Abstract 12779: Over Expression of the Insulin Like Growth Factor Type 1 Receptors in Endothelial Cells Protects Against the Development of Obesity

Introduction: Insulin like growth factor type 1 receptors (IGF-1R) are expressed in the endothelium. However, the role of the IGF-1R in the micro-vasculature and lymphatic system of the small intestine is currently unexplored.

Hypothesis: Manipulation of the endothelium IGF-1R is a novel target for preventing obesity and obesity related cardiovascular complications.

Methods and Results: We generated mice with endothelial specific over-expression of the human IGF-1R (hIGFREO). To model diet-induced obesity, male hIGFREO mice and their wildtype litter mate controls received free access to a high fat diet for 8 weeks. After high fat feeding, hIGFREO mice weighed less and had smaller epididymal fat pads. They also had improved glucose tolerance and whole body insulin sensitivity. Indirect calorimetery failed to demonstrate any difference in activity, food intake or energy expenditure. Canonical insulin and IGF-I signalling nodes in primary endothelial cells isolated from hIGFREO mice were also unchanged. Despite a reduction in body weight, histological examination revealed no difference in liver fat content, adipose vascularisation or adipocyte size. Expression of ‘browning’ genes in both white and brown adipose depots also remained unchanged. In addition, there was no difference in circulating leukocytes or adipose resident macrophages. Urine glucose, gut transit time and faecal output were again unchanged. However, histological evaluation of the jejunum showed that hIGFREO mice had increased intestinal lipids and qPCR revealed a reduction in the expression of chylomicron related genes and increase in expression of cytoplasmic lipid droplet related genes.

Conclusion: Here we show a novel cross talk between the endothelium and the enterocytes of the small intestine, which regulates fat absorption and that over-expression of endothelial IGF-1R protects against the development of diet-induced obesity by altering this cross talk.