Doctoral Degrees (Medical Physiology)

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Browsing Doctoral Degrees (Medical Physiology) by Subject "Adipose tissues"

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    Evaluation of mitochondrial and molecular derangements in cardiac adipose tissue during type 2 diabetes and relationship with cardiovascular risk
    (Stellenbosch : Stellenbosch University, 2023-06) Nyawo, Thembeka Amanda; Pheiffer, Carmen; Mazibuko-Mbeje, Sithandiwe; Phiwayinkosi, Dludla; Hanel, Sadie Van Gijsen; Hans, Strijdom; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology.
    ENGLISH ABSTRACT: Cardiovascular disease (CVD) affects hundreds of millions of people globally, and 18.6 million deaths were attributed to CVD during 2019 alone. Type 2 diabetes (T2D) and obesity contribute significantly towards the increasing prevalence of CVD. Ageing and adipose tissue dysfunction are important mechanisms in the pathology of these metabolic diseases and their downstream cardiovascular complications. The roles of visceral (VAT) and subcutaneous (SAT) adipose depots in T2D and CVD development have been well documented; however, there is limited evidence on the pathological contribution of cardiac fat (CF) to CVD. The aim of this study was to elucidate the role of CF, in comparison to retroperitoneal (RF) and inguinal (IF) fat depots, representatives of VAT and SAT, respectively, in the development and progression of CVD in an experimental mouse model of obesity and diabetes. The study used male obese, diabetic db/db mice and their lean db/+ counterparts to explore morphological features of CF, gene expression signatures, mitochondrial bioenergetics, and associations with CVD risk factors. Briefly, mice were monitored for 8, 12 and 18 weeks, during which body weight and fasting blood glucose concentrations were measured weekly. Glucose tolerance was assessed using the oral glucose tolerance test one week prior to euthanasia. Blood and tissue samples of the heart, CF, RF, and IF were collected for assessment of biochemical markers, histological examination using Haematoxylin and Eosin staining, and gene expression analysis using quantitative real time PCR. In addition, CF, RF and IF were harvested for the assessment of mitochondrial function in adipose-derived stromal cells (ADSCs). Phenotypic and metabolic parameters deteriorated with disease and age, where db/db mice displayed conditions of hyperglycaemia, hyperinsulinaemia, hyperlipidaemia and glucose intolerance with ageing. In addition, an age-related increase in adiponectin serum levels were observed in db/+ mice, while in db/db mice, adiponectin levels decreased with age. Furthermore, histological analysis showed that adipocyte size in all depots increased over time in both the non-diabetic and diabetic state. Adipose depot-, disease- and age-related changes in gene expression signatures in CF, RF and IF were observed, with RF and IF in db/db mice exhibiting upregulation of genes involved in inflammation and oxidative stress, while CF appears to possess increased expression of genes representing thermogenic capacity. Disease- and age-related differential regulation of circulating CVD risk markers were observed. Dysregulation of markers such as metalloproteinase 9 (MMP9), intercellular adhesion molecule 1 (ICAM1), platelet endothelial cell adhesion molecule 1 (Pecam1) and Thrombomodulin (THBD) suggested vascular remodelling and dysfunction during CVD progression. Moreover, circulating levels of MMP9, ICAM and P-Selectin positively correlated with CF adipocyte size. In heart tissue, signs of histological myocardial changes with microarchitecture disruption and the presence of intramyocardial lipid droplets in db/db mice were observed in with ageing. Moreover, gene expression analysis in heart tissue revealed a disease- and age- related downregulation of brain natriuretic peptide (BNP) levels in db/db mice. Furthermore, ADSCs from CF had higher mitochondrial bioenergetics parameters compared to ADSCs from RF. This may be attributed to the higher uncoupling protein 1 (UCP1) expression in CF which reportedly decreases oxidative phosphorylation through thermogenesis. In conclusion, the positive correlation between CVD risk markers with CF adipocyte size in the diabetic state indicates a relationship with CF, supporting the notion that increased CF adiposity is associated with increased CVD risk. Importantly, CF, unlike RF and IF, displays beige-like adipocytes and thermogenic capacity, which may help mitigate the harmful effects of diabetes and its cardiovascular complications.