Leptin, an adipocyte-released hormone, modifies food intake and energy 
expenditure regulating hypothalamic-pituitary-thyroid axis function. We 
previously reported that thyrotropin-releasing hormone (TRH) precursor gene 
overexpression induces hypertension in the normal rat and that spontaneously 
hypertensive rats have central TRH hyperactivity with increased TRH synthesis 
and release and an elevated TRH receptor number. In both models, 
intracerebroventricular antisense (AS) treatment against the TRH precursor 
produced a dose-dependent reduction of the increased diencephalic TRH content 
while normalizing high arterial blood pressure. In this article, we report that 
male Wistar rats that were made hypertensive by intracerebroventricular 
injection of a eucaryotic expression plasmid containing the pre-TRH cDNA showed 
decreased leptin plasma levels and that pre-TRH AS treatment reversed this 
phenomenon. In addition, male and female spontaneously hypertensive rats showed 
lower levels of circulating leptin than did sex-matched Wistar-Kyoto control 
rats. This difference also was abated by the pre-TRH AS treatment. Conversely, 
20 microg ICV leptin induced a long-lasting pressor effect (18 +/- 5 mm Hg, n=6, 
P<0.01, >60 minutes) that was not observed in pre-TRH AS pretreated rats (2 +/- 
3 mm Hg, n=6) but persisted in rats used as controls that were treated with 
inverted oligonucleotide (20 +/- 6 mm Hg, n=4, P<0.01). These data suggest that 
in rats with TRH-induced hypertension, leptin is decreased, inducing 
compensatory adiposity. We propose that because leptin produces central TRH 
synthesis and release, obesity may induce hypertension through TRH system 
activation and that the TRH-leptin interaction may thus contribute to the strong 
association between hypertension and obesity.