AbstractIntroduction: Obesity is a complex, multifactorial disease that is the greatest epidemic of the 21st century and presents a major risk factor for the development of the metabolic syndrome and co-morbidities, contributing to medical, social and economic burdens. Dysregulated expansion of the adipose tissue in obesity is associated with changes in with the changes in its blood flow leading to the onset of local tissue hypoxia and presence of hypertrophic and dysfunctional adipocytes. Adipocyte hypertrophy is associated with increased endoplasmic reticulum stress, mitochondrial dysfunction, necrosis, apoptosis and altered secretory profiles adipokine and cytokine causing activation and infiltration of immune cells into the adipose tissue, boosting inflammation and further underpinning adipocyte dysfunction and death. The imbalance between signals that initiate inflammation and signals that resolve inflammation, worsen inflammation towards chronic irreversibility. The presence of low-grade chronic inflammation is considered to be a key underlying mechanism that links excessive adiposity to the development of the metabolic syndrome and obesity associated co-morbidities. Annexin A1 (ANXA1) and its peptides pose anti-inflammatory, pro-resolving properties and have shown to have significant effects in resolving inflammation in several disease models, however, their effects in obesity associated inflammation is not well explored.
Research Aim and studies: The primary aim of this PhD project was to investigate the role of ANXA1 in obesity and associated inflammation. This project consists of four research studies including: Study 1: an in vivo study to investigate the potential roles of ANXA1 in mature adipocytes using a model mimicking the inflammatory status observed during obesity; Study 2: an in vivo study to investigate the role of ANXA1 in the differentiation of preadipocytes into mature adipocytes; Study 3: an in vitro pilot study to investigate the plasma ANXA1 levels in response to rapid weight loss induced by bariatric surgery; and Study 4: an in vitro study to investigate the plasma ANXA1 levels in lipodystrophy patients.
Results: Study 1: Acute treatment with ANXA1 peptide, AC2-26 differentially regulated gene expression in mature adipocytes to indicate ANXA1 plays a protective role in obesity and inflammation. Treatment with AC2-26 significantly upregulated the mRNA expressions of BAX, PER3, PPARA, ADIPOQ, IL6 and ACHE, and downregulated the mRNA expressions of CD36, DPP4, ACOX1, PPP3CC, LEP, NAMPT, RETN, CFD, TNF, IRS1, SLC2A4, IGFR1, JUN and VEGFA. Study 2: Mature adipocytes differentiated with ANXA1 receptor antagonist and/or agonist accumulated significantly less lipids, indicative of an immature adipocyte phenotype. This effect was only apparent during later stages of adipocyte differentiation and it was concluded that ANXA1 may regulate the rate of adipogenesis through differential regulation of MAPK intracellular pathways associated with different receptors. Study 3: Plasma ANXA1 indicate increasing trends with decreasing body mass index (BMI), however, a firm conclusion regarding its associations with plasma biomarkers is difficult to form due to low number of participants. Study 4: Plasma ANXA1 levels were significantly reduced in lipodystrophy patients of all genotypes in comparison to control and inversely correlated with BMI and plasma C-reactive protein levels.
Conclusion: Locally, in the adipose tissue ANXA1 may be involved in regulating adipogenesis and reducing adipocyte hypertrophy to prevent adipocyte dysfunction, local inflammation and development of insulin resistance. Peripherally, ANXA1 may act in an endocrine manner to regulate inflammatory biomarkers to dampen inflammation, regulate insulin secretion and improve the metabolic profile to reduce the risk of developing obesity associated co-morbidities. However, this effect may be overshadowed by the continued increase in systematic inflammation associated with rapid adipose tissue expansion.
|Date of Award||Apr 2020|
|Supervisor||Derek Renshaw (Supervisor), Jane Goodfellow (Supervisor), Bernard Burke (Supervisor) & Christopher Mee (Supervisor)|