Differential expression of leptin receptor in high-and low-fat-fed OM and S5B/Pl rats. Obes Res. 2000; 8:467-474. Objective: The regulation of body weight and body composition involves input from genes and the environment. This interaction is demonstrated by the different susceptibility of Osborne-Mendel (OM) and S5B/P1 rat strains to obesity when offered a high-fat diet. In animals and humans, diet-induced obesity 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 dietinduced obesity between OM and S5B/Pl rats. Research Methods and Procedures: OM and S5B/Pl rats were fed high-fat (HF) or low-fat (LF) diets for 14 days. Ribonuclease protection assays and Western 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 hypothalamus. Results: The mRNA encoding ObR-L, the predominant signaling form of the receptor, was higher in OM rats than in S5B/P1 rats (p Ͻ 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 diet. On the contrary, there were no changes in ObR-S mRNA expression due to diet or strain. Western blots showed that both the short and long forms of the receptor were increased on the LF diet, but there were no strain differences. OM and S5B/Pl rats had comparable leptin levels after maintenance on a LF diet (6.20 Ϯ 0.63 and 4.81 Ϯ 0.82 ng/mL, respectively). Serum leptin levels in OM rats were increased by the HF diet and were elevated 2-fold over those of their S5B/Pl 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 resistance seen in HF-fed rats. These effects appear to be post-transcriptional, because equivalent changes were not observed in the expression of ObR-L and ObR-S mRNAs. They may be related to the increase in circulating leptin levels, suggesting that high serum leptin levels contribute to increased leptin resistance and subsequently lead to obesity. We conclude that downregulation of receptor protein levels is associated with hypothalamic leptin resistance of HF-fed rats.
JENSON, MICHELLE, GAIL KILROY, DAVID YORK AND DOUGLAS BRAYMER. Abnormal regulation of hepatic glucocorticoid receptor mRNA and receptor proteinn distribution in the obese Zucker rat. Obes Res. 1996;4:133-143. This study examines the cellular distribution of glucocorticoid receptor (GR) protein and transcriptional activity of the GR gene in the liver of Zucker obese (fa/fa) rats. Immunoabsorption and Western blotting showed an increase in nuclear GR protein level but a decrease in cytosolic GR levels in the liver of 5-week old male obese rats (fa/fa) compared to their lean Iittermates (Fa/-). These changes were confirmed by receptor-ligand binding assays with [3H]-dexamethasone which showed a sixfold increase in average obese nuclear GR binding and a twofold reduction in cytosolic GR binding. HSP90, but not HSP70, levels were reduced in hepatic cytosol and increased in hepatic nuclei prepared from obese rats. Using Northern blot analysis of hepatic RNA, we demonstrated a twofold increase in hepatic mRNAs for GR, malic enzyme (ME), tyrosine aminotransferase (TAT), and glyceraldehyde 3-P04-dehydrogenase in the obese rat. Increased transcription of GR and ME mRNAs in obese nuclei was indicated in nuclear run-on assays. These data suggest that there is increased nuclear localization of GR in the liver of obese rats and suggests that increased transcription
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