Rl. Martin et al., Leptin resistance is associated with hypothalamic leptin receptor mRNA andprotein downregulation, METABOLISM, 49(11), 2000, pp. 1479-1484
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.