Evaluation of mitochondrial and molecular derangements in cardiac adipose tissue during type 2 diabetes and relationship with cardiovascular risk

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dc.contributor.advisorPheiffer, Carmenen_ZA
dc.contributor.advisorMazibuko-Mbeje, Sithandiween_ZA
dc.contributor.advisorPhiwayinkosi, Dludlaen_ZA
dc.contributor.advisorHanel, Sadie Van Gijsenen_ZA
dc.contributor.advisorHans, Strijdomen_ZA
dc.contributor.authorNyawo, Thembeka Amandaen_ZA
dc.contributor.otherStellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Biomedical Sciences. Division of Medical Physiology.en_ZA
dc.date.accessioned2023-07-04T20:28:41Zen_ZA
dc.date.accessioned2024-01-08T11:05:02Zen_ZA
dc.date.available2023-07-04T20:28:41Zen_ZA
dc.date.available2024-01-08T11:05:02Zen_ZA
dc.date.issued2023-06en_ZA
dc.descriptionThesis (PhD)--Stellenbosch University, 2023.en_ZA
dc.description.abstractENGLISH 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.en_ZA
dc.description.abstractAFRIKAANSE OPSOMMING: Kardiovaskulêre siektes (KVS) raak honderde miljoene mense wêreldwyd, en in 2019 alleen is 18.6 miljoen sterftes aan KVS toegeskryf. Risikofaktore soos tipe 2 diabetes (T2D) en vetsug dra beduidend by tot die toename in die voorkoms van KVS. Ouderdom en vetweefselwanfunksie verteenwoordig belangrike meganismes in die patologie van hierdie metaboliese siektes sowel as hul sekondêre kardiovaskulêre komplikasies. Die rol van viserale vetweefsel (VV) en subkutane vetweefsel (SV) in die ontwikkeling van T2D en KVS is goed beskryf, maar daar is beperkte inligting aangaande die patologiese bydrae van kardiale vetweefsel (KV). Die doel van hierdie studie was om die rol van KV in die ontstaan en progressie van KVS in ‘n eksperimentele muis-model van vetsug en T2D te ondersoek, en te vergelyk met dié van retroperitoneale vet (RV) en inguinale vet (IV), as verteenwoordigers van onderskeidelik VV en SV. Die studie het gebruikgemaak van vetsugtige diabetiese db/db muise (mannetjies) en hul gesonde db/+ eweknieë om morfologiese eienskappe van KV, geen-uitdrukking, mitochondriale funksie en verwantskappe met KVS risikofaktore te ondersoek. Die muise is vir 8, 12 en 18 weke bestudeer, waartydens liggaamsgewig en vastende bloedglukosevlakke weekliks gemeet is. ‘n Glukose-toleransietoets is een week voor elkeen van die tydpunte uitgevoer. Bloed- en weefselmonsters van die hart, KV, RV en IV is gebruik vir die meting van biochemiese merkers, histologiese ondersoeke met hematoksilien/eosien-kleuring asook geenuitdrukking-analises met kwantitatiewe PKR. Die mitochondriale funksie van geїsoleerde vetweefsel-stamselle uit KV, RV en IV is ook ondersoek. Fenotipiese en metaboliese parameters het verswak met ouderdom en siekte, met toestande soos hiperglisemie, hiperinsulinemie, hiperlipidemie en glukose-intoleransie wat met ouderdom in db/db muise waargeneem is. ‘n Ouderdom-verwante toename in serumvlakke van adiponektien is waargeneem in db/+ muise, terwyl adiponektienvlakke in db/db muise gedaal het met ouderdom. Verder is gevind dat vetselgrootte in beide diabetiese en nie-diabetiese muise oor tyd in alle vetweefseltipes toegeneem het. Vetweefseltipe-, siekte- en ouderdomsverwante veranderinge in geenuitdrukking is in KV, RV en IV waargeneem, met inflammasie- en oksidatiewe stres-verwante geenuitdrukking wat toegeneem het in RV en IV, terwyl KV verhoogde geenuitdrukking van termogenese-verwante faktore getoon het. Die bevindinge van hierdie studie het ook gedui op heterogene uitdrukking van sirkulerende KVS merkers wat gevarieer het met siekte en ouderdom. Die wanregulering van merkers soos metalloproteïenase 9 (MMP9), intersellulêre adhesie-molekuul 1 (ICAM1), plaatjie-endoteelseladhesie-molekuul 1 (Pecam1) en trombomodulien (THBD) het gedui op vaskulêre hermodellering en wanfunksie tydens KVS. Sirkulerende vlakke van MMP9, ICAM en Pselektien het ook positiewe korrelasies met KV selgrootte getoon. Histologiese tekens van miokardiale veranderinge met versteurings van die mikro-argitektuur en die teenwoordigheid van intramiokardiale vetdruppels is waargeneem in ouer db/db muise. Geenuitdrukkinganalise in hartweefsel het ook ‘n siekte- en ouderdomsverwante afname van B-tipe natriuretiese peptied (BNP) in db/db muise aangetoon. Vetweefsel-stamselle uit KV het ook hoër mitochondriale bio-energetiese lesings getoon, in vergelyking met stamselle uit RV. Hierdie bevindings mag moontlik verband hou met die verhoogde uitdrukking van ontkoppelingsproteïen-1 (UCP-1) in KV, wat oksidatiewe fosforilasie verlaag deur middel van termogenese. Ter opsomming dui die positiewe korrelasie tussen KVS risikomerkers en vetselgrootte in KV daarop dat daar wel ‘n verband tussen KVS en KV is, ter ondersteuning van die idee dat vergrote KV volume verbind kan word met verhoogde KVS risiko. ‘n Belangrike bevinding van hierdie studie is dat KV, anders as RV en IV, eienskappe van bruin/beige vetweefsel openbaar (kleiner vetselle, termogenese), wat dalk mag help om die skadelike effekte van diabetes in die hart te beperk.af_ZA
dc.description.versionMastersen_ZA
dc.format.extentxviii, 213 pages : illustrationsen_ZA
dc.identifier.urihttps://scholar.sun.ac.za/handle/10019.1/128785en_ZA
dc.language.isoen_ZAen_ZA
dc.language.isoen_ZAen_ZA
dc.publisherStellenbosch : Stellenbosch Universityen_ZA
dc.rights.holderStellenbosch Universityen_ZA
dc.subject.lcshCardiovascular system -- Diseasesen_ZA
dc.subject.lcshAdipose tissuesen_ZA
dc.subject.lcshMitochondrial pathologyen_ZA
dc.subject.lcshType 2 diabetesen_ZA
dc.subject.lcshAge factors in diseaseen_ZA
dc.titleEvaluation of mitochondrial and molecular derangements in cardiac adipose tissue during type 2 diabetes and relationship with cardiovascular risken_ZA
dc.typeThesisen_ZA
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