Neurobiochemistry Unit, Department of Biochemistry and Molecular Biology, Facultad de Medicina, Universidad de Alcalá, Alcalá de Henares, E-28871 Madrid, Spain.
Neurochem Int. 2012 Dec;61(8):1385-96. doi: 10.1016/j.neuint.2012.09.019. Epub 2012 Oct 13.
The learning and memory mechanisms in the hippocampus translate hormonal signals of energy balance into behavioral outcomes involved in the regulation of food intake. As leptin and its receptors are expressed in the hippocampus and somatostatin (SRIF), an orexigenic neuropeptide, may inhibit leptin-mediated suppression of food intake in other brain areas, we asked whether chronic leptin infusion induces changes in the hippocampal somatostatinergic system and whether these modifications are involved in leptin-mediated effects. We studied 18 male Wistar rats divided into three groups: controls (C), treated intracerebroventricularly (icv) with leptin (12 μg/day) for 14 days (L) and a pair-fed group (PF) that received the same amount of food consumed by the L group. Food restriction increased whereas leptin decreased the hippocampal SRIF receptor density, due to changes in SRIF receptor 2 protein levels. These changes in the PF group were concurrent with an increase of hippocampal G protein-coupled receptor kinase 2 protein levels and activation of Akt and cyclic AMP response element binding protein. The inhibitory effect of SRIF on adenylyl cyclase (AC) activity, however, was decreased in L rats, coincident with lower G inhibitory α3 and higher AC-I levels as well as signal transducer and activator of transcription factor 3 activation. In addition, 20 male Wistar rats were included to analyze whether the leptin antagonist L39A/D40A/F41A and the SRIF receptor agonist SMS 201-995 modify SRIF signaling and food intake, respectively. Administration of L39A/D40A/F41A reversed changes in SRIF signaling, whereas SMS 201-995 ameliorated food consumption in L. Altogether, these results suggest that increased somatostatinergic tone in PF rats may be a mechanism to improve the hippocampal orexigenic effects in a situation of metabolic demand, whereas down-regulation of this system in L rats may represent a mechanism to enhance the anorexigenic effects of leptin.
海马体中的学习和记忆机制将能量平衡的激素信号转化为参与调节食物摄入的行为结果。由于瘦素及其受体在海马体中表达，而生长抑素（SRIF）是一种食欲肽，可能会抑制瘦素在其他脑区介导的食物摄入抑制作用，我们想知道慢性瘦素输注是否会引起海马体生长抑素能系统的变化，以及这些变化是否与瘦素介导的作用有关。我们研究了 18 只雄性 Wistar 大鼠，分为三组：对照组（C）、连续 14 天脑室注射（icv）瘦素（12μg/天）的治疗组（L）和接受与 L 组相同量食物的配对喂养组（PF）。由于 SRIF 受体 2 蛋白水平的变化，食物限制增加而瘦素减少了海马体的生长抑素受体密度。PF 组的这些变化伴随着海马体 G 蛋白偶联受体激酶 2 蛋白水平的增加和 Akt 和环磷腺苷反应元件结合蛋白的激活。然而，在 L 大鼠中，生长抑素对腺苷酸环化酶（AC）活性的抑制作用降低，同时 G 抑制α3 和 AC-I 水平降低，信号转导和转录激活因子 3 激活。此外，还纳入了 20 只雄性 Wistar 大鼠，以分析瘦素拮抗剂 L39A/D40A/F41A 和生长抑素受体激动剂 SMS 201-995 是否分别改变生长抑素信号和食物摄入。给予 L39A/D40A/F41A 逆转了生长抑素信号的变化，而 SMS 201-995 改善了 L 大鼠的食物消耗。总的来说，这些结果表明，PF 大鼠中生长抑素能张力的增加可能是一种在代谢需求情况下改善海马体食欲作用的机制，而 L 大鼠中这种系统的下调可能代表了增强瘦素的厌食作用的机制。
