B = 0.034, 95% CI [0.003, 0.065], pdom = 0.035) in non-drug-treated T2D. In contrast, rs2943641 C allele was associated with lower FG levels in control subjects (B = -0.17, 95% CI [-0.03, -0.002], padd = 0.030) and HbA1c (B = 0.03, 95% CI [0.002, 0.06], pdom = 0.040) in non-drug-treated T2D. Conclusions We report the association between common variants in IRS1 gene with insulin resistance, glucose, and HbA1c levels in Bosnia and Herzegovina's population.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Variação Genética , Proteínas Substratos do Receptor de Insulina/genética , Resistência à Insulina/genética , Bósnia e Herzegóvina , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/diagnóstico , Genótipo , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/genética , Humanos
18.
EBioMedicine ; 42: 481-493, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30879920

RESUMO

BACKGROUND: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of the epigenetic regulators in these processes remain largely elusive. METHODS: Hepatocyte-specific Arid1a knockout mice were administrated with high-fat diet (HFD) for 12 weeks, then insulin sensitivity was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT). The metabolism-related indicators were determined by employing a variety of biological methods, including histology, real-time PCR, enzyme-linked immunosorbent assay (ELISA), Western blotting assay, Chromatin immunoprecipitation (ChIP), RNA-seq and assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq). FINDINGS: Hepatocyte-specific Arid1a deletion significantly increases susceptibility to develop hepatic steatosis, insulin resistance and inflammation in mice fed a HFD. In vitro, Arid1a deletion in isolated hepatocytes directly leads to free fatty acid-induced lipid accumulation and insulin resistance. Mechanically, Arid1a deficiency impairs fatty acid oxidation by downregulating PPARα and altering the epigenetic landscape of some metabolism genes. INTERPRETATION: These findings reveal that targeting Arid1a might be a promising therapeutic strategy for liver steatosis and insulin resistance. FUND: This work was supported by National Natural Science Foundation of China (81672772 and 81472621), China National Science and Technology Major Project for Prevention and Treatment of Infectious Diseases (No.2017ZX 10203207) and National Program on Key Research Project of China (grant no. 2016YFC0902701).


Assuntos
Proteínas de Ligação a DNA/genética , Resistência à Insulina/genética , Metabolismo dos Lipídeos/genética , Proteínas Nucleares/genética , Animais , Suscetibilidade a Doenças , Glucose/metabolismo , Hepatócitos/metabolismo , Histonas/metabolismo , Insulina/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Ativados por Proliferador de Peroxissomo , Transdução de Sinais
19.
Oxid Med Cell Longev ; 2019: 2695289, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30863477

RESUMO

Insulin resistance is associated with oxidative stress, mitochondrial dysfunction, and a chronic low-grade inflammatory status. In this sense, cerium oxide nanoparticles (CeO2 NPs) are promising nanomaterials with antioxidant and anti-inflammatory properties. Thus, we aimed to evaluate the effect of CeO2 NPs in mouse 3T3-L1 adipocytes, RAW 264.7 macrophages, and C2C12 myotubes under control or proinflammatory conditions. Macrophages were treated with LPS, and both adipocytes and myotubes with conditioned medium (25% LPS-activated macrophages medium) to promote inflammation. CeO2 NPs showed a mean size of ≤25.3 nm (96.7%) and a zeta potential of 30.57 ± 0.58 mV, suitable for cell internalization. CeO2 NPs reduced extracellular reactive oxygen species (ROS) in adipocytes with inflammation while increased in myotubes with control medium. The CeO2 NPs increased mitochondrial content was observed in adipocytes under proinflammatory conditions. Furthermore, the expression of Adipoq and Il10 increased in adipocytes treated with CeO2 NPs. In myotubes, both Il1b and Adipoq were downregulated while Irs1 was upregulated. Overall, our results suggest that CeO2 NPs could potentially have an insulin-sensitizing effect specifically on adipose tissue and skeletal muscle. However, further research is needed to confirm these findings.


Assuntos
Células 3T3-L1/metabolismo , Adipócitos/metabolismo , Cério/metabolismo , Inflamação/genética , Resistência à Insulina/genética , Síndrome Metabólica/genética , Animais , Síndrome Metabólica/metabolismo , Camundongos , Fibras Musculares Esqueléticas , Nanopartículas , Estresse Oxidativo
20.
Gene ; 698: 150-156, 2019 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-30851423

RESUMO

OBJECTIVE: Investigating the expression of the lnc RNAs screened above between normal and insulin resistant 3T3-L1 adipocytes. Addressing the mechanism underlying the regulation of inflammation response by lnc TINCR. METHODS: 3T3-L1 preadipocytes were induced to differentiate into mature adipocytes. Oil red O staining was used to find the fat droplets in mature adipocytes. Mature adipocytes were randomized to normal control group and Tri-DAP (NOD1 ligand) group. After the establishment of insulin resistance model, we used deep RNA sequencing(RNA-Seq) to identify lncRNAs that are regulated during NODI activation in mouse adipocytes. Real-time PCR was used to analyze the expression of lnc TINCR, proinflammatory IL-6, TNF-α, Cxcl1 and RIPK2 in the presence or absence of Tri-DAP(10 µg/ml). We employed siRNA against lnc TINCR to confirm its effects in inflammatory response. RESULTS: Deep RNA sequencing identified 81 lncRNAs and 167 coding genes that were significantly up-related while 78 lncRNAs and 82 coding genes that were significantly down-related greater than twofold during NOD1 activation in adipocytes. We discovered that lnc TINCR, termed lnc TINCR(Tri-DAP-inducible non-protein coding RNA) is greatly upregulated in Tri-DAP activated adipocytes. Moreover knockdown of lnc TINCR dampens the proinflammatory response (P < 0.05; in adipocytes). CONCLUSIONS: lnc TINCR is a positive regulator of inflammation-induced insulin resistance presumably via activation of NOD1 signaling pathways.


Assuntos
Inflamação/genética , Proteína Adaptadora de Sinalização NOD1/genética , RNA Longo não Codificante/genética , Células 3T3-L1 , Adipócitos/metabolismo , Animais , Diferenciação Celular , Insulina/metabolismo , Resistência à Insulina/genética , Camundongos , Proteína Adaptadora de Sinalização NOD1/metabolismo , Fosforilação , RNA Longo não Codificante/metabolismo , RNA Mensageiro , Análise de Sequência de RNA/métodos , Transdução de Sinais
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