Low grade endotoxemia is a feature of obesity which is linked to development of steatohepatitis in non-alcoholic fatty liver disease. In this study, macrophages (J774) and hepatocytes (HepG2) were stimulated with lipopolysaccharide (LPS) from E.coli 0111: B4 and analysed for modulation of this response when preconditioned or stimulated subsequent to LPS, with different doses of Vitamin D3 or docosahexaenoic acid (DHA) over a time period of one and five days. Pro-inflammatory TNF and pro-fibrotic TGF released into the supernatants were measured by ELISA. qPCR was performed for Srebp-1c and PPAR mRNA (genes for products involved in fatty acid synthesis and catabolism, respectively). Vitamin D3 and DHA exerted a consistent, dose dependent anti-inflammatory effect and increased PPAR relative to Srebp-1c in both cell types. By contrast, addition of free fatty acids (FFA, oleic acid/palmitic acid 2:1) caused aggravation of LPS-induced inflammatory reaction and an increase of Srebp-1c relative to PPAR. Our results argue in favour of dietary supplementation of Vitamin D3 or DHA (and avoidance of monounsaturated/saturated fatty acids) to alleviate development of fatty liver disease.

Protein O-GlcNAcylation, a dynamic and reversible glucose-dependent post-translational modification of serine and threonine residues on target proteins, has been proposed to promote vascular smooth muscle cell proliferation and migration events implicated in vein graft failure (VGF). Therefore, targeting the enzymes (glutamine fructose-6P amidotransferase (GFAT), O-GlcNAc transferase (OGT), and O-GlcNAcase (OGA)) that regulate cellular O-GlcNAcylation could offer therapeutic options to reduce neointimal hyperplasia and venous stenosis responsible for VGF. However, it is unclear how type 2 diabetes mellitus (T2DM) and hyperglycaemia affect the expression of these enzymes in human saphenous vein smooth muscle cells (HSVSMCs), a key cell type involved in the vascular dysfunction responsible for saphenous VGF. Therefore, our aim was to assess whether T2DM and hyperglycaemia affect GFAT, OGT, and OGA expression levels in HSVSMCs in vitro. Expression levels of GFAT, OGT, and OGA were determined in low-passage HSVSMCs from T2DM and non-T2DM patients, and in HSVSMCs treated for 48 h with hyperglycaemic (10 mM and 25 mM) glucose concentrations, by quantitative immunoblotting. Expression levels of OGT, OGA, and GFAT were not significantly different in HSVSMC lysates from T2DM patients versus non-T2DM controls. In addition, treatment with high glucose concentrations (10 mM and 25 mM) had no significant effect on the protein levels of these enzymes in HSVSMC lysates. From our findings, T2DM and hyperglycaemia do not significantly impact the expression levels of the O-GlcNAcylation-regulating enzymes OGT, OGA, and GFAT in HSVSMCs. This study provides a foundation for future studies to assess the role of O-GlcNAcylation on VGF in T2DM.

Few studies show the potential changing effect of fat-mass and obesity-associated (FTO) rs9939609 gene on cardiometabolic risk after a lifestyle intervention. This study aims to evaluate whether overweight and obese adolescents, carriers of the risk genotypes for obesity of the FTO rs9939609 gene polymorphism, have different anthropometric and biochemical responses to an interdisciplinary intervention program. The quasi-experimental study involved 34 adolescents aged 10 to 15 years. Schoolchildren with AA/AT genotype decreased glucose, total cholesterol, low-density lipoprotein cholesterol, and increased high-density lipoprotein cholesterol. However, there were no differences between the genotypes, suggesting that the “A” allele did not modify the subject's response to the intervention program.

Introduction: In addition to childhood obesity status, the family history of cardiovascular disorders might be used as a tool for screening youth to identify those at the highest risk of developing metabolic impairments later in life. Thus, the aim of the present study was to examine associations between parental history of cardiovascular disease risk factors and childhood cardiometabolic risk, and to examine the role of cardiorespiratory fitness (CRF) and obesity in mediating the relationship between parental history and global cardiometabolic risk. Methods: A cross-sectional study was developed with 2,213 Brazilian youth. The cardiometabolic risk factor (CMRF) score, CRF, and waist circumference (WC) were evaluated. Parental family history of cardiovascular risk factors was obtained through a self-reported questionnaire. Results: Family history of hypertension, high cholesterol, diabetes, and obesity were associated with a higher CMRF score. Also, hypertensive father and high maternal cholesterol, and obesity in both parents increased the prevalence rates of these conditions in the offspring. WC was a mediator in some of these associations, while CRF was a protector for a lower metabolic risk. Conclusion: Evaluating family history, along with WC and CRF is essential for determining pediatric cardiometabolic risk.

Aims: Glucose-driven mitochondrial dysfunction has been proposed to promote vascular cell proliferation and migration events responsible for saphenous vein graft failure (VGF) following bypass surgery. However, it is unclear how type 2 diabetes mellitus (T2DM) impacts mitochondrial function in human saphenous vein smooth muscle cells (HSVSMCs) responsible for the maladaptive remodelling responsible for VGF. Therefore, identifying and targeting the signalling pathways involved could offer new therapeutic options to limit VGF. Our aim was to identify signalling pathways that mediate any mitochondrial dysfunction in HSVSMCs in vitro and assess the impact of T2DM. Methods and results: HSVSMCs explanted from surplus HSV tissues from consenting T2DM and non-diabetic patients undergoing coronary artery bypass graft surgery were treated with known activators and inhibitors of the JAK/STAT and MAPK/ERK pathways. Following this, real-time oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) measures of mitochondrial function were then determined. Our findings revealed that both IL-6/sIL-6Rα trans-signalling complexes and PDGF-BB significantly increased OCR in HSVSMCs from T2DM patients but not non-diabetic controls. Meanwhile, only PDGF-BB increased ECAR in HSVSMCs from T2DM patients but not non-diabetic controls. The observed increases in OCR and ECAR were abolished by JAK1/2-selective inhibitor ruxolitinib. Furthermore, thrombin caused a significant increase in OCR specifically in HSVSMCs from T2DM patients, and this was abolished by MEK1/2-selective inhibitor trametinib. Both ruxolitinib and trametinib significantly reduced basal OCR and ECAR in HSVSMCs from both T2DM and non-diabetic patients. Conclusion: Together, these findings demonstrate a JAK/STAT- and MAPK/ERK-mediated regulation of mitochondrial function in HSVSMCs. As such, they represent potential targets for regulation of HSVSMC function that can be explored for drug development to limit saphenous VGF in T2DM.