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1.
Nat Commun ; 11(1): 3794, 2020 07 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732906

RESUMO

Defective rhythmic metabolism is associated with high-fat high-caloric diet (HFD) feeding, ageing and obesity; however, the neural basis underlying HFD effects on diurnal metabolism remains elusive. Here we show that deletion of BMAL1, a core clock gene, in paraventricular hypothalamic (PVH) neurons reduces diurnal rhythmicity in metabolism, causes obesity and diminishes PVH neuron activation in response to fast-refeeding. Animal models mimicking deficiency in PVH neuron responsiveness, achieved through clamping PVH neuron activity at high or low levels, both show obesity and reduced diurnal rhythmicity in metabolism. Interestingly, the PVH exhibits BMAL1-controlled rhythmic expression of GABA-A receptor γ2 subunit, and dampening rhythmicity of GABAergic input to the PVH reduces diurnal rhythmicity in metabolism and causes obesity. Finally, BMAL1 deletion blunts PVH neuron responses to external stressors, an effect mimicked by HFD feeding. Thus, BMAL1-driven PVH neuron responsiveness in dynamic activity changes involving rhythmic GABAergic neurotransmission mediates diurnal rhythmicity in metabolism and is implicated in diet-induced obesity.


Assuntos
Fatores de Transcrição ARNTL/genética , Ritmo Circadiano/fisiologia , Obesidade/patologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de GABA-A/metabolismo , Animais , Ritmo Circadiano/genética , Dieta Hiperlipídica , Metabolismo Energético/fisiologia , Comportamento Alimentar/fisiologia , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Obesidade/genética , Núcleo Hipotalâmico Paraventricular/citologia
2.
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
3.
PLoS One ; 15(8): e0237974, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32841271

RESUMO

BACKGROUND: Cardiometabolic disorders are frequently observed among those who have obesity as measured by body mass index (BMI). However, there is limited data available on the cardiometabolic profile of those who are non-obese by BMI but with a high body fat percentage (BFP), a phenotype frequently observed in the Indian population. We examined the prevalence of individuals with normal weight obesity (NWO) and the cardiometabolic profile of NWO individuals at high risk for type 2 diabetes(T2D) in a south Asian population. MATERIAL AND METHODS: In the Kerala Diabetes Prevention Program, individuals aged between 30 to 60 years were screened using the Indian Diabetes Risk Score(IDRS) in 60 rural communities in the Indian state of Kerala. We used data from the baseline survey of this trial for this analysis which included 1147 eligible high diabetes risk individuals(IDRS >60). NWO was defined as BMI within the normal range and a high BFP (as per Asia-pacific ethnicity based cut-off); Non-obese (NO) as normal BMI and BFP and overtly obese (OB) as BMI ≥25 kg/m2 irrespective of the BFP. Data on demographic, clinical and biochemical characteristics were collected using standardized questionnaires and protocols. Body fat percentage was assessed using TANITA body composition analyser (model SC330), based on bioelectrical impedance. RESULTS: The mean age of participants was 47.3 ± 7.5 years and 46% were women. The proportion with NWO was 32% (n = 364; 95% CI: 29.1 to 34.5%), NO was 17% (n = 200) and OB was 51% (n = 583). Among those with NWO, 19.7% had T2D, compared to 18.7% of those who were OB (p value = 0.45) and 8% with NO (p value = 0.003). Among those with NWO, mean systolic and diastolic blood pressure were 129 ± 20; 78 ± 12 mmHg, compared to 127 ± 17; 78±11 mmHg among those with OB (p value = 0.12;0.94) and 120 ± 16; 71±10 mmHg among with NO (p value<0.001; 0.001), respectively. A similar pattern of association was observed for LDL cholesterol and triglycerides. After adjusting for other risk factors, the odds of having diabetes (OR:2.72[95% CI:1.46-5.08]) and dyslipidemia (2.37[1.55-3.64]) was significantly more in individuals with NWO as compared to non-obese individuals. CONCLUSIONS: Almost one-third of this South Asian population, at high risk for T2D, had normal weight obesity. The significantly higher cardiometabolic risk associated with increased adiposity even in lower BMI individuals has important implications for recognition in clinical practice.


Assuntos
Tecido Adiposo/patologia , Peso Corporal , Bases de Dados Factuais , Diabetes Mellitus Tipo 2/prevenção & controle , Miocárdio/metabolismo , Obesidade/epidemiologia , Obesidade/metabolismo , Adulto , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Obesidade/patologia , Fenótipo , Prevalência , Fatores de Risco
4.
PLoS One ; 15(8): e0237983, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32822397

RESUMO

OBJECTIVES: Although smoking is known to have a negative impact in patients with metabolic syndrome (MetS), only a few studies have examined the association between electronic cigarette (e-cig) use and MetS. METHODS: Among 22,948 participants in the 6th Korea National Health and Nutrition Examination Survey, 14,738 (13,459 [91.3%] never, 954 [6.5%] ever, and 325 [2.2%] current e-cig users) were selected. The relationship between e-cig exposure and MetS (based on the National Cholesterol Education Program Adult Treatment Panel [NCEP-ATP] III criteria) was evaluated using a multivariable logistic regression analysis. An unweighted analysis was performed to evaluate this association without a sampling weight. A subgroup analysis was performed among active smokers to compare dual users with never e-cig users. RESULTS: Among current e-cig users, 85.0% were dual users, 12.7% were former cigarette users, and 2.2% were only e-cig users. After adjustment for covariates, abdominal obesity and hypertriglyceridemia were significantly associated with current e-cig exposure (odds ratio [OR]: 1.88, 95% confidence interval [CI]: 1.41-2.50 and OR: 1.32, 95% CI: 1.00-1.74 respectively [compared with the never e-cig users group]). Compared with never e-cig users, current e-cig users showed an OR of 1.27 (95% CI: 0.96-1.70, Ptrend = 0.01) for MetS. In the unweighted analysis, the OR for MetS in current e-cig users was 1.40 (95% CI: 1.08-1.81, Ptrend <0.01). Compared with never e-cig users, dual users showed a higher OR for abdominal obesity (OR: 1.71, 95% CI: 1.25-2.34, Ptrend <0.001). CONCLUSIONS: Current e-cig exposure was associated with an increased risk of MetS. Dual use of e-cigs and cigarettes was associated with abdominal obesity. Further longitudinal studies and better assessment of e-cig use and type are needed to clarify this relationship.


Assuntos
Síndrome Metabólica/patologia , Vaping , Adulto , HDL-Colesterol/sangue , Fumar Cigarros , Feminino , Humanos , Hipertrigliceridemia/epidemiologia , Hipertrigliceridemia/patologia , Modelos Logísticos , Masculino , Síndrome Metabólica/epidemiologia , Pessoa de Meia-Idade , Inquéritos Nutricionais , Obesidade/epidemiologia , Obesidade/patologia , Razão de Chances , República da Coreia/epidemiologia , Triglicerídeos/sangue
5.
PLoS One ; 15(8): e0237667, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32833960

RESUMO

BACKGROUND AND AIMS: This is the first time that obesity and diabetes mellitus (DM) as protein conformational diseases (PCD) are reported in children and they are typically diagnosed too late, when ß-cell damage is evident. Here we wanted to investigate the level of naturally-ocurring or real (not synthetic) oligomeric aggregates of the human islet amyloid polypeptide (hIAPP) that we called RIAO in sera of pediatric patients with obesity and diabetes. We aimed to reduce the gap between basic biomedical research, clinical practice-health decision making and to explore whether RIAO work as a potential biomarker of early ß-cell damage. MATERIALS AND METHODS: We performed a multicentric collaborative, cross-sectional, analytical, ambispective and blinded study; the RIAO from pretreated samples (PTS) of sera of 146 pediatric patients with obesity or DM and 16 healthy children, were isolated, measured by sound indirect ELISA with novel anti-hIAPP cytotoxic oligomers polyclonal antibody (MEX1). We carried out morphological and functional studied and cluster-clinical data driven analysis. RESULTS: We demonstrated by western blot, Transmission Electron Microscopy and cell viability experiments that RIAO circulate in the blood and can be measured by ELISA; are elevated in serum of childhood obesity and diabetes; are neurotoxics and works as biomarkers of early ß-cell failure. We explored the range of evidence-based medicine clusters that included the RIAO level, which allowed us to classify and stratify the obesity patients with high cardiometabolic risk. CONCLUSIONS: RIAO level increases as the number of complications rises; RIAOs > 3.35 µg/ml is a predictor of changes in the current indicators of ß-cell damage. We proposed a novel physio-pathological pathway and shows that PCD affect not only elderly patients but also children. Here we reduced the gap between basic biomedical research, clinical practice and health decision making.


Assuntos
Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 2/patologia , Células Secretoras de Insulina/patologia , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Obesidade/patologia , Estrutura Quaternária de Proteína , Adolescente , Animais , Linhagem Celular , Sobrevivência Celular , Células Cultivadas , Criança , Pré-Escolar , Estudos Transversais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/sangue , Polipeptídeo Amiloide das Ilhotas Pancreáticas/toxicidade , Polipeptídeo Amiloide das Ilhotas Pancreáticas/ultraestrutura , Microscopia Eletrônica de Transmissão , Neurônios/efeitos dos fármacos , Obesidade/sangue , Obesidade/complicações , Projetos Piloto , Cultura Primária de Células , Multimerização Proteica , Ratos , Testes de Toxicidade Aguda
6.
Int J Mol Sci ; 21(13)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32630032

RESUMO

Obesity is a characteristic of COVID-19 patients and the risk of malnutrition can be underestimated due to excess of fat: a paradoxical danger. Long ICU hospitalization exposes patients to a high risk of wasting and loss of lean body mass. The complex management precludes the detection of anthropometric parameters for the definition and monitoring of the nutritional status. The use of imaging diagnostics for body composition could help to recognize and treat patients at increased risk of wasting with targeted pathways. COVID-19 patients admitted to the ICU underwent computed tomography within 24 hours and about 20 days later, to evaluate the parameters of the body and liver composition. The main results were the loss of the lean mass index and a greater increase in liver attenuation in obese subjects. These could be co-caused by COVID-19, prolonged bed rest, the complex medical nutritional therapy, and the starting condition of low-grade inflammation of the obese. The assessment of nutritional status, with body composition applied to imaging diagnostics and metabolic profiles in COVID-19, will assist in prescribing appropriate medical nutritional therapy. This will reduce recovery times and complications caused by frailty.


Assuntos
Caquexia , Infecções por Coronavirus/patologia , Obesidade/patologia , Pneumonia Viral/patologia , Adulto , Idoso , Betacoronavirus/isolamento & purificação , Composição Corporal , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico por imagem , Feminino , Humanos , Fígado/diagnóstico por imagem , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/metabolismo , Estado Nutricional , Obesidade/complicações , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico por imagem , Estudos Prospectivos , Fatores de Risco , Tomografia Computadorizada por Raios X
7.
Diab Vasc Dis Res ; 17(4): 1479164120945675, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32722929

RESUMO

Activation of the prostaglandin E2 receptor EP4 alters polarization of adipose tissue macrophages towards the anti-inflammatory M2 phenotype to suppress chronic inflammation. However, the role of EP4 signalling in pancreatic macrophages that affect insulin secretion is unclear. We examined the role of EP4 signalling in islet inflammation in vitro and in vivo. Obese diabetic db/db mice were treated with an EP4-selective agonist or vehicle for 4 weeks. Islet morphology did not significantly differ and glucose-stimulated insulin secretion was increased, whereas the pancreatic M1/M2 ratio was decreased in the EP4 agonist-treated group compared to the vehicle group. Because EP4 activation in MIN6 cells did not affect insulin secretion, we used a MIN6/macrophage co-culture system to evaluate the role of EP4 signalling in islet inflammation and subsequent inhibition of insulin release. Co-culture with M1-polarized macrophages markedly suppressed insulin expression in MIN6 cells; however, modulation of M1 polarization by the EP4 agonist significantly reversed the negative impact of co-cultivation on insulin production. The enhanced expression levels of pro-inflammatory cytokines in co-cultured MIN6 cells were markedly inhibited by EP4 agonist treatment of M1 macrophages. Thus, EP4 activation may suppress islet inflammation and protect ß-cell function by altering inflammatory macrophages in the diabetic pancreas.


Assuntos
Plasticidade Celular , Diabetes Mellitus Tipo 2/metabolismo , Inflamação/metabolismo , Células Secretoras de Insulina/metabolismo , Macrófagos Peritoneais/metabolismo , Obesidade/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Linhagem Celular Tumoral , Técnicas de Cocultura , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/patologia , Modelos Animais de Doenças , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/patologia , Ativação de Macrófagos , Macrófagos Peritoneais/patologia , Camundongos , Obesidade/patologia , Fenótipo , Via Secretória , Transdução de Sinais
8.
PLoS One ; 15(7): e0236741, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730300

RESUMO

Aryl hydrocarbon receptor (AHR) agonists such as dioxin have been associated with obesity and the development of diabetes. Whole-body Ahr knockout mice on high-fat diet (HFD) have been shown to resist obesity and hepatic steatosis. Tissue-specific knockout of Ahr in mature adipocytes via adiponectin-Cre exacerbates obesity while knockout in liver increases steatosis without having significant effects on obesity. Our previous studies demonstrated that treatment of subcutaneous preadipocytes with exogenous or endogenous AHR agonists disrupts maturation into functional adipocytes in vitro. Here, we used platelet-derived growth factor receptor alpha (Pdgfrα)-Cre mice, a Cre model previously established to knock out genes in preadipocyte lineages and other cell types, but not liver cells, to further define AHR's role in obesity. We demonstrate that Pdgfrα-Cre Ahr-floxed (Ahrfl/fl) knockout mice are protected from HFD-induced obesity compared to non-knockout Ahrfl/fl mice (control mice). The Pdgfrα-Cre Ahrfl/fl knockout mice were also protected from increased adiposity, enlargement of adipocyte size, and liver steatosis while on the HFD compared to control mice. On a regular control diet, knockout and non-knockout mice showed no differences in weight gain, indicating the protective phenotype arises only when animals are challenged by a HFD. At the cellular level, cultured cells from brown adipose tissue (BAT) of Pdgfrα-Cre Ahrfl/fl mice were more responsive than cells from controls to transcriptional activation of the thermogenic uncoupling protein 1 (Ucp1) gene by norepinephrine, suggesting an ability to burn more energy under certain conditions. Collectively, our results show that knockout of Ahr mediated by Pdgfrα-Cre is protective against diet-induced obesity and suggest a mechanism by which enhanced UCP1 activity within BAT might confer these effects.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/fisiologia , Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/prevenção & controle , Integrases/metabolismo , Obesidade/prevenção & controle , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/fisiologia , Receptores de Hidrocarboneto Arílico/fisiologia , Adiposidade , Animais , Metabolismo Energético , Fígado Gorduroso/etiologia , Fígado Gorduroso/patologia , Feminino , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/etiologia , Obesidade/patologia , Termogênese
9.
PLoS One ; 15(7): e0235926, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645116

RESUMO

PURPOSE: To evaluate the changes in the retinochoroidal vasculature in patients with exogenous obesity using swept-source optical coherence tomography (SS-OCT) and OCT angiography (OCTA). METHODS: In this prospective study, 60 patients diagnosed with obesity (47 males) (mean age: 46.47±10.9 years) were included, of which 30 patients underwent bariatric surgery (Group A), and 30 patients underwent conservative management (exercise/diet) (Group B). Parameters including choroidal thickness (CT), choroidal vascularity index (CVI) and retinal capillary density index (CDI) and arteriovenous ratio (AVR) were measured at the baseline and three months follow up. 30 eyes (30 age and gender-matched) of normal participants were included for comparison. RESULTS: Baseline CT was lower in 60 participants with obesity compared to controls. Compared with normal subjects, subjects with obesity had higher mean CVI (0.66±0.02 versus 0.63±0.04; p<0.01), smaller FAZ area (0.26±0.07 versus 0.45±0.32; p<0.01), higher CDI (superficial plexus: 0.7±0.04 versus 0.68±0.06; p = 0.04, deep plexus: 0.38±0.02 versus 0.35±0.06; p = 0.01), and lower AVR (0.68±0.05 versus 0.70±0.03 versus; p<0.01). At 3-month after intervention, CT showed a significant increase in participants from Group A (329.27±79µm; p<0.01) but not in Group B from baseline. No significant change was noted in CVI or CDI at 3-month in either group compared to baseline. AVR significantly increased in Group B (p = 0.03). CONCLUSION: Subclinical changes in retinochoroidal vasculature occurs in participants with exogenous obesity compared to healthy subjects. Surgical intervention (bariatric surgery) may have a favorable outcome on the choroidal thickness in these patients.


Assuntos
Corioide/fisiologia , Obesidade/patologia , Retina/fisiologia , Adulto , Cirurgia Bariátrica , Estudos de Casos e Controles , Corioide/irrigação sanguínea , Exercício Físico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Vasos Retinianos/fisiologia , Perda de Peso
11.
Arterioscler Thromb Vasc Biol ; 40(9): 2227-2243, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640901

RESUMO

OBJECTIVE: Perivascular adipose tissue (PVAT) surrounding arteries supports healthy vascular function. During obesity, PVAT loses its vasoprotective effect. We study pathological conversion of PVAT, which involves molecular changes in protein profiles and functional changes in adipocytes. Approach and Results: C57BL6/J mice were fed a 60% high-fat diet for 12 weeks or a cardioprotective 30% calorie-restricted diet for 5 weeks. Proteomic analysis identified PVAT as a molecularly distinct adipose depot, and novel markers for thermogenic adipocytes, such as GRP75 (stress-70 protein, mitochondrial), were identified. High-fat diet increased the similarity of protein signatures in PVAT and brown adipose, suggesting activation of a conserved whitening pathway. The whitening phenotype was characterized by suppression of UCP1 (uncoupling protein 1) and increased lipid deposition, leptin, and inflammation, and specifically in PVAT, elevated Notch signaling. Conversely, PVAT from calorie-restricted mice had decreased Notch signaling and less lipid. Using the Adipoq-Cre strain, we constitutively activated Notch1 signaling in adipocytes, which phenocopied the changes in PVAT caused by a high-fat diet, even on a standard diet. Preadipocytes from mouse PVAT expressed Sca1, CD140a, Notch1, and Notch2, but not CD105, showing differences compared with preadipocytes from other depots. Inhibition of Notch signaling during differentiation of PVAT-derived preadipocytes reduced lipid deposition and adipocyte marker expression. CONCLUSIONS: PVAT shares features with other adipose depots, but has a unique protein signature that is regulated by dietary stress. Increased Notch signaling in PVAT is sufficient to initiate the pathological conversion of PVAT by promoting adipogenesis and lipid accumulation and may thus prime the microenvironment for vascular disease.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Lipogênese , Obesidade/metabolismo , Receptores Notch/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Ataxina-1/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Restrição Calórica , Dieta Hiperlipídica , Modelos Animais de Doenças , Endoglina/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/patologia , Fenótipo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Proteômica , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Notch/genética , Transdução de Sinais
12.
Nat Commun ; 11(1): 2695, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32483258

RESUMO

Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors that are characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority are located in non-coding DNA regions. This suggests that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNFα. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Elementos Facilitadores Genéticos , Resistência à Insulina/genética , Músculo Esquelético/metabolismo , Obesidade/genética , Obesidade/metabolismo , Animais , Linhagem Celular , Cromatina/genética , Cromatina/metabolismo , Diabetes Mellitus Tipo 2/patologia , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Obesidade/patologia , Ácido Palmítico/farmacologia , Fatores de Iniciação de Peptídeos/genética , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Fator de Necrose Tumoral alfa/farmacologia
13.
Ann Biol Clin (Paris) ; 78(3): 243-252, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32540813

RESUMO

Adiponectin is a major adipokine involved in energy homeostasis that exerts insulin-sensitizing properties. The level of adiponectin is reduced in situations of insulin resistance and is negatively associated with several pathophysiological situations including abdominal obesity, metabolic syndrome, steatosis and non-alcoholic steatohepatitis, type 2 diabetes, some cancers and cognitive diseases. These aspects are discussed in this review.


Assuntos
Adiponectina/fisiologia , Animais , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/metabolismo , Transtornos Cognitivos/patologia , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/etiologia , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Obesidade/metabolismo , Obesidade/patologia , Obesidade/fisiopatologia
14.
Gene ; 754: 144850, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32505844

RESUMO

Obesity is associated with germ cell apoptosis, spermatogenesis arrest, and testicular endocrine suppression. The aim of the present study was to investigate the crosstalk between germ cell apoptosis and cell cycle machinery in sedentary and obese rats after moderate-intensity continuous (MICT), high-intensity continuous (HICT) and High-intensity interval (HIIT) exercise trainings. Male Wistar rats (n = 30) were randomly divided into 5 groups; the control, sedentary high-fat diet (HFD)-received (HFD-sole), MICT, HICT and HIIT-induced HFD-received groups. The serum levels of LDL-C, HDL-C, triglyceride, and testosterone, mRNA and protein levels of Cyclin D1, Cdk4, p21, apoptotic cell number/mm2 of testicular tissue and testicular DNA fragmentation ratio were investigated. The obese animals in HFD-sole group represented a significant (p < 0.05) reduction in serum HDL-C and testosterone levels, Cyclin D1, Cdk4 expressions, and exhibited a remarkable (p < 0.05) increment in LDL-C, triglyceride, p21 expression, apoptotic cell number and DNA fragmentation ratio versus control animals. However, the animals in MICT, HICT, HIIT groups exhibited a significant (p < 0.05) increment in serum HDL-C and testosterone, Cyclin D1 and Cdk4 expressions and showed a significant (p < 0.05) reduction in serum LDL-C and triglyceride, p21 expression, apoptotic cell number and DNA fragmentation versus the HFD-sole group. In conclusion, a crosslink between cell cycle machinery and apoptosis of germ cells was revealed in the testicles of HFD-sole animals, and MICT, HICT and HIIT could ameliorate the obesity-induced impairments, respectively. This effect may be attributed to the effect of exercise training protocols on maintaining Cyclin D1 and Cdk4 and suppressing p21 expression levels in the testicles.


Assuntos
Apoptose , Proteínas de Ciclo Celular/metabolismo , Dieta Hiperlipídica/efeitos adversos , Treinamento Intervalado de Alta Intensidade/métodos , Obesidade/terapia , Condicionamento Físico Animal/métodos , Testículo/metabolismo , Animais , Proteínas de Ciclo Celular/genética , Lipídeos/análise , Masculino , Obesidade/etiologia , Obesidade/metabolismo , Obesidade/patologia , Ratos , Ratos Wistar , Testosterona/sangue
15.
PLoS One ; 15(6): e0235219, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579592

RESUMO

The obesity epidemic is a pervasive health issue affecting all population groups in developed countries. The purpose of this research was to ascertain obesity risk reduction behaviors and their psychosocial determinants in young adult Americans residing in New Jersey state. A cross-sectional survey design was implemented in which a convenience sample of 174 participants (18 to 40 years) completed a validated online self-administered questionnaire. Nineteen obesity risk reduction behaviors, self-efficacy and psychosocial constructs derived from the Theory of Planned Behavior were measured. Statistical analyses were conducted using frequency distributions, t-tests and regression analysis. Regression analysis indicated that 37.5% of the variance in obesity risk reduction behavior was accounted by self-efficacy alone. T-test comparisons indicated greater frequency of adoption of 17 health behaviors among individuals categorized in the 'high self-efficacy' group (p<0.05). These behaviors included limiting portion sizes of food, eating fruits and vegetables, engaging in physical activity, and monitoring stress and body weight. Nutrition professionals working with young adult Americans need to assess their self-efficacy to engage in obesity risk reduction behaviors. In fostering confidence in adopting these behaviors, executing skill building nutrition interventions is critical for obesity prevention.


Assuntos
Obesidade/patologia , Comportamento de Redução do Risco , Autoeficácia , Adolescente , Adulto , Peso Corporal , Estudos Transversais , Grupo com Ancestrais do Continente Europeu , Exercício Físico , Comportamento Alimentar , Feminino , Humanos , Masculino , Obesidade/psicologia , Estresse Psicológico , Inquéritos e Questionários , Estados Unidos , Adulto Jovem
17.
Life Sci ; 256: 117965, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32544463

RESUMO

BACKGROUND: Several studies have proved that physical activity (PA) regulates energetic metabolism associated with mitochondrial dynamics through AMPK activation in healthy subjects. Obesity, a condition that induces oxidative stress, mitochondrial dysfunction, and low AMPK activity leads to mitochondrial fragmentation. However, few studies describe the effect of PA on mitochondrial dynamics regulation in obesity. AIM: The present study aimed to evaluate the effect of a single session of PA on mitochondrial dynamics regulation as well as its effect on mitochondrial function and organization in skeletal muscles of obese rats (Zucker fa/fa). MAIN METHODS: Male Zucker lean and Zucker fa/fa rats aged 12 to 13 weeks were divided into sedentary and subjected-to-PA (single session swimming) groups. Gastrocnemius muscle was dissected into isolated fibers, mitochondria, mRNA, and total proteins for their evaluation. KEY FINDINGS: The results showed that PA increased the Mfn-2 protein level in the lean and obese groups, whereas Drp1 levels decreased in the obese group. OMA1 protease levels increased in the lean group and decreased in the obese group. Additionally, AMPK analysis parameters (expression, protein level, and activity) did not increase in the obese group. These findings correlated with the partial restoration of mitochondrial function in the obese group, increasing the capacity to maintain the membrane potential after adding calcium as a stressor, and increasing the transversal organization level of the mitochondria analyzed in isolated fibers. SIGNIFICANCE: These results support the notion that obese rats subjected to PA maintain mitochondrial function through mitochondrial fusion activation by an AMPK-independent mechanism.


Assuntos
Mitocôndrias/patologia , Fibras Musculares Esqueléticas/patologia , Obesidade/patologia , Condicionamento Físico Animal , Adenilato Quinase/metabolismo , Animais , Biomarcadores/metabolismo , Citrato (si)-Sintase/metabolismo , DNA Mitocondrial/metabolismo , Regulação da Expressão Gênica , Masculino , Potencial da Membrana Mitocondrial , Dinâmica Mitocondrial , Proteínas Mitocondriais/genética , Proteínas Mitocondriais/metabolismo , Tamanho do Órgão , Estresse Oxidativo , Fosforilação , Ratos Zucker
18.
PLoS One ; 15(6): e0234768, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555694

RESUMO

BACKGROUND: There is a growing interest in the life course approach for the prevention, early detection and subsequent management of morbidity in women of reproductive age to ensure optimal health and nutrition when they enter pregnancy. Reliable estimates of such morbidities are lacking. We report the prevalence of health or nutrition-related morbidities, specifically, anemia, undernutrition, overweight and obesity, sexually transmitted infections (STIs) or reproductive tract infections (RTIs), diabetes or prediabetes, hypothyroidism, hypertension, and depressive symptoms, during the preconception period among women aged 18 to 30 years. METHODS: A cross-sectional study was conducted among 2000 nonpregnant married women aged 18 to 30 years with no or one child who wished to have more children in two low- to middle-income urban neighborhoods in Delhi, India, in the context of a randomized controlled trial. STIs and RTIs were measured by symptoms and signs, blood pressure by a digital device, height by stadiometer and weight by a digital weighing scale. A blood specimen was taken to screen for anemia, diabetes, thyroid disorders and syphilis. Maternal depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9). Multivariable logistic regression analysis was performed to identify sociodemographic factors associated with individual morbidity. RESULTS: Overall, 58.7% of women were anemic; 16.5%, undernourished; 26%, overweight or obese; 13.2%, hypothyroid; and 10.5% with both symptoms and signs of STIs/RTIs. There was an increased risk of RTI/STI symptoms and signs in undernourished women and an increased risk of diabetes or prediabetes in overweight or obese women. An increased risk of undernutrition was also observed in women from lower categories of wealth quintiles. A decreased risk of moderate to severe anemia was seen in overweight women and those who completed at least secondary education. CONCLUSIONS: Our findings show a high burden of undernutrition, anemia, RTIs, hypothyroidism and prediabetes among women in the study. This information will aid policymakers in planning special programs for women of reproductive age.


Assuntos
Infecções do Sistema Genital/patologia , Doenças Sexualmente Transmissíveis/patologia , Adolescente , Adulto , Anemia/complicações , Anemia/patologia , Estudos Transversais , Diabetes Mellitus Tipo 2/etiologia , Feminino , Humanos , Hipotireoidismo/patologia , Índia/epidemiologia , Morbidade , Obesidade/complicações , Obesidade/patologia , Prevalência , Infecções do Sistema Genital/epidemiologia , Fatores de Risco , Índice de Gravidade de Doença , Doenças Sexualmente Transmissíveis/epidemiologia , Adulto Jovem
19.
PLoS One ; 15(6): e0234812, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555738

RESUMO

BACKGROUND: Due to the absence and or costliness of biological measures such as glycated haemoglobin, diabetes case ascertainment and prevalence studies are usually conducted using surveys or routine health service use databases. However, the use of each of these sources is associated with its limitations potentially impacting the quality of the case ascertainment and prevalence estimation. This study aimed at ascertaining diabetes cases and estimating prevalence among mid- and older-age women through simultaneous use of a longitudinal survey and multiple healthcare administrative data sources. METHODS: Data were available for 12,432 and 13,714 women born in 1921-26 and 1946-51 from the Australian Longitudinal Study on Women's Health (ALSWH). Diabetes was ascertained using the ALSWH survey, health service use, and cause of death data. Parsimonious multiple logistic regression analyses tested associations between sociodemographic and health variables and the presence of diabetes. RESULTS: In both cohorts, two or more of the sources captured more than 80% of the women with diabetes. The point prevalence of diabetes increased from 8.4% when the mean age of the women were aged 73, to 22.0% of surviving women at age 90 in the 1921-26 cohort; and from 2.6% at age 48 to 15.8% at age 68 in the 1946-51 cohort. In the 1921-26 cohort, women who were obese (OR: 3.56; 95 CI: 3.04-4.17) and women who were sedentary (OR: 1.18; 95 CI: 1.09-1.40) were more likely to have diabetes compared to those who had a normal weight and engaged in a moderate level of physical activity. In the 1946-51 cohort, the odds of diabetes increased three times (OR: 2.99; 95 CI: 2.54-3.52) for overweight women and nine times (OR: 8.78; 95 CI: 7.46-10.33) for obese women compared to those who had normal weight. CONCLUSIONS: The simultaneous use of multiple data sources improved the validity of diabetes case ascertainment. Application of this methodology in future studies may have important benefits including estimation of disease burden, health service needs, and resource allocation with improved precision. Diabetes prevalence increased with age, was much higher in the 1946-51 cohort than in 1921-26 at similar ages, and was significantly associated with physical inactivity and obesity. Interventions to promote physical activity and a healthy weight are needed to prevent the rising prevalence of diabetes across successive generations.


Assuntos
Diabetes Mellitus/diagnóstico , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Austrália/epidemiologia , Estudos de Coortes , Complicações do Diabetes/patologia , Diabetes Mellitus/epidemiologia , Exercício Físico , Feminino , Inquéritos Epidemiológicos , Humanos , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/patologia , Prevalência , Saúde da Mulher
20.
Mol Genet Genomics ; 295(4): 1013-1026, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32363570

RESUMO

Obesity, a risk factor for multiple diseases (e.g. diabetes, hypertension, cancers) originates through complex interactions between genes and prevailing environment (food habit and lifestyle) that varies across populations. Indians exhibit a unique obesity phenotype with high abdominal adiposity for a given body weight compared to matched white populations suggesting presence of population-specific genetic and environmental factors influencing obesity. However, Indian population-specific genetic contributors for obesity have not been explored yet. Therefore, to identify potential genetic contributors, we performed a two-staged genome-wide association study (GWAS) for body mass index (BMI), a common measure to evaluate obesity in 5973 Indian adults and the lead findings were further replicated in 1286 Indian adolescents. Our study revealed novel association of variants-rs6913677 in BAI3 gene (p = 1.08 × 10-8) and rs2078267 in SLC22A11 gene (p = 4.62 × 10-8) at GWAS significance, and of rs8100011 in ZNF45 gene (p = 1.04 × 10-7) with near GWAS significance. As genetic loci may dictate the phenotype through modulation of epigenetic processes, we overlapped genetic data of identified signals with their DNA methylation patterns in 236 Indian individuals and performed methylation quantitative trait loci (meth-QTL) analysis. Further, functional roles of discovered variants and underlying genes were speculated using publicly available gene regulatory databases (ENCODE, JASPAR, GeneHancer, GTEx). The identified variants in BAI3 and SLC22A11 genes were found to dictate methylation patterns at unique CpGs harboring critical cis-regulatory elements. Further, BAI3, SLC22A11 and ZNF45 variants were located in repressive chromatin, active enhancer, and active chromatin regions, respectively, in human subcutaneous adipose tissue in ENCODE database. Additionally, these genomic regions represented potential binding sites for key transcription factors implicated in obesity and/or metabolic disorders. Interestingly, GTEx portal identify rs8100011 as a robust cis-expression quantitative trait locus (cis-eQTL) in subcutaneous adipose tissue (p = 1.6 × 10-7), and ZNF45 gene expression in skeletal muscle of Indian subjects showed an inverse correlation with BMI indicating its possible role in obesity. In conclusion, our study discovered 3 novel population-specific functional genetic variants (rs6913677, rs2078267, rs8100011) in 2 novel (SLC22A11 and ZNF45) and 1 earlier reported gene (BAI3) for BMI in Indians. Our study decodes key genomic loci underlying obesity phenotype in Indians that may serve as prospective drug targets in future.


Assuntos
Estudo de Associação Genômica Ampla , Fatores de Transcrição Kruppel-Like/genética , Obesidade/genética , Transportadores de Ânions Orgânicos Sódio-Independentes/genética , Proteínas Repressoras/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Índice de Massa Corporal , Metilação de DNA , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Humanos , Índios Norte-Americanos/genética , Masculino , Obesidade/patologia , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Sequências Reguladoras de Ácido Nucleico/genética , Adulto Jovem
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