Tesis doctoral de Ivet Elias Puigdoménech
Obesity is a metabolic disease which has reached epidemic proportions in both developed and developing countries. Moreover, obesity is a major risk factor for serious chronic diseases including insulin resistance, type 2 diabetes and cardiovascular disease. However, the mechanisms through which obesity predisposes to these metabolic complications are not fully understood. During obesity development, there is a fat mass expansion associated with an increase in fat depot vascularization. However, the increase in blood vessel density is insufficient to maintain adipose tissue normoxia and local hypoxia occurs. It has been postulated that hypoxia may induce adipokine expression and pro-inflammatory macrophage recruitment which in turn, may trigger insulin resistance. an increase in adipose tissue angiogenesis may protect from obesity-induced hypoxia, inflammation and insulin resistance. Vascular endothelial growth factor (vegf) is a key factor involved in adipose tissue angiogenesis. In this study, transgenic mice overexpressing vegf in the adipose tissue under the control of the ap2 promoter were obtained to increase adipose tissue vascularization and, to determine the role of increased blood flow in obesity-mediated insulin resistance. transgenic mice overexpressing vegf presented higher vascularization of white (wat) and brown (bat) adipose tissue than wild-type mice. Blood vessels were functional but highly dilated, suggesting increased oxygen supply in the adipose tissue. No metabolic differences were observed between wild-type and transgenic mice, although the weight of transgenic bat was higher, probably due to greater vessel content of this depot. When fed a high fat diet (hfd), transgenic mice gained less weight than wild-type littermates, and showed decreased epididymal wat weight and decreased mean adipocyte area. Consistent with the lack of fat accumulation, serum leptin, glycerol, triglyceride and cholesterol levels did not increase in transgenic mice. In addition, transgenic mice presented increased pgc-1a and ucp1 protein levels in bat, indicating enhanced thermogenesis. Energy expenditure was also increased. In contrast to hfd-fed wild-type obese and insulin resistant mice, transgenic mice remained insulin sensitive and glucose tolerant. Despite being neither obese nor insulin resistant, transgenic mice presented high macrophage infiltration in wat and bat. Flow cytometry analysis of wat macrophage population in transgenic mice showed a decrease in the percentage of m1 pro-inflammatory and an increase in m2 anti-inflammatory macrophages. This was parallel to a reduction in the levels of pro-inflammatory cytokines, such as mcp-1 and ifn-gamma, which were elevated in wat of hfd-fed wild-type mice. thus, this study suggests that vegf overexpression increased vessel number and vascular flow in adipose tissue, thus enhancing thermogenesis in bat and reducing fat accumulation in wat. In addition, increased vegf overexpression led to increased m2 macrophage recruitment in adipose tissue. All these effects protected transgenic mice from high fat diet-induced obesity and insulin resistance. Therefore, these results are consistent with a key role of vegf overexpression in adipose tissue in the prevention of obesity and insulin resistance.
Datos académicos de la tesis doctoral «Study of the role of vegf overexpression in adipose tissue in diet-induced obesity and insulin resistance«
- Título de la tesis: Study of the role of vegf overexpression in adipose tissue in diet-induced obesity and insulin resistance
- Autor: Ivet Elias Puigdoménech
- Universidad: Autónoma de barcelona
- Fecha de lectura de la tesis: 15/12/2010
Dirección y tribunal
- Director de la tesis
- Fatima Bosch Tubert
- Tribunal
- Presidente del tribunal: ulf Smith
- Antonio Vidal puig (vocal)
- (vocal)
- (vocal)