Obesity is associated with increased cardiovascular morbidity and mortality, in part through development of hypertension. Leptin promotes weight loss by reducing food intake and increasing energy expenditure through sympathetic stimulation. It also counteracts the starvation-induced suppression of thyroid hormone by up-regulating the expression of TRH. On the other hand, it is known that the extrahypothalamic TRH system participates in cardiovascular function modulating sympathetic system activity. In order to challenge the testable hypothesis that obesity may raise arterial blood pressure (ABP) through TRH system activation, we herein analyze the participation of the TRH system in the elevation of ABP in the obese agouti yellow mice. These mice are characterized by resistance to the weight reducing effect of leptin although they show a preserved sympathetic response to leptin along with a mild hypertension compared with the control strain (121+/-2 vs 102+/-2 mmHg, p less than 0.001, n=10). We report here that hyperleptinemic agouti mice showed a 1.8-fold elevation of diencephalic TRH content compared with controls, and we demonstrate that a long lasting specific inhibition of TRH system by icv treatment with siRNA against preproTRH normalizes systolic ABP independently of the thyroid status. These results suggest that the interaction leptin-diencephalic TRH may be one of the mechanisms involved in the mild hypertension of the obese agouti mice.