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1.
Life Sci ; 258: 118204, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32763296

RESUMO

AIMS: Liver kinase B1 (LKB1) is a serine/threonine kinase. Although many biological functions of LKB1 have been identified, the role of hypothalamic LKB1 in the regulation of central energy metabolism and susceptibility to obesity is unknown. Therefore, we constructed POMC neuron-specific LKB1 knockout mice (PomcLkb1 KO) and studied it at the physiological, morphological, and molecular biology levels. MAIN METHODS: Eight-week-old male PomcLkb1 KO mice and their littermates were fed a standard chow fat diet (CFD) or a high-fat diet (HFD) for 3 months. Body weight and food intake were monitored. Dual-energy X-ray absorptiometry was used to measure the fat mass and lean mass. Glucose and insulin tolerance tests and serum biochemical markers were evaluated in the experimental mice. In addition, the levels of peripheral lipogenesis genes and central energy metabolism were measured. KEY FINDINGS: PomcLkb1 KO mice did not exhibit impairments under normal physiological conditions. After HFD intervention, the metabolic phenotype of the PomcLkb1 KO mice changed, manifesting as increased food intake and an enhanced obesity phenotype. More seriously, PomcLkb1 KO mice showed increased leptin resistance, worsened hypothalamic inflammation and reduced POMC neuronal expression. SIGNIFICANCE: We provide evidence that LKB1 in POMC neurons plays a significant role in regulating energy homeostasis. LKB1 in POMC neurons emerges as a target for therapeutic intervention against HFD-induced obesity and metabolic diseases.


Assuntos
Deleção de Genes , Neurônios/enzimologia , Obesidade/enzimologia , Pró-Opiomelanocortina/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tecido Adiposo/patologia , Animais , Dieta Hiperlipídica , Epididimo/patologia , Comportamento Alimentar , Regulação da Expressão Gênica , Glucose/metabolismo , Hipotálamo/patologia , Inflamação/patologia , Leptina/metabolismo , Fígado/enzimologia , Fígado/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Obesidade/sangue , Obesidade/patologia , Pró-Opiomelanocortina/genética , Ganho de Peso
2.
Proc Natl Acad Sci U S A ; 117(28): 16616-16625, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601203

RESUMO

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensing O-linked ß-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase in O-GlcNAc signaling in macrophages. O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. Suppressing O-GlcNAc signaling by O-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1) O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophage O-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.


Assuntos
Macrófagos/imunologia , N-Acetilglucosaminiltransferases/imunologia , Obesidade/imunologia , Proteínas Quinases S6 Ribossômicas 90-kDa/imunologia , Acetilglucosamina/imunologia , Tecido Adiposo/imunologia , Animais , Humanos , Ativação de Macrófagos , Macrófagos/enzimologia , Camundongos , Camundongos Knockout , N-Acetilglucosaminiltransferases/genética , Obesidade/enzimologia , Obesidade/genética , Obesidade/metabolismo , Fosforilação , Proteínas Quinases S6 Ribossômicas 90-kDa/genética , Transdução de Sinais
3.
Am J Physiol Endocrinol Metab ; 319(2): E401-E409, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32634320

RESUMO

Adipose tissue plays a central role in regulating whole body energy and glucose homeostasis at both organ and systemic levels. Inositol polyphosphates, such as 5-diphosphoinositol pentakisphosphate, reportedly control adipocyte functions and energy expenditure. However, the physiological roles of the inositol polyphosphate (IP) pathway in the adipose tissue are not yet fully defined. The aim of the present study was to test the hypothesis that inositol polyphosphate multikinase (IPMK), a key enzyme in the IP metabolism, plays a critical role in adipose tissue biology and obesity. We generated adipocyte-specific IPMK knockout (Ipmk AKO) mice and evaluated metabolic phenotypes by measuring fat accumulation, glucose homeostasis, and insulin sensitivity in adult mice fed either a regular-chow diet or high-fat diet (HFD). Despite substantial reduction of IPMK, Ipmk AKO mice exhibited normal glucose tolerance and insulin sensitivity and did not show changes in fat accumulation in response to HFD-feeding. In addition, loss of IPMK had no major impact on thermogenic processes in response to cold exposure. Collectively, these findings suggest that adipocyte IPMK is dispensable for normal adipose tissue and its physiological functions in whole body metabolism, suggesting the complex roles that inositol polyphosphate metabolism has in the regulation of adipose tissue.


Assuntos
Adipócitos/enzimologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Fosfotransferases (Aceptor do Grupo Álcool)/fisiologia , Tecido Adiposo/fisiologia , Tecido Adiposo Marrom/fisiologia , Animais , Temperatura Baixa , Dieta Hiperlipídica/efeitos adversos , Glucose/metabolismo , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Obesidade/enzimologia , Obesidade/etiologia , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Termogênese/fisiologia
4.
Proc Natl Acad Sci U S A ; 117(22): 12359-12367, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32404422

RESUMO

Hepsin is a transmembrane serine protease primarily expressed in the liver. To date, the physiological function of hepsin remains poorly defined. Here we report that hepsin-deficient mice have low levels of blood glucose and lipids and liver glycogen, but increased adipose tissue browning and basal metabolic rates. The phenotype is caused by reduced hepatocyte growth factor activation and impaired Met signaling, resulting in decreased liver glucose and lipid metabolism and enhanced adipocyte browning. Hepsin-deficient mice exhibit marked resistance to high-fat diet-induced obesity, hyperglycemia, and hyperlipidemia. In db/db mice, hepsin deficiency ameliorates obesity and diabetes. These data indicate that hepsin is a key regulator in liver metabolism and energy homeostasis, suggesting that hepsin could be a therapeutic target for treating obesity and diabetes.


Assuntos
Adipócitos/metabolismo , Fígado/metabolismo , Obesidade/enzimologia , Serina Endopeptidases/metabolismo , Adipócitos/citologia , Animais , Diferenciação Celular , Glucose/metabolismo , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Homeostase , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Serina Endopeptidases/genética
7.
J Vasc Res ; 57(3): 136-142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32224624

RESUMO

Acute coronary syndrome occurs when the heart muscle does not receive adequate oxygen and nutrients in a timely manner. Acute coronary syndromes are primarily due to atherosclerosis of the coronary arteries, i.e., coronary heart disease. Nitric oxide (NO) is synthesised from L-arginine in endothelial cells by the constitutive calcium-calmodulin-dependent enzyme, nitric oxide synthase (NOS), which mediates endothelium-dependent vasodilatation. Endothelial nitric oxide synthase (eNOS) is predominantly expressed in endothelial cells. Three NOS isoforms have been detected in different tissue: (1) neuronal NOS (nNOS) (NOS1), (2) eNOS (NOS2), and (3) inducible NOS (iNOS) (NOS3). These isoforms are encoded by three different genes. NOS3 is located on chromosome 7q35-36 and contains 26 exons. Previous studies have suggested that NOS3 polymorphisms may be associated with acute coronary syndromes. Therefore, the aim of the study was to examine the associations between NOS3 rs1799983 (894G/T)andrs2070744 (-786T/C) polymorphisms and unstable angina. This study included 246 patients with unstable angina, as confirmed by coronary angiography. We also included 189 healthy controls who were also assessed by this technique. There were no significant differences in genotype distributions of NOS3 rs1799983and rs2070744 polymorphisms in patients with unstable angina and healthy controls in both univariate and multivariate analyses. In patients with the NOS3 rs1799983 TT genotype, we observed a higher BMI (TT vs. GT + GG, p = 0.068), and in patients with the NOS3 rs2070744 TT genotype, we observed a higher waist circumference (TT vs. TC + CC, p = 0.023; TT vs. CC, p = 0.0053). These data suggest a lack of association between the NOS3 rs1799983andrs2070744 polymorphisms and unstable angina in our patient population. However, these polymorphisms may be associated with some obesity parameters, rs1799983 in females and rs2070744 in males.


Assuntos
Angina Instável/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Idoso , Angina Instável/diagnóstico , Angina Instável/enzimologia , Estudos de Casos e Controles , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/diagnóstico , Obesidade/enzimologia , Obesidade/genética , Fenótipo , Fatores de Risco , Circunferência da Cintura/genética
8.
Am J Physiol Renal Physiol ; 318(4): F1030-F1040, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150446

RESUMO

Manipulation of circulating histidine-containing dipeptides (HCD) has been shown to affect the development of diabetes and early-stage diabetic nephropathy (DN). The aim of the present study was to investigate whether such interventions, which potentially alter levels of circulating HCD, also affect the development of advanced-stage DN. Two interventions, aerobic exercise training and overexpression of the human carnosinase-1 (hCN1) enzyme, were tested. BTBR ob/ob mice were either subjected to aerobic exercise training (20 wk) or genetically manipulated to overexpress hCN1, and different diabetes- and DN-related markers were compared with control ob/ob and healthy (wild-type) mice. An acute exercise study was performed to elucidate the effect of obesity, acute running, and hCN1 overexpression on plasma HCD levels. Chronic aerobic exercise training did not affect the development of diabetes or DN, but hCN1 overexpression accelerated hyperlipidemia and aggravated the development of albuminuria, mesangial matrix expansion, and glomerular hypertrophy of ob/ob mice. In line, plasma, kidney, and muscle HCD were markedly lower in ob/ob versus wild-type mice, and plasma and kidney HCD in particular were lower in ob/ob hCN1 versus ob/ob mice but were unaffected by aerobic exercise. In conclusion, advanced glomerular damage is accelerated in mice overexpressing the hCN1 enzyme but not protected by chronic exercise training. Interestingly, we showed, for the first time, that the development of DN is closely linked to renal HCD availability. Further research will have to elucidate whether the stimulation of renal HCD levels can be a therapeutic strategy to reduce the risk for developing DN.


Assuntos
Nefropatias Diabéticas/enzimologia , Dipeptidases/biossíntese , Terapia por Exercício , Glomérulos Renais/enzimologia , Músculo Esquelético/enzimologia , Obesidade/enzimologia , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Dipeptidases/genética , Dipeptídeos/metabolismo , Modelos Animais de Doenças , Indução Enzimática , Histidina/análogos & derivados , Histidina/metabolismo , Humanos , Glomérulos Renais/patologia , Camundongos Transgênicos , Músculo Esquelético/patologia , Obesidade/complicações , Obesidade/genética , Obesidade/patologia , Fatores de Tempo
9.
Proc Natl Acad Sci U S A ; 117(15): 8431-8436, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32220957

RESUMO

Intestinal barrier dysfunction, which leads to translocation of bacteria or toxic bacterial products from the gut into bloodstream and results in systemic inflammation, is a key pathogenic factor in many human diseases. However, the molecular mechanisms leading to intestinal barrier defects are not well understood, and there are currently no available therapeutic approaches to target intestinal barrier function. Here we show that soluble epoxide hydrolase (sEH) is an endogenous regulator of obesity-induced intestinal barrier dysfunction. We find that sEH is overexpressed in the colons of obese mice. In addition, pharmacologic inhibition or genetic ablation of sEH abolishes obesity-induced gut leakage, translocation of endotoxin lipopolysaccharide or bacteria, and bacterial invasion-induced adipose inflammation. Furthermore, systematic treatment with sEH-produced lipid metabolites, dihydroxyeicosatrienoic acids, induces bacterial translocation and colonic inflammation in mice. The actions of sEH are mediated by gut bacteria-dependent mechanisms, since inhibition or genetic ablation of sEH fails to attenuate obesity-induced gut leakage and adipose inflammation in mice lacking gut bacteria. Overall, these results support that sEH is a potential therapeutic target for obesity-induced intestinal barrier dysfunction, and that sEH inhibitors, which have been evaluated in human clinical trials targeting other human disorders, could be promising agents for prevention and/or treatment.


Assuntos
Translocação Bacteriana , Epóxido Hidrolases/imunologia , Enteropatias/enzimologia , Intestinos/enzimologia , Obesidade/complicações , Tecido Adiposo/imunologia , Animais , Bactérias/genética , Bactérias/isolamento & purificação , Fenômenos Fisiológicos Bacterianos , Epóxido Hidrolases/genética , Microbioma Gastrointestinal , Humanos , Enteropatias/etiologia , Enteropatias/imunologia , Enteropatias/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/enzimologia , Obesidade/genética
10.
Oxid Med Cell Longev ; 2020: 3071658, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32082477

RESUMO

This study is aimed at investigating the effect of different exercise loads on the reproductive function of obese male mice and the underlying mechanisms. Male mice with high-fat diet-induced obesity were divided into obesity control (OC), obesity moderate-load exercise (OME), and obesity high-load exercise (OHE) groups. The OME and OHE groups were subjected to swimming exercise 5 days per week over a duration of 8 weeks, with the exercise load progressively increased to 2 h per day in the OME group and 2 h twice per day in the OHE group. In the OC group mice without exercise regimen, we observed a decrease in mRNA expression of antioxidant enzymes, increase in free radical products, upregulation of mRNA and protein expression of nuclear factor-κB and proinflammatory cytokines, inhibition of mRNA and protein expression of testosterone synthases, decrease in the serum testosterone level and sperm quality, and increase in sperm apoptosis. Although both moderate-load exercise and high-load exercise reduced body fat, only moderate-load exercise effectively alleviated obesity-induced oxidative stress, downregulated the expression of nuclear factor-κB and proinflammatory cytokines, and reversed the decrease in mRNA and protein expression of testosterone synthases, serum testosterone level, and sperm quality. These changes were not observed in the OHE group mice. Obesity-induced testicular oxidative stress and inflammatory response decreased testosterone synthesis and sperm quality. Moderate-load exercise alleviated the negative effect of obesity on male reproductive function by decreasing testicular oxidative stress and inflammatory responses. Although high-load exercise effectively reduced body fat, its effects on alleviating oxidative stress and improving male reproductive function were limited.


Assuntos
Obesidade/metabolismo , Estresse Oxidativo/fisiologia , Condicionamento Físico Animal/fisiologia , Espermatozoides/metabolismo , Testículo/metabolismo , Testosterona/sangue , Animais , Apoptose/fisiologia , Peso Corporal/fisiologia , Citocinas/metabolismo , Dieta Hiperlipídica/efeitos adversos , Glutationa Peroxidase/metabolismo , Inflamação/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , NF-kappa B/metabolismo , Obesidade/enzimologia , Obesidade/fisiopatologia , Espécies Reativas de Oxigênio/metabolismo , Reprodução/fisiologia , Superóxido Dismutase-1/metabolismo , Natação
11.
J Endocrinol ; 245(2): 193-205, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32092034

RESUMO

The kidneys release glucose into the systemic circulation through glucose reabsorption and renal gluconeogenesis. Currently, the significance of renal glucose release in pathological conditions has become a subject of interest. We examined the effect of sodium-dependent glucose cotransporter 2 inhibitor (SGLT2i) on renal gluconeogenic enzyme expression in obese rats. Male Wistar rats (180-200 g) were fed either a normal diet (ND, n = 6) or a high-fat diet. At 16 weeks, after confirming the degree of glucose intolerance, high-fat diet-fed rats were randomly subdivided into three groups (n = 6/group): untreated group (HF), treated with dapagliflozin 1 mg/kg/day (HFSG) and treated with metformin 30 mg/kg/day (HFM). The treatment was continued for 4 weeks. We observed that dapagliflozin or metformin mitigated the enhanced expression of renal gluconeogenic enzymes, PEPCK, G6Pase and FBPase, as well as improved glucose tolerance and renal function in obese rats. Dapagliflozin downregulated the elevated expression of gluconeogenic transcription factors p-GSK3ß, p-CREB and coactivator PGC1α in the renal cortical tissue. Metformin reduced the expression levels of renal cortical FOXO1 and CREB. Furthermore, reduced renal insulin signaling was improved and renal oxidative stress was attenuated by either dapagliflozin or metformin treatment in obese rats. We concluded that glucose tolerance was improved by dapagliflozin in obese prediabetic rats by suppressing renal glucose release from not only glucose reabsorption but also renal gluconeogenesis through improving renal cortical insulin signaling and oxidative stress. The efficacy of dapagliflozin in improving renal insulin signaling, oxidative stress and renal function was greater than that of metformin.


Assuntos
Compostos Benzidrílicos/farmacologia , Gluconeogênese/efeitos dos fármacos , Glucosídeos/farmacologia , Hipoglicemiantes/farmacologia , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Animais , Dieta Hiperlipídica , Glucose-6-Fosfatase/efeitos dos fármacos , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , Rim/enzimologia , Masculino , Metformina/farmacologia , Obesidade/etiologia , Fosfoenolpiruvato Carboxiquinase (GTP)/efeitos dos fármacos , Ratos , Ratos Wistar
12.
Proc Natl Acad Sci U S A ; 117(5): 2462-2472, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953260

RESUMO

Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote "beiging" of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.


Assuntos
Complexo II de Transporte de Elétrons/metabolismo , Gorduras/metabolismo , Obesidade/enzimologia , Estearoil-CoA Dessaturase/genética , Ácido Succínico/metabolismo , Adipócitos Bege/citologia , Adipócitos Bege/metabolismo , Adipogenia , Animais , Metabolismo Energético , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Obesidade/genética , Obesidade/metabolismo , Obesidade/fisiopatologia , Estearoil-CoA Dessaturase/metabolismo , Termogênese
13.
Mol Cell Biol ; 40(8)2020 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-31988105

RESUMO

Fibrosis is recognized as the major pathological change in adipose tissue during the development of obesity. However, the detailed mechanisms governing the interactions between the fibrotic components and their modifiers remain largely unclear. Here, we reported that matrix metalloproteinase 14 (MMP14), a key pericellular collagenase, is dramatically upregulated in obese adipose tissue. We generated a doxycycline-inducible adipose tissue-specific MMP14 overexpression model to study its regulatory function. We found that overexpression of MMP14 in the established obese adipose tissue leads to enlarged adipocytes and increased body weights in transgenic mice. Furthermore, the mice exhibited decreased energy expenditure, impaired lipid metabolism, and insulin resistance. Mechanistically, we found that MMP14 digests collagen 6α3 to produce endotrophin, a potent costimulator of fibrosis and inflammation. Unexpectedly, when overexpressing MMP14 in the early-stage obese adipose tissue, the transgenic mice showed a healthier metabolic profile, including ameliorated fibrosis and inflammation, as well as improved lipid and glucose metabolism. This unique metabolic phenotype is likely due to digestion/modification of the dense adipose tissue extracellular matrix by MMP14, thereby releasing the mechanical stress to allow for its healthy expansion. Understanding these dichotomous impacts of MMP14 provides novel insights into strategies to treat obesity-related metabolic disorders.


Assuntos
Tecido Adiposo/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Obesidade/enzimologia , Adipócitos/enzimologia , Adipócitos/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Adiposidade , Animais , Linhagem Celular , Metabolismo Energético , Feminino , Fibrose/metabolismo , Células HEK293 , Humanos , Inflamação/genética , Insulina/metabolismo , Resistência à Insulina , Masculino , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Regulação para Cima , Ganho de Peso
14.
Stroke ; 51(1): 224-231, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31726963

RESUMO

Background and Purpose- The role of dual-antiplatelet therapy with clopidogrel plus aspirin has been demonstrated to substantially decrease the risk of recurrent stroke among patients with minor stroke and transient ischemic attack. We aimed to determine whether the efficacy of clopidogrel-aspirin therapy among patients with minor stroke / transient ischemic attack was influenced by the stratification of CYP2C19 genotype and body mass index (BMI). Methods- CYP2C19 loss-of-function allele (LoFA) carriers were defined as patients with either LoFA of *2 or *3. Low/normal weight and overweight/obesity was defined as BMI <25 and ≥25 kg/m2, respectively. Primary outcome was defined as stroke recurrence at 3 months. Results- In a total of 2933 patients, there were 1726 (58.8%) LoFA carriers and 1275 (43.5%) patients with overweight/obesity (BMI ≥25 kg/m2). Stratified analyses by LoFA carrying status and BMI, hazard ratios (hazard ratios 95% CIs) of the clopidogrel-aspirin therapy for stroke recurrence were 0.90 (0.60-1.36), 0.87 (0.56-1.35), 0.65 (0.39-1.09), and 0.40 (0.22-0.71) among subgroups of LoFA carriers with overweight/obesity, LoFA carriers with low/normal weight, LoFA noncarriers with overweight/obesity, and LoFA noncarriers with low/normal weight, respectively, with P=0.049 for interaction. Conclusions- Efficacy of clopidogrel-aspirin therapy in reducing the risk of stroke recurrence is not present in CYP2C19 LoFA noncarriers with overweight/obesity. Our study suggests that BMI significantly influences the correlation between CYP2C19 genotype and efficacy of clopidogrel-aspirin therapy. Clinical Trial Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00979589.


Assuntos
Alelos , Aspirina/administração & dosagem , Clopidogrel/administração & dosagem , Citocromo P-450 CYP2C19/genética , Mutação com Perda de Função , Obesidade , Acidente Vascular Cerebral , Idoso , Índice de Massa Corporal , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Obesidade/genética , Fatores de Risco , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/genética
15.
Swiss Med Wkly ; 149: w20152, 2019 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-31846507

RESUMO

As a result of epidemic levels of obesity and diabetes mellitus, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) will contribute to increases in the liver-related disease burden in Switzerland. A Markov model was built to quantify fibrosis progression among the NAFLD and NASH populations, and predict disease burden up to 2030. Long-term trending of NAFLD prevalence was based on changes in the prevalence of adult obesity. Published estimates and surveillance data were applied to build and validate the model projections. The prevalence of NAFLD increased up to 2030 in tandem with projected increases in adult obesity. By 2030, there were an estimated 2,234,000 (1,918,000–2,553,000) NAFLD cases, or 24.3% (20.9–27.8%) of the total Swiss population (all ages). Increases in NASH cases were relatively greater than NAFLD cases. Incident cases of advanced liver disease are projected to increase by approximately 40% by 2030, and incident NAFLD liver deaths to increase from 580 deaths in 2018 to 820 deaths in 2030. Continued growth in obesity, in combination with an aging population, will result in increasing number of cases of advanced liver disease and mortality related to NAFLD and NASH. Slowing the growth in obesity and metabolic syndrome, along with future potential therapies, are required to reduce liver disease burden.  .


Assuntos
Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/epidemiologia , Obesidade/complicações , Adolescente , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Cadeias de Markov , Pessoa de Meia-Idade , Obesidade/enzimologia , Suíça/epidemiologia , Adulto Jovem
16.
Ann Nutr Metab ; 75(3): 153-162, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31722334

RESUMO

INTRODUCTION: Recent studies indicate that alkaline phosphatase (ALP) may affect expression and activity of fatty acid (FA) transport proteins in placenta and other tissues. OBJECTIVE: To evaluate if disturbed FA profile in offspring of gestational diabetes mellitus (GDM) with different maternal pregestational weight could be related to maternal or neonatal ALP. METHODS: Prospective observational study of pregnant women recruited in the third trimester (25 controls, 23 lean-GDM, 20 obese-GDM). Fetal ultrasound was performed. At delivery, FAs were analyzed in placenta, maternal, and venous cord blood. Western blotting analysis of lipid carriers was performed in placenta. RESULTS: Newborns from obese-GDM tended to higher birthweight (p = 0.059) than those from both lean-GDM and controls. ALP in maternal blood tended to be lower in GDM (p = 0.170) while increased significantly in cord blood of obese-GDM with respect to controls (p = 0.039). Saturated FA percentages in cord blood were significantly higher (p < 0.000), while polyunsaturated FA (PUFA) percentages were lower (p = 0.003) in both GDM, which could be due to a lower expression of major family domain 2a receptor (MFSD2a) in the placenta. Plasma ALP in the offspring of obese-GDM was inversely associated to cord essential PUFAs (ß = -6.18, p = 0.005) and to placental MFSD2a (ß = -38.46, p = 0.014). CONCLUSIONS: Cord PUFA and placental MFSD2a are decreased in both lean and obese-GDM pregnancies. Higher ALP in cord blood of obese-GDM could play a role in the FA levels in these pregnancies.


Assuntos
Fosfatase Alcalina/sangue , Diabetes Gestacional/enzimologia , Ácidos Graxos Insaturados/análise , Sangue Fetal/enzimologia , Obesidade/enzimologia , Adulto , Estudos de Casos e Controles , Ácidos Graxos Insaturados/sangue , Feminino , Sangue Fetal/química , Humanos , Obesidade/complicações , Placenta/química , Gravidez , Terceiro Trimestre da Gravidez , Estudos Prospectivos
17.
Nutrients ; 11(10)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618980

RESUMO

Gynostemma pentaphyllum is widely used in Asia as a herbal medicine to treat type 2 diabetes, dyslipidemia, and inflammation. Here, we investigated the anti-obesity effect and underlying mechanism of G. pentaphyllum extract (GPE) enriched in gypenoside L, gypenoside LI, and ginsenoside Rg3 and obtained using a novel extraction method. Five-week-old male C57BL/6N mice were fed a control diet (CD), high-fat diet (HFD), HFD + 100 mg/kg body weight (BW)/day GPE (GPE 100), HFD + 300 mg/kg BW/day GPE (GPE 300), or HFD + 30 mg/kg BW/day Orlistat (Orlistat 30) for 8 weeks. The HFD-fed mice showed significant increases in body weight, fat mass, white adipose tissue, and adipocyte hypertrophy compared to the CD group; but GPE inhibited those increases. GPE reduced serum levels of triglyceride, total cholesterol, and LDL-cholesterol, without affecting HDL-cholesterol. GPE significantly increased AMPK activation and suppressed adipogenesis by decreasing the mRNA expression of CCAAT/enhancer binding protein-α (C/EBPα), peroxisome proliferator-activated receptor-γ (PPARγ), sterol regulatory element-binding protein-1c (SREBP1c), PPARγ coactivator-1α, fatty acid synthase (FAS), adipocyte protein 2 (AP2), and sirtuin 1 (SIRT1) and by increasing that of carnitine palmitoyltransferase (CPT1) and hormone- sensitive lipase (HSL). This study demonstrated the ameliorative effect of GPE on obesity and elucidated the underlying molecular mechanism.


Assuntos
Adipogenia/efeitos dos fármacos , Tecido Adiposo Branco/efeitos dos fármacos , Fármacos Antiobesidade/farmacologia , Dieta Hiperlipídica , Gynostemma/química , Obesidade/prevenção & controle , Extratos Vegetais/farmacologia , Sirtuína 1/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Tecido Adiposo Branco/enzimologia , Tecido Adiposo Branco/fisiopatologia , Adiposidade/efeitos dos fármacos , Animais , Fármacos Antiobesidade/isolamento & purificação , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Modelos Animais de Doenças , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/enzimologia , Obesidade/fisiopatologia , Oxirredução , Extratos Vegetais/isolamento & purificação , Transdução de Sinais , Regulação para Cima , Ganho de Peso/efeitos dos fármacos
18.
Oxid Med Cell Longev ; 2019: 2481592, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31662816

RESUMO

Maternal obesity is associated with placental oxidative stress. However, the mechanism underlying this association remains poorly understood. In the present study, a gilt obesity model was developed by exposure to different energy diets and used to investigate the role of NADPH oxidase 2 (Nox2) in the placenta. Specifically, 99 gilts (Guangdong Small-ear Spotted pig) at day 60 of gestation were randomly assigned to one of the following three treatments: low-energy group (L, DE = 11.50 MJ/kg), medium-energy group (M, DE = 12.41 MJ/kg), and high-energy group (H, DE = 13.42 MJ/kg), with 11 replicate pens per treatment and 3 gilts per pen. At the start of the study, maternal body weight and backfat thickness were not significantly different in the three treatments. After the study, data indicated that the H group had higher body weight and backfat thickness gain for gilts during gestation and lower piglet birth weight compared with the other two groups. Additionally, the H group showed glucolipid metabolic disorders and increased triglyceride and nonesterified fatty acid contents in the placenta of gilts. Compared with the L group, the H group exhibited lower mitochondrial biogenesis and increased oxidative damage in the placenta. Importantly, increased mRNA expression and protein abundance of Nox2 were observed for the first time in H group placentae. Furthermore, compared with the L group, the H group showed a decrease in the density of placental vessels and the protein levels of vascular endothelial cadherin (VE-cadherin), vascular endothelial growth factor A (VEGF-A), and phosphorylation of vascular endothelial growth factor receptor 2 (p-VEGFR2) as well as the immunostaining intensity of platelet endothelial cell adhesion molecule-1 (CD31). Our findings suggest that maternal high-energy diet-induced obesity increases placental oxidative stress and decreases placental angiogenesis possibly through the upregulation of Nox2.


Assuntos
Dieta , NADPH Oxidase 2/metabolismo , Neovascularização Fisiológica , Obesidade/patologia , Estresse Oxidativo , Placenta/irrigação sanguínea , Placenta/patologia , Regulação para Cima , Trifosfato de Adenosina/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Alimentar , Feminino , NADPH Oxidase 4/genética , NADPH Oxidase 4/metabolismo , Neovascularização Fisiológica/genética , Obesidade/enzimologia , Biogênese de Organelas , Placenta/enzimologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Suínos , Fator de von Willebrand/metabolismo
19.
Am J Physiol Heart Circ Physiol ; 317(5): H1166-H1172, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31603345

RESUMO

Insulin modulates vasomotor tone through vasodilator and vasoconstrictor signaling pathways. The purpose of the present work was to determine whether insulin-stimulated vasoconstriction is a pathophysiological phenomenon that can result from a combination of persistent insulin signaling, suppressed phosphatidylinositol-3 kinase (PI3K) activation, and an ensuing relative increase in MAPK/endothelin-1 (ET-1) activity. First, we examined previously published work from our group where we assessed changes in lower-limb blood flow in response to an oral glucose tolerance test (endogenous insulin stimulation) in lean and obese subjects. The new analyses showed that the peak rise in vascular resistance during the postprandial state was greater in obese compared with lean subjects. We next extended on these findings by demonstrating that insulin-induced vasoconstriction in isolated resistance arteries from obese subjects was attenuated with ET-1 receptor antagonism, thus implicating ET-1 signaling in this constriction response. Last, we examined in isolated resistance arteries from pigs the dual roles of persistent insulin signaling and blunted PI3K activation in modulating vasomotor responses to insulin. We found that prolonged insulin stimulation did not alter vasomotor responses to insulin when insulin-signaling pathways remained unrestricted. However, prolonged insulinization along with pharmacological suppression of PI3K activity resulted in insulin-induced vasoconstriction, rather than vasodilation. Notably, such aberrant vascular response was rescued with either MAPK inhibition or ET-1 receptor antagonism. In summary, we demonstrate that insulin-induced vasoconstriction is a pathophysiological phenomenon that can be recapitulated when sustained insulin signaling is coupled with depressed PI3K activation and the concomitant relative increase in MAPK/ET-1 activity.NEW & NOTEWORTHY This study reveals that insulin-induced vasoconstriction is a pathophysiological phenomenon. We also provide evidence that in the setting of persistent insulin signaling, impaired phosphatidylinositol-3 kinase activation appears to be a requisite feature precipitating MAPK/endothelin 1-dependent insulin-induced vasoconstriction.


Assuntos
Artérias/efeitos dos fármacos , Insulina/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Vasoconstrição/efeitos dos fármacos , Animais , Artérias/enzimologia , Artérias/fisiopatologia , Endotelina-1/metabolismo , Ativação Enzimática , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Obesidade/enzimologia , Obesidade/fisiopatologia , Transdução de Sinais , Sus scrofa
20.
Nutr. hosp ; 36(5): 1095-1100, sept.-oct. 2019. graf
Artigo em Espanhol | IBECS | ID: ibc-184632

RESUMO

Introducción: el principal problema de salud pública en México es la obesidad y sus enfermedades asociadas, incluyendo las bucales. Objetivo: evaluar el efecto del tratamiento con metformina en pacientes obesos de clase I sobre la actividad de las metaloproteinasas presentes en el periodonto con periodontitis crónica. Métodos: se realizó un estudio clínico con 68 pacientes mujeres con obesidad de clase I y enfermedad periodontal. Se dividieron en 4 grupos; a 2 de ellos, además del tratamiento periodontal, se les administro metformina de 850 mg al día durante seis semanas. Se tomaron 2 muestras por paciente de tejido periodontal antes y después de cada tratamiento y se midió el índice de masa corporal (IMC), el índice de placa dentobacteriana y de inflamación. Mediante zimografía en gel de acrilamida se midió la actividad de las metaloproteinasas en la muestra de tejido recolectada. Los datos obtenidos fueron analizados mediante estadística descriptiva t de student para muestras relacionadas y se realizó ANOVA de una vía considerando p < 0,01 como estadísticamente significativa. Resultados: en el grupo de pacientes a las que se les administro metformina al final del tratamiento se observó una disminución del índice de masa corporal, del grado de inflamación y menor actividad de metaloproteinasas respecto al grupo control (65% frente a 25%; p < 0,01). Conclusiones: el tratamiento con metformina en pacientes con obesidad de clase I y enfermedad periodontal disminuye el IMC, mejora los síntomas de la periodontitis crónica y disminuye la actividad de las metaloproteinasas 1, 3, 8 y V presentes en el periodonto de estos pacientes


Introduction: in Mexico the main problem in public health is obesity and other diseases that are associated whit this condition, including oral health. Objective: to evaluate the effect of metformin treatment in patients with class I obese on the activity of metalloproteinases present in periodontium with chronic periodontitis. Methods: a clinical study was conducted in 68 patients with class I obesity and periodontal disease. They were divided into 4 groups. 2 of them, in addition to the periodontal treatment, were administered metformin 850 mg per day for six weeks; 2 samples were taken per patient of periodontal tissue before and after each treatment, body mass index, plaque index and inflammation were measured. Acrylamide gel zymography was used to measure the activity of metalloproteinases in the sample of tissue collected. The data obtained were analyzed by descriptive statistics, student t for related samples and one-way ANOVA was performed considering p < 0.01 as statistically significant. Results: in the group of patients who were administered metformin at the end of the treatment, there was a decrease in the body mass index, the degree of inflammation and lower metalloproteinase activity, compared with the control group (65% vs 25%; < 0.01). Conclusions: treatment with metformin in patients with obesity class I and periodontal disease decreases BMI, improves the symptoms of chronic periodontitis and decreases the activity of metalloproteinases 1, 3, 8, V present in periodontium of these patients


Assuntos
Humanos , Feminino , Adulto , Obesidade/tratamento farmacológico , Obesidade/enzimologia , Metformina/administração & dosagem , Metaloproteases/metabolismo , Periodontite/complicações , Periodontite/diagnóstico , Metformina/metabolismo , Periodontite/terapia , Análise de Variância , Placa Dentária/diagnóstico , Índice de Placa Dentária
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