Increased protease activity in obese rats: implications on LDL and insulin receptors

Abstract

Obesity leads to increased morbidity and mortality from cardiovascular complications. Among other characteristics of the metabolic syndrome, obesity is a major risk factor for Insulin resistance and high levels of LDL, although the mechanisms are not completely understood. We hypothesize that calorie over consumption can lead to increased proteolytic activity which in turn cleave extracellular domains of key receptors e.g. the insulin and LDL receptors, therefore impairing their uptake and contributing to their high levels in the circulation. Wister rats were fed high fat diet (HD) for 16 weeks. A control group was provided with regular chow (ND). Enzymatic activity was measured in vivo on the mesentery microcirculation using intravital fluorescent microscope. Levels of the extracellular domain of the insulin and LDL receptors were measured by immunohistochemistry on isolated leukocytes. Glucose and LDL uptake were measured by fluorescent imaging. HF rats had significantly higher enzymatic activity in the mesentery microcirculation compared to controls. This activity was accompanied with reduced levels of the extracellular domain of both insulin and LDL receptors. Leukocytes of obese rats uptake glucose and LDL in a slower rate compared to controls. Our results suggest that calorie over‐consumption can promote proteolytic activity and cleavage of key receptors thus promoting insulin resistance and high circulating levels of LDL in obesity.