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ISHIHARA, YURI, CHRISTY L. WHITE, HARUAKI KAGEYAMA, ASAKO KAGEYAMA, DAVID A. YORK, AND GEORGE A. BRAY. Effects of diet and time of the day on serum and CSF leptin levels in Osborne-Mendel and S5B/Pl Rats. Obes Res. 2004;12:1067-1076. Objective: To characterize the effects of dietary fat on the diurnal variation in serum and cerebrospinal fluid (CSF) leptin levels in Osborne-Mendel (OM) and S5B/Pl rats and quantitate the dose response to lower doses of leptin administered into the third cerebral ventricle. Research Methods and Procedures: Rats were fitted with implanted vascular ports or third ventricular cannulas and fed either laboratory chow or one of two semipurified high-fat or low-fat diets. Leptin and insulin were measured by immunoassay. Results: Serum leptin and insulin levels were positively correlated and had similar patterns of diurnal change. CSF leptin and insulin also had diurnal rhythms, with a peak at 7:00 AM, but the diurnal oscillations of leptin and insulin were significantly lower in the S5B/Pl rats than the OM rats. Thus, the ratio of CSF to serum leptin was significantly higher in the S5B/Pl rats than in the OM rats. Dietary fat had no effect on these diurnal patterns. There was a right shift in the dose response to leptin in the OM rats compared with the S5B/P1 rats. S5B/P1 rats treated with leptin had higher signal transduction and translation (STAT-3) mRNA levels compared with pair-fed or saline injected S5B/P1 rats. Hypothalamic suppressors of cytokine signaling mRNA levels were not statistically different between the groups. Discussion: The higher CSF-to-serum leptin ratio in the S5B/P1 rats, the enhanced suppression of food intake and body weight with leptin injections, and the higher STAT-3 activity in these animals suggest that S5B/P1 rats are more sensitive to leptin than OM rats.

BACKGROUND:We demonstrated that ventromedial hypothalamus (VMH) lesions facilitate DNA synthesis, which reflects cell proliferation in abdominal organs, including the liver, pancreas, stomach, small intestine and large intestine, all of which are amply innervated by the vagal nerve. OBJECTIVE: To investigate which area DNA synthesis facilitates and what factors contribute to cell proliferation in the small intestine in VMH-lesioned rats. DESIGN: At 7 days after VMH lesions or sham operations, a segment of rat jejunum was taken for histological examination. A part of the jejunum was also removed from VMH-lesioned and sham-operated rats after 3 days and examined for 5-bromo-2 0 -deoxyuridine (BrdU) incorporation. At 6, 12 and 24 h after VMH lesions, the proximal intestine was removed from individual rats, from the pylorus to the mid-jejunum. Total RNA was extracted from these tissues of each rat, and the levels of epidermal growth factor (EGF) and transforming growth factor (TGF)-a mRNA were determined using reverse-transcription polymerase chain reaction. Cyclooxygenase (COX)-1 and -2 mRNA levels were determined using Northern blotting. RESULTS: Jejunal villi in VMH-lesioned rats were markedly enlarged compared to those of sham-operated rats and jejunal crypts in VMH-lesioned rats more markedly incorporated BrdU. Northern blot analysis revealed an increase in COX-1 mRNA after 6, 12 and 24 h in the jejunum of VMH-lesioned rats. COX-2 mRNA was decreased 6 and 12 h after VMH lesioning; however, it was significantly increased 24 h after VMH lesions in comparison to sham-operated rats. The levels of EGF and TGF-a mRNA were unchanged in VMH lesioned rats. CONCLUSION: VMH lesions induced enlargement of jejunal villi and increased the gene expression of COX-1 in the small intestine. Prostaglandins, probably E 2 , induced by COX-1 may be one candidate factor responsible for the cell proliferation of the small intestinal epithelium in these rats.