Elsevier

Metabolism

Volume 56, Issue 10, October 2007, Pages 1439-1443
Metabolism

Association between diencephalic thyroliberin and arterial blood pressure in agouti-yellow and ob/ob mice may be mediated by leptin

https://doi.org/10.1016/j.metabol.2007.06.008Get rights and content

Abstract

Leptin, a hormone secreted by the adipose tissue, stimulates anorexigenic peptides and also inhibits orexigenic peptides in hypothalamic arcuate nuclei-located neurons. It also counteracts the starvation-induced suppression of thyroid hormones by up-regulating the expression of preproTRH gene. On the other hand, in addition to its role as a modulator of the thyroid-hypothalamic-hypophysial axis, thyrotropin-releasing hormone (TRH) acts as a modulator of the cardiovascular system. In fact, we reported that overexpression of diencephalic TRH (dTRH) induces hypertension. We have recently shown that, in rats with obesity-induced hypertension, hyperleptinemia may produce an increase of dTRH together with an elevation of arterial blood pressure (ABP) through an increase of sympathetic activity and that these alterations were reversed by antisense oligonucleotide and small interfering RNA against preproTRH treatments. Here we explore the possible role of dTRH as a mediator involved in leptin-induced hypertension in 2 obesity mouse models: agouti-yellow mice, which are hyperleptinemic and hypertensive, and ob/ob mice, which lack functional circulating leptin. These 2 models share some characteristics, but ob/ob mice show lower ABP and plasma catecholamines levels. Then, for the first time, we report that there is a clear association between ABP and dTRH levels in both mouse models, as we have found that dTRH content was elevated in agouti-yellow mice and diminished in ob/ob mice compared with their controls. We also show that, after 3 days of subcutaneous leptin injections (10 μg/12 hours), ABP and dTRH increased significantly in ob/ob mice with no alterations of thyroid hormone levels. These results add evidence to the putative molecular mechanisms for the strong association between obesity and hypertension.

Introduction

The leptin hormone is mainly produced and secreted by adipose tissue [1]. As a consequence, plasma leptin levels are directly proportional to body fat content [2], [3]. This hormone acts in 2 ways: (1) stimulating neurons from hypothalamic arcuate nuclei that express and release anorexigenic peptides such as α-melanocyte–stimulating hormone (α-MSH) and cocaine- and amphetamine-regulated transcript peptide and (2) inhibiting other neurons that coexpress the orexigenic peptides neuropeptide Y and agouti-yellow–related protein (AgRP) [4], [5], [6]. AgRP acts as an antagonist of α-MSH for the binding to 3 of the 5 types of the α-MSH receptors: MC1R in the skin and MC3R and/or MC4R in the central nervous system [7]. A high leptin level reduces AgRP and increases α-MSH release. As a result, leptin causes a decrease in energy intake and an increase in energy expenditure [8], [9].

As reported by Ahima et al [10], leptin also counteracts the starvation-induced suppression of thyroid hormones by up-regulating the expression of the thyrotropin-releasing hormone precursor gene (preproTRH). In other words, leptin can regulate the expression of thyrotropin-releasing hormone (TRH) directly or indirectly by increasing the production of α-MSH [11], [12], [13], [14] and enzymes that are necessary for the processing of proTRH in TRH [12], [15].

Apart from the classic role of TRH in the thyroid-hypothalamic-hypophysial axis, it acts as a neuropeptide modulating cardiovascular function among several other physiological functions [16]. We have previously reported that overexpression of diencephalic TRH (dTRH) induces hypertension in the normal rat [17]. Furthermore, in rats with obesity-induced hypertension, high levels of leptin produce an increase in dTRH along with an elevation in systolic arterial blood pressure (SABP) through an increase of sympathetic activity, an alteration that can be reversed by intracerebroventricular antisense or interfering RNA treatments [18].

Agouti-yellow mice characterized by an agouti protein overexpression are hyperleptinemic but obese, a consequence of a selective leptin resistance with loss of leptin-reducing appetite and weight responses but preservation of the leptin-induced sympathetic activation [19], which is a fact that seems to explain the elevation of ABP in this model [20].

On the other hand, ob/ob mice lack functional circulating leptin. Thus, they resemble some but not all of the characteristics of agouti-yellow mice. For instance, obesity in ob/ob mice is not associated with hypertension but with lower blood pressure levels owing to low levels of plasma catecholamines [21]. As expected, leptin treatment reversed the ob/ob phenotype, producing a decrease in body weight and food intake [21].

Bearing this background in mind, we propose that cardiovascular leptin actions are, in part, mediated by the dTRH system. We therefore studied the expression of dTRH and its possible association with ABP values in 2 obesity models: agouti-yellow mice and ob/ob mice. We report here for the first time that there is a clear association between ABP and dTRH levels in both mouse models and show that leptin can increase both blood pressure and dTRH in ob/ob mice. These results add evidence to the putative molecular mechanisms for the strong association between obesity and hypertension.

Section snippets

Animals

We studied 12-week-old male agouti-yellow (C57BL/6J-Ay), Ob/Ob (C57BL/6J-ob/ob), and their wild-type control (C57BL/6J) mice from The Jackson Laboratory (Bar Harbor, ME) (n = 4 for each group). They were housed individually in environmentally controlled conditions (temperature, 20°C ± 2°C; light/dark cycle of 12/12 hours) and had access to food (standard laboratory diet) and water ad libitum.

In some experiments, control and ob/ob mice (5 per group) were treated with a subcutaneous injection of

Results

As expected, the body weight of both obese strains was significantly greater than that of wild-type controls (Fig. 1, upper panel). Consistent with their well-known hyperleptinemic state, agouti-yellow mice had a 10-fold increase in plasma leptin level with respect to control animals. In contrast, ob/ob mice had no detectable leptin levels owing to the null mutation that they carry in the leptin (Lep, formerly ob) gene (Fig. 1, lower panel).

As hypothesized, ob/ob mice showed significantly lower

Discussion

By using 2 different strains of obese mice, we show evidence of the relation between plasma leptin levels, dTRH content, and blood pressure levels. First, ob/ob mice lack functional leptin and show low levels of ABP and dTRH content. On the other hand, hyperleptinemic and hypertensive agouti-yellow mice present high dTRH content. These results show a highly significant correlation between dTRH content and SABP in all the animals studied, suggesting that dTRH may be mediating leptin

Acknowledgment

This work was supported by grants TM018 and B119 (Universidad de Buenos Aires); PIPs 901/98, 1045/98, and 5195 (Consejo Nacional de Investigaciones Científicas y Técnicas); Beca Ramón Carrillo-Arturo Oñativia (Ministerio de Salud Pública de la Nación, Convocatoria 2006); and PICT 05-08719 and PICT 2003-13862 (Agencia Nacional de Promoción Científica y Tecnológica).

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