Role of zinc-alpha2-glycoprotein in the prevention of adipose tissue expansion by modulating the adipogenic programme

Increased body fat in obesity has a strong link to insulin resistance, type-2 diabetes and heart disease. Too much fat in obesity results from a combination of increased lipid storage in existing fat cells and the generation of new fat cells from precursors cells. Recently, the direct importance of fat tissue in the control of body weight has become recognised. This is because the fat cells, in addition to lipid storage, can produce a wide range of proteins that regulate the total amount of body fat and different biological processes, including appetite and metabolism. Our recent work has found that a protein called zinc-alpha2-glycoprotein (ZAG) is also made by fat cells. ZAG production in fat cells is inversely related to the amount of body fat, being reduced in obesity while greatly increased in mice with little fat. Our subsequent work in these mice indicates that overproduction of ZAG is associated with a major reduction in several key genes and proteins involved in making new fat cells. However, it is unclear whether ZAG acts directly to influence this process. The aim of this project is to test our new idea that ZAG has a major role in limiting the expansion of fat mass, especially in the control of the number of fat cells and lipid accumulation during the formation of new fat cells. To examine this idea, we will study to what extent ZAG modifies the early and late events of making new fat cells, by analysing the effects of ZAG on the key factors, particularly those promoting fat cell formation and development. We will also examine whether ZAG influences lipid storing capacity through altering lipid accumulation in fat cells, and whether ZAG treatment reduces fat mass expansion in obesity, using an obese mouse model. Given, the current high interest in body fat regulation, clarification of the mechanisms by which ZAG hinders fat cell formation will give important new insights into the control of body fat. Recently, a report by the UK Government Foresight Group has suggested that Britain could be a mainly obese society by 2050; this research is therefore very timely and the findings may ultimately lead to new treatments for protecting against body fat accumulation in obesity. The progress and findings of this research will be transmitted to the general public through publications, meetings, press releases by the University and public awareness events.

The importance of white adipose tissue in the control of energy homeostasis is now firmly recognised.
In addition to fuel storage, adipocytes secrete an array of proteins (adipokines) which modulate multiple physiological and metabolic processes. Disorders of adipocyte formation and function, such as abnormal adipose expansion in obesity, predisposes to insulin resistance, type-2 diabetes and cardiovascular disease. The excess of body fat in obesity results from a combination of increased lipid storage in existing adipocytes and the generation of new adipocytes from precursors residing within the adipose tissue. The latter cellular process, termed adipogenesis, involves transcriptional control of preadipocyte differentiation and adipocyte maturation, which are influenced by hormones and signalling factors. Recent work from our group has identified zinc-a2-glycoprotein (ZAG) as a novel adipokine. ZAG expression in adipose tissue is inversely related to the expansion of fat mass, being reduced in obesity while upregulated in cancer cachexia. Our subsequent work has demonstrated that ZAG overproduction in cachexia, is associated with adipose atrophy and a major reduction of gene transcripts encoding several key adipogenic factors. However, whether ZAG functions directly to inhibit adipogenesis has not been identified. This research aims to investigate a proposed novel function of ZAG in adipose tissue, specifically adipocyte differentiation through targeting the induction of key adipogenic factors. The main specific objectives are to study: (1) whether ZAG inhibits the transcriptional control of early and late events of the adipogenic programme, and the signalling pathways involved, employing murine and human adipocytes with ZAG overexpression; (2) whether ZAG affects lipid accumulation in differentiated adipocytes and antagonises the maintenance of the adipocyte phenotype, using ZAG gene transfection; (3) whether ZAG modulates adipocyte lipid storage capacity with lipogenic analysis; (4) whether ZAG restrains adipose tissue expansion in obesity, using obese (ob/ob) mice treated with recombinant ZAG; (5) whether ZAG knockdown with siRNA enhances lipid accumulation and fatty acid synthesis in human adipocytes; (6) whether forced expression of the key adipogenic factors reverses the effects of ZAG. Given the escalation in obesity and its associated type-2 diabetes, this work is timely and important. Clarification that ZAG has a major role in adipogenesis will give new insights into adipocyte regulation and function. Findings from this research will have clinical importance in providing a better understanding of fat mass expansion in obesity and also severe fat loss in cachexia.