9. DIENCEPHALIC THYROTROPIN-RELEASING HORMONE (TRH) MAY PARTICIPATE IN LEPTIN-MEDIATED CONTROL OF ARTERIAL BLOOD PRESSURE (ABP) EXERTED BY PROTEIN TYROSINE PHOSPHATASE 1B

MARÍA S. LANDA, SILVIA I. GARCÍA, CARLOS J. PIROLA

CIRCULATION

LIPPINCOTT WILLIAMS & WILKINS

Año: 2009

0009-7322

Recently, Belin de Chantemele et al.  reported that protein tyrosine phosphatase 1B (PTP1B) may be a major player in the leptin-mediated control of arterial blood pressure (ABP) in mice. We invite authors to consider that hypothalamic TRH system may be involved in this pathway. Leptin effects include increases in sympathetic activity and inhibition of the starvation-induced suppresion of thyroid hormones apparently by up-regulating preproTRH gene expression. Furthermore, we have shown that icv leptin injections induce a pressor effect that is avoided by preproTRH antisense olignucleotide (AS)-pretreatment . In addition, we showed that diencephalic TRH levels were correlated with ABP and leptin levels in two genetic models of obesity,the hyperleptinemic and moderately hypertensive agouti yellow mice and the Ob/Ob mice, which lack leptin and are hypotensive. Another important aspect is that leptin can increase the melanocortin receptor type 4 (MCR4) ligand (aMSH) production to regulate TRH expression. Hence, we proposed that melanocortin activity may raise ABP through TRH activation and we recently reported that in Wistar rats, the MCR4 agonist (MTII)-induced elevation of ABP can be blocked by 24 hs icv pretreatment with a preproTRH AS. Then, we show that the MCR3/4 agonist induced hypertension only in the presence of an intact hypothalamic TRH system and we proposed that an activation of the axis leptin-melanocortin-TRH might explain increases of ABP in a genetic model of hypertension, the spontanously hypertensive rat. This is particularly important because it was recently reported that the activation of melanocortinergic pathways by synthetic MC4R agonists may increase ABP in patients bearing mutation in the MC4R, who are genetically obese but with basal low ABP levels. This point is crucial to the development of antiobesity drugs. Then we absolutely agreed with the cleaver comment of Dr Mark in the companion editorial to the work of Belin de Chantemele et al.  about the necessity to rice a yellow flag in the race to safe Pharmacotherapy for Obesity owing to the cardiovascular side effects of antiobesity drugs. To conclude, it is tempeting to propose that TRH may participate in the mechanism by which leptin through PTP1B modulates ABP and be a target for disociating the effects of therapeutic interventions on body weight and ABP if it were possible.