Knocking down the diencephalic thyrotropin-releasing hormone precursor gene normalizes obesity-induced hypertension in the rat

1 Cardiología Molecular, Instituto de Investigaciones Médicas A. Lanari, 2 Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires; and 3 Laboratorio de Bioquimica Neuroendocrina, Instituto de Biologia y Medicina Experimental, Buenos Aires, Argentina Submitted 17 May 2006 ; accepted in final form 10 January 2007 We recently showed that diencephalic TRH may mediate the 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 wk, 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 (si)RNA against the prepro-TRH. Antisense significantly decreased diencephalic TRH content and SABP at 24 and 48 h posttreatment. Similar effects were observed with siRNA against prepro-TRH but for up to 4 wk. Conversely, vehicle, an inverted antisense sequence and siRNA against green fluorescence protein, produced no changes. SABP decrease seems to be owing 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. thyroliberin; antisense; small interfering ribonucleic acid; blood pressure; leptin Address for reprint requests and other correspondence: C. J. Pirola, Instituto de Investigaciones Médicas A. Lanari, Combatiente de Malvinas 3150, 1427 Buenos Aires, Argentina (e-mail: pirola.carlos{at}lanari.fmed.uba.ar )