Increased protease activity and receptor cleavage in a rat model of diet‐induced obesity

Obesity is a major health problem and leads to increased morbidity and mortality from cardiovascular complications. Leptin acts on the brain to regulate food intake through its interactions with its receptor (ObR). Defects in leptin production and in ObR leads to the development of obesity. In addition previous studies have found leptin resistance concomitantly with high circulating leptin levels in obese patients. We hypothesize that calorie overconsumption can lead to increased proteolytic activity in the brain, promoting cleavage of key receptors governing food intake. Wister rats were fed high‐fat diet (HF) for 10 weeks. A control group was provided with regular chow. At 10 weeks, rats were sacrificed and the brain was removed for determination of proteolytic activity and levels of the intra and extracellular domains of the ObR. In‐situ zymography showed increased proteolytic activity in the HF rat's brain, which could be blocked by EDTA. Gel zymography of whole brain lysate revealed an approximately 70 KDa protein that was highly active compared to controls. Western blot analysis and immunohistochemistry demonstrated lower levels of the ObR extracellular domain in HF brain, while levels of the intracellular domain were not significantly different. We conclude that calorie over‐consumption can promote proteolytic activity and cleavage of key receptors in the brain. The origin of the proteolytic activity in HF rat's brain needs to be further elucidated.