Leptin resistance is associated with hypothalamic leptin receptor mRNA and protein downregulation

It is well known that leptin plays a predominant role in body weight regulation. Leptin receptors are especially abundant in the hypothalamus, where the majority of leptin's biologic activity occurs. In instances where leptin has no or limited activity, it is easy to implicate leptin resistance...

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Published in:Metabolism, clinical and experimental clinical and experimental, 2000-11, Vol.49 (11), p.1479-1484
Main Authors: Martin, Robin Leigh, Perez, Evelyn, He, Yun-Ju, Dawson, Ralph, Millard, William J
Format: Article
Language:English
Subjects:
Animals
Base Sequence
Biological and medical sciences
Blood Glucose - metabolism
Body Weight
Carrier Proteins - genetics
DNA Primers
Down-Regulation
Feeding Behavior
Hypothalamus - metabolism
Insulin - blood
Insulin-Like Growth Factor I - metabolism
Leptin - metabolism
Leptin - physiology
Male
Medical sciences
Metabolic diseases
Obesity
Rats
Rats, Long-Evans
Receptors, Cell Surface
Receptors, Leptin
RNA, Messenger - genetics
RNA, Messenger - metabolism
Triglycerides - metabolism
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Summary:It is well known that leptin plays a predominant role in body weight regulation. Leptin receptors are especially abundant in the hypothalamus, where the 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 levels where resistance may occur. We hypothesize that leptin resistance is associated with hypothalamic leptin receptor downregulation. Rats were randomly divided into 3 groups receiving phosphate-buffered saline (PBS) or low- or high-dose leptin continually over a 28-day period. Body weight and food intake were measured daily. Long-term leptin treatment resulted in a dose-dependent decrease in body weight for the duration of the study. It also resulted in a dose-dependent decrease in food intake, but only for the first half of the study. A test of leptin resistance was performed at week 3 demonstrating the development of resistance to the anorectic effects of leptin in both treatment groups. The results of the resistance test together with the food intake data suggest that resistance to the appetite-regulating effects of leptin developed during the final 2 weeks of the study. In addition, we show a downregulation of leptin receptor mRNA and protein in the hypothalamus, which may be one of the mechanisms by which the food-intake effects of leptin were lost. Copyright © 2000 by W.B. Saunders Company
ISSN:0026-0495
1532-8600
DOI:10.1053/meta.2000.17695