Caloric excess and a sedentary lifestyle are major contributors to epidemic obesity levels in western society. Understanding the molecular mechanisms of obesity, insulin resistance and type 2 diabetes is important in the search for anti-obesity and anti-diabetic therapies. Protein Tyrosine Phosphatase 1B (PTP1B) is a key negative regulator of insulin and leptin signalling. Expression levels and activity of PTP1B are augmented in obese animals and humans. This leads to reduced insulin sensitivity and impaired glucose tolerance. Mice lacking PTP1B globally or in individual insulin-sensitive tissues exhibit improved glucose homeostasis and increased insulin sensitivity, even in the obese state. Due to the highly conserved and positively charged active-site pocket the development of PTP1B inhibitors has been challenging, although several have now been reported. These have been shown to decrease PTP1B levels and improve insulin sensitivity in adipose and liver tissue. The aim of my project was to investigate the physiological and molecular consequences of adipocyte-specific PTP1B deletion. Mice with an adipocyte-specific deletion of PTP1B were produced by crossing PTP1B floxed mice with novel Adiponectin promoter-driven Cre mice (deleting PTP1B specifically in adipocytes, unlike aP2 promoter-driven Cre mice which delete in adipocytes and macrophages). These mice were fed a high fat diet (55% fat) or chow diet for 16 weeks. Glucose homeostasis, insulin sensitivity, body weight and adiposity were analysed. Adipocyte-specific PTP1B heterozygous mice (n=4) display no differences in body weight compared with control mice (n=6) but appear more sensitive to insulin as evidenced by slight improvements in insulin tolerance tests (area under the curve trending towards significance; p = 0.079). As these heterozygous mice only have ~50% deletion of PTP1B in adipocytes, it is expected that the total adipocyte-specific PTP1B knockout mice will have significantly improved glucose homeostasis. These experiments are presently being conducted. The insulin and AMP-activated protein kinase signalling pathways were also investigated and appear to mirror physiological changes. It therefore seems that adipocyte-specific PTP1B deletion protects against insulin resistance caused by a prolonged high fat diet. This suggests that adipocyte-specific PTP1B inhibition may be an excellent strategy in future anti-diabetic drug development.