Leptin resistance is associated with hypothalamic leptin receptor mRNA andprotein downregulation

It is well known that leptin plays a predominant role in body weight regula tion. Leptin receptors are especially abundant in the hypothalamus, where t he majority of leptin's biologic activity occurs. In instances where leptin has no or limited activity, it is easy to implicate leptin resistance and speculate as to the multiple revels where resistance may occur. We hypothes ize that leptin resistance is associated with hypothalamic leptin receptor downregulation. Rats were randomly divided into 3 groups receiving phosphat e-buffered saline (PBS) or low- or high-dose leptin continually over a 28-d ay period. Body weight and food intake were measured daily. Long-term lepti n treatment resulted in a dose-dependent decrease in body weight for the du ration of the study. It a Iso resulted in a dose-dependent decrease in food intake, but only for the first half of the study. A test of leptin resista nce was performed at week 3 demonstrating the development of resistance to the anorectic effects of leptin in both treatment groups. The results of th e resistance test together with the food intake data suggest that resistanc e to the appetite-regulating effects of leptin developed during the final 2 weeks of the study. In addition, we show a down-regulation of leptin recep tor mRNA and protein in the hypothalamus, which may be one of the mechanism s by which the food-intake effects of leptin were lost. Copyright (C) 2000 by W.B. Saunders Company.