The Auto‐Digestive Hypothesis: A New Mechanism For Development of Leptin Resistance And Obesity

Abstract

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, however, obesity is associated with high circulating leptin levels concomitantly with leptin resistance. The mechanism leading to leptin resistance is unknown. We hypothesize that calorie over consumption 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 (NC). At 10 weeks, rats were sacrificed and the brain was removed for determination of proteolytic activity and levels of the extracellular domain of the ObR. HF rats had significantly higher body weight compared to NC. Zymography showed increased proteolytic activity in HF rat's brain, which was accompanied with reduced levels of the extracellular domain of the ObR. Our results also suggest MMP‐9 as a possible mediator of ObR cleavage. We conclude that calorie over‐consumption can promote proteolytic activity and cleavage of key receptors in the brain; therefore can mediate the development of obesity. The origin of the proteolytic activity in HF rat's brain remains to be elucidated.