We recently showed that diencephalic TRH may mediate central leptin-induced pressor effect. Here, to study the role of TRH in obesity-induced hypertension (OIH), we used a model of OIH produced by a high-fat diet (HFD, 45 days) in male Wistar rats. After 4 weeks, body weight and systolic arterial blood pressure (SABP) increased in HFD animals. Plasma leptin was correlated with peritoneal adipose tissue. Then, we treated OIH animals with an antisense oligodeoxynucleotide and small interfering RNA (siRNA) against the preproTRH. Antisense significantly decreased diencephalic TRH content and SABP at 24 and 48 hours post-treatment. Similar effects were observed with siRNA against preproTRH but for up to 4 weeks. Conversely, vehicle, an inverted antisense sequence and siRNA against green fluorescence protein produced no changes. SABP decrease seems to be due to an inhibition of the obesity-enhanced sympathetic outflow but not to an alteration in thyroid status. Using a simple OIH model we demonstrated, for the first time, that central TRH participates in the hypertension induced by body weight gain probably through its well-known action on sympathetic activity. Thus the TRH-leptin interaction may contribute to the strong association between hypertension and obesity.