Differential expression of leptin receptor in high- and low-fat-fed Osborne-Mendel and S5B/P1 rats

Objective: The regulation of body weight and body composition involves inpu t from genes and the environment. This interaction is demonstrated by the d ifferent susceptibility of Osborne-Mendel (OM) and S5B/P1 rat strains to ob esity when offered a high-fat diet. In animals and humans, diet-induced obe sity has been characterized by hyperleptinemia, which has been interpreted as evidence for leptin resistance. This investigation determined if altered expression of leptin receptors (ObR) in the hypothalamus could potentially contribute to altered sensitivity to diet-induced obesity between OM and S 5B/P1 rats. Research Methods and Procedures: OM and S5B/P1 rats were fed high-fat (HF) or low-fat (LF) diets for 14 days. Ribonuclease protection assays and Weste rn blotting were used to assay the levels of mRNA and protein, respectively , for short (ObR-S) and long (ObR-L) forms of the leptin receptor in the hy pothalamus. Results: The mRNA encoding ObR-L, the predominant signaling form of the rec eptor, was higher in OM rats than in S5B/P1 rats (p < 0.01) both on HF and LF diets. No changes in ObR-L mRNA expression were observed in OM rats with diet, but, S5B/P1 rats showed a slight increase in the ObR-L on the LF die t. On the contrary, there were no changes in ObR-S mRNA expression due to d iet or strain. Western blots showed that both the short and long forms of t he receptor were increased on the LF diet, but there were no strain differe nces. OM and S5B/P1 rats had comparable leptin levels after maintenance on a LF diet (6.20 +/- 0.63 and 4.81 +/- 0.82 ng/mL, respectively). Serum lept in levels in OM rats were increased by the HF diet and were elevated 2-fold over those of their S5B/P1 counterparts. Discussion: These results suggest that a decrease in the levels of both the long form and short form of the receptor may contribute to the leptin resi stance seen in HF-fed rats, These effects appear to be post-transcriptional , because equivalent changes were not observed in the expression of ObR-L a nd ObR-S mRNAs. They may be related to the increase in circulating leptin l evels, suggesting that high serum leptin levels contribute to increased lep tin resistance and subsequently lead to obesity. We conclude that downregul ation of receptor protein levels is associated with hypothalamic leptin res istance of HF-fed rats.