Regulation of hypothalamic proopiomelanocortin by leptin in lean and obeserats

The mechanisms by which leptin influences energy homeostasis are not entire ly understood. Several observations indicate that proopiomelanocortin (POMC ) is involved in the regulation of food intake and may be a mediator of lep tin action. To further study this interaction, a sensitive solution hybridi zation assay was used to compare the levels of POMC mRNA in the medial basa l hypothalamus (MBH) of lean (+/+, +/fa(f)) and obese leptin receptor-defic ient (fa(f)/fa(f)) rats. POMC peptide products were also measured by RIA in the same animals. Cytoplasmic POMC RNA levels were significantly reduced b y 53% in obese rats as compared with lean controls: 0.30 +/- 0.04 vs. 0.64 +/- 0.07 pg/mu g total RNA(p < 0.02). Significant reductions in mean concen trations of hypothalamic POMC-derived peptides from the same dissections we re detected in the obese rats vs, lean controls: a-MSH 1.77 +/- 0.07 vs. 2. 34, +/- 0.10; beta-EP 4.06 +/- 0.24 vs. 5.86 +/- 0.36; gamma(3)-MSH 5.32 +/ - 0.20 vs. 6.52 +/- 0.12 ng/mg protein (p < 0.001). To determine whether le ptin stimulates POMC gene transcription, the acute effect of an intracerebr oventricular (i.c.v.) injection of leptin (5 mu g) on POMC primary transcri pt was quantified in the MBH of lean rats after a 16-hour fast. There was a significant 167% increase in mean POMC hnRNA levels 3 h after i.c.v. lepti n injection (1.15 +/- 0.22 pg/MBH; p < 0.02), but not after 1 h (0.76 +/- 0 .08 pg/MBH), compared to saline controls (0.69 +/- 0.08 pg/MBH). 4 h after the injection of leptin, POMC hnRNA was still increased, but to a lesser ex tent (140%), as compared with control animals (p = 0.006). These studies de monstrate for the first time in the leptin receptor-deficient rat that ther e is an associated decrease in POMC gene expression and peptide levels in t he MBH. Furthermore, the acute increase in the levels of POMC primary trans cript in non-obese rats after a single i.c.v. injection of leptin supports a role for leptin in the regulation of POMC gene transcription. Taken toget her, these studies provide further evidence that POMC is an important media tor of the effects of leptin on food intake and energy expenditure. Copyrig ht (C) 1999 S. Karger AG, Basel.