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Introduction: Obesity is a major risk factor associated with multiple pathological conditions including diabetes and cardiovascular disease. Endothelial dysfunction is an early predictor of obesity. However, little is known regarding how early endothelial changes trigger obesity. In the present work we report a novel endothelial-mediated mechanism essential for regulation of metabolic homeostasis, driven by c-Myc. Methods: We used conditional knockout (EC-Myc KO) and overexpression (EC-Myc OE) mouse models to investigate the endothelial-specific role of c-Myc in metabolic homeostasis during aging and high-fat diet exposure. Body weight and metabolic parameters were collected over time and tissue samples collected at endpoint for biochemical, pathology and RNA-sequencing analysis. Animals exposed to high-fat diet were also evaluated for cardiac dysfunction. Results: In the present study we demonstrate that EC-Myc KO triggers endothelial dysfunction, which precedes progressive increase in body weight during aging, under normal dietary conditions. At endpoint, EC-Myc KO animals showed significant increase in white adipose tissue mass relative to control littermates, which was associated with sex-specific changes in whole body metabolism and increase in systemic leptin. Overexpression of endothelial c-Myc attenuated diet-induced obesity and visceral fat accumulation and prevented the development of glucose intolerance and cardiac dysfunction. Transcriptome analysis of skeletal muscle suggests that the protective effects promoted by endothelial c-Myc overexpression are associated with the expression of genes known to increase weight loss, energy expenditure and glucose tolerance. Conclusion: Our results show a novel important role for endothelial c-Myc in regulating metabolic homeostasis and suggests its potential targeting in preventing obesity and associated complications such as diabetes type-2 and cardiovascular dysfunction.
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Endothelial cells play an essential role in inflammation through synthesis and secretion of chemoattractant cytokines and expression of adhesion molecules required for inflammatory cell attachment and infiltration. The mechanisms by which endothelial cells control the pro-inflammatory response depend on the type of inflammatory stimuli, endothelial cell origin, and tissue involved. In the present study, we investigated the role of the transcription factor c-Myc in inflammation using a conditional knockout mouse model in which Myc is specifically deleted in the endothelium. At a systemic level, circulating monocytes, the chemokine CCL7, and the extracellular-matrix protein osteopontin were significantly increased in endothelial c-Myc knockout (EC-Myc KO) mice, whereas the cytokine TNFSF11 was downregulated. Using an experimental model of steatohepatitis, we investigated the involvement of endothelial c-Myc in diet-induced inflammation. EC-Myc KO animals displayed enhanced pro-inflammatory response, characterized by increased expression of pro-inflammatory cytokines and leukocyte infiltration, and worsened liver fibrosis. Transcriptome analysis identified enhanced expression of genes associated with inflammation, fibrosis, and hepatocellular carcinoma in EC-Myc KO mice relative to control (CT) animals after short-exposure to high-fat diet. Analysis of a single-cell RNA-sequencing dataset of human cirrhotic livers indicated downregulation of MYC in endothelial cells relative to healthy controls. In summary, our results suggest a protective role of endothelial c-Myc in diet-induced liver inflammation and fibrosis. Targeting c-Myc and its downstream pathways in the endothelium may constitute a potential strategy for the treatment of inflammatory disease.
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Dieta Alta en Grasa/efectos adversos , Endotelio/metabolismo , Hígado Graso , Cirrosis Hepática , Proteínas Proto-Oncogénicas c-myc/deficiencia , Animales , Endotelio/patología , Hígado Graso/inducido químicamente , Hígado Graso/genética , Hígado Graso/metabolismo , Hígado Graso/patología , Femenino , Técnicas de Inactivación de Genes , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Inflamación/inducido químicamente , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Masculino , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
BACKGROUND: To evaluate the effect of nicotinamide prior to streptozotocin-induced (STZ) diabetes in baroreflex sensitivity and cardiovascular autonomic modulation, and its association with hemodynamics and metabolic parameters. METHODS: Methods: Male Wistar rats were divided into control (Cont) and STZ-induced diabetes (Diab). Half of the rats from each group received a single dose of nicotinamide (100 mg/Kg) before STZ injection (Cont+NicA and Diab+NicA). All groups were followed-up for 5 weeks. RESULTS: Body weight loss of more than 40% was observed in Diab throughout the period (Diab: 271.00 ± 12.74 g; Diab+NicA: 344.62 ± 17.82). Increased glycemia was seen in Diab rats (541.28 ± 18.68 mg/dl) while Diab+NicA group had a slight decrease (440.87 ± 20.96 mg/dl). However, insulin resistance was observed only in Diab. In relation to Cont, heart rate, mean blood pressure and diastolic function were reduced when compared to Diab, together with parasympathetic modulation and baroreflex sensitivity. All of these parameters were improved in Diab+NicA when compared to Diab. Improved baroreflex sensitivity and parasympathetic modulation were correlated with glycemia, insulin resistance, and body weight mass. Additionally, Diab+NicA group increased survival rate. CONCLUSIONS: Results suggest that the association of nicotinamide in STZ-induced diabetic rats prevents most of the expected derangements mainly by preserving parasympathetic and baroreflex parameters.
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Sistema Nervioso Autónomo/efectos de los fármacos , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Frecuencia Cardíaca/efectos de los fármacos , Niacinamida/uso terapéutico , Animales , Sistema Nervioso Autónomo/fisiología , Barorreflejo/fisiología , Presión Sanguínea/fisiología , Diabetes Mellitus Experimental/inducido químicamente , Diabetes Mellitus Experimental/mortalidad , Frecuencia Cardíaca/fisiología , Masculino , Niacinamida/farmacología , Ratas , Ratas Wistar , Tasa de Supervivencia/tendencias , Complejo Vitamínico B/farmacología , Complejo Vitamínico B/uso terapéuticoRESUMEN
Objective: To evaluate autonomic and cardiovascular function, as well as inflammatory and oxidative stress markers in ob/ob female mice. Methods: Metabolic parameters, cardiac function, arterial pressure (AP), autonomic, hormonal, inflammatory, and oxidative stress markers were evaluated in 12-weeks female wild-type (WT group) and ob/ob mice (OB group). Results: OB animals showed increased body weight, blood glucose, and triglyceride levels, along with glucose intolerance, when compared to WT animals. Ejection fraction (EF) and AP were similar between groups; however, the OB group presented diastolic dysfunction, as well as an impairment on myocardial performance index. Moreover, the OB group exhibited important autonomic dysfunction and baroreflex sensitivity impairment, when compared to WT group. OB group showed increased Angiotensin II levels in heart and renal tissues; decreased adiponectin and increased inflammatory markers in adipose tissue and spleen. Additionally, OB mice presented a higher damage to proteins and lipoperoxidation and lower activity of antioxidant enzymes in kidney and heart. Correlations were found between autonomic dysfunction with angiotensin II and inflammatory mediators, as well as between inflammation and oxidative stress. Conclusions: Our results showed that female adult ob/ob mice presented discrete diastolic dysfunction accompanied by autonomic disorder, which is associated with inflammation and oxidative stress in these animals.
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The aim of this study was to investigate metabolic and cardiovascular responses to walking in fructose-fed rats. Male Wistar rats were divided into control (C), sedentary fructose (SF) and walking fructose (WF). Fructose-fed rats received D-fructose (100 g/l). WF rats walked on a treadmill at constant load (0.3 km/h) during 1 h/day, 5 days/week for 8 weeks. Measurements of triglyceride concentrations, adipose tissue and glycemia were carried out together with insulin tolerance test to evaluate metabolic profile. Arterial pressure (AP) signals were directly recorded. Baroreflex sensitivity (BR) was evaluated by the reflex tachycardia (TR) and bradycardia (BR) to AP changes. The results showed that walking decreased the adipose tissue (SF: 6.5 ± 0.4; WF: 2.8 ± 0.1; C: 3.0 ± 0.3 g), blood triglyceride levels (SF: 291 ± 6.5; WF: 150 ± 8.1; C: 103 ± 4.5 mg/dl) and increased insulin sensitivity (SF: 2.5 ± 0.2; WF: 3.3 ± 0.32; C: 4.8 ± 0.4 %/min). Baroreflex sensitivity was improved in the WF group expressed by BR (SF: 0.75 ± 0.10; WF: 1.18 ± 0.10; C: 1.5 ± 0.14 ms/mmHg) and TR (SF: 0.80 ± 0.12; WF: 1.21 ± 0.10; C: 1.35 ± 0.11 ms/mmHg), as well as when verified by the alpha index. Although the WF group showed decreased AP when compared with the SF group, the values still enhanced in relation to C rats (SF: 137 ± 2; WF: 129 ± 1; C: 115 ± 6 mmHg). Our findings allow a better understanding of the effects of walking, a low-intensity exercise training, on the hemodynamic and metabolic aspects of male rats with metabolic syndrome and indicate that walking seems to be particularly effective in treating metabolic disturbances in this model.