Human preadipocyte proliferation and differentiation

Obesity represents a major health, social and economic burden to many developing and Westernized communities, with the prevalence increasing at a rate exceeding almost all other medical conditions. Despite major recent advances in our understanding of adipose tissue metabolism and dynamics, we still have limited insight into the regulation of adipose tissue mass in humans. Any significant increase in adipose tissue mass requires proliferation and differentiation of precursor cells (preadipocytes) present in the stromo-vascular compartment of adipose tissue. These processes are very complex and an increasing number of growth factors and hormones have been shown to modulate the expression of genes involved in preadipocyte proliferation and differentiation. A number of transcription factors, including the C/EBP family and PP ARy, have been identified as integral to adipose tissue development and preadipocyte differentiation. Together PP ARy and C/EBPa regulate important events in the activation and maintenance of the terminally differentiated phenotype. The ability of PP ARy to increase transcription through its DNA recognition site is dependent on the binding of ligands. This suggests that an endogenous PP ARy ligand may be an important regulator of adipogenesis. Adipose tissue functions as both the major site of energy storage in the body and as an endocrine organ synthesizing and secreting a number of important molecules involved in regulation of energy balance. For optimum functioning therefore, adipose tissue requires extensive vascularization and previous studies have shown that growth of adipose tissue is preceded by development of a microvascular network. This suggests that paracrine interactions between constituent cells in adipose tissue may be involved in both new capillary formation and fat cell growth. To address this hypothesis the work in this project was aimed at (a) further development of a method for inducing preadipocyte differentiation in subcultured human cells; (b) establishing a method for simultaneous isolation and separate culture of both preadipocytes and microvascular endothelial cells from the same adipose tissue biopsies; (c) to determine, using conditioned medium and co-culture techniques, if endothelial cell-derived factors influence the proliferation and/or differentiation of human preadipocytes; and (d) commence characterization of factors that may be responsible for any observed paracrine effects on aspects of human adipogenesis. Major findings of these studies were as follows: (A) Inclusion of either linoleic acid (a long-chain fatty acid reported to be a naturally occurring ligand for PP ARy) or Rosiglitazone (a member of the thiazolidinedione class of insulin-sensitizing drugs and a synthetic PPARy ligand) in differentiation medium had markedly different effects on preadipocyte differentiation. These studies showed that human preadipocytes have the potential to accumulate triacylglycerol irrespective of their stage of biochemical differentiation, and that thiazolidinediones and fatty acids may exert their adipogenic and lipogenic effects via different biochemical pathways. It was concluded that Rosiglitazone is a more potent inducer of human preadipocyte differentiation than linoleic acid. (B) A method for isolation and culture of both endothelial cells and preadipocytes from the same adipose tissue biopsy was developed. Adipose-derived microvascular endothelial cells were found to produce factor/s, which enhance both proliferation and differentiation of human preadipocytes. (C) The adipogenic effects of microvascular endothelial cells can be mimicked by exposure of preadipocytes to members of the Fibroblast Growth Factor family, specifically ~-ECGF and FGF-1. (D) Co-culture of human preadipocytes with endothelial cells or exposure of preadipocytes to either ~-ECGF or FGF-1 were found to 'prime' human preadipocytes, during their proliferative phase of growth, for thiazolidinedione-induced differentiation. (E) FGF -1 was not found to be acting as a ligand for PP ARy in this system. Findings from this project represent a significant step forward in our understanding of factors involved in growth of human adipose tissue and may lead to the development of therapeutic strategies aimed at modifying the process. Such strategies would have potential clinical utility in the treatment of obesity and obesity related disorders such as Type II Diabetes.

A grounded theory study of technology appropriation in anaesthesia

The human-technology nexus is a strong focus of Information Systems (IS) research; however, very few studies have explored this phenomenon in anaesthesia. Anaesthesia has a long history of adoption of technological artifacts, ranging from early apparatus to present-day information systems such as electronic monitoring and pulse oximetry. This prevalence of technology in modern anaesthesia and the rich human-technology relationship provides a fertile empirical setting for IS research. This study employed a grounded theory approach that began with a broad initial guiding question and, through simultaneous data collection and analysis, uncovered a core category of technology appropriation. This emergent basic social process captures a central activity of anaesthestists and is supported by three major concepts: knowledge-directed medicine, complementary artifacts and culture of anaesthesia. The outcomes of this study are: (1) a substantive theory that integrates the aforementioned concepts and pertains to the research setting of anaesthesia and (2) a formal theory, which further develops the core category of appropriation from anaesthesia-specific to a broader, more general perspective. These outcomes fulfill the objective of a grounded theory study, being the formation of theory that describes and explains observed patterns in the empirical field. In generalizing the notion of appropriation, the formal theory is developed using the theories of Karl Marx. This Marxian model of technology appropriation is a three-tiered theoretical lens that examines appropriation behaviours at a highly abstract level, connecting the stages of natural, species and social being to the transition of a technology-as-artifact to a technology-in-use via the processes of perception, orientation and realization. The contributions of this research are two-fold: (1) the substantive model contributes to practice by providing a model that describes and explains the human-technology nexus in anaesthesia, and thereby offers potential predictive capabilities for designers and administrators to optimize future appropriations of new anaesthetic technological artifacts; and (2) the formal model contributes to research by drawing attention to the philosophical foundations of appropriation in the work of Marx, and subsequently expanding the current understanding of contemporary IS theories of adoption and appropriation.