Neurobiochemistry Group, Unit of Biochemistry and Molecular Biology, Facultad de Medicina, Universidad de Alcalá, E-28871 Alcalá de Henares, Spain.
Neuroscience. 2013 Nov 12;252:289-301. doi: 10.1016/j.neuroscience.2013.08.019. Epub 2013 Aug 23.
Leptin and somatostatin (SRIF) have opposite effects on food seeking and ingestive behaviors, functions partially regulated by the frontoparietal cortex and hippocampus. Although it is known that the acute suppression of food intake mediated by leptin decreases with time, the counter-regulatory mechanisms remain unclear. Our aims were to analyze the effect of acute central leptin infusion on the SRIF receptor-effector system in these areas and the implication of related intracellular signaling mechanisms in this response. We studied 20 adult male Wister rats including controls and those treated intracerebroventricularly with a single dose of 5 μg of leptin and sacrificed 1 or 6h later. Density of SRIF receptors was unchanged at 1h, whereas leptin increased the density of SRIF receptors at 6h, which was correlated with an elevated capacity of SRIF to inhibit forskolin-stimulated adenylyl cyclase activity in both areas. The functional capacity of SRIF receptors was unaltered as cell membrane levels of αi1 and αi2 subunits of G inhibitory proteins were unaffected in both brain areas. The increased density of SRIF receptors was due to enhanced SRIF receptor subtype 2 (sst2) protein levels that correlated with higher mRNA levels for this receptor. These changes in sst2 mRNA levels were concomitant with increased activation of the insulin signaling, c-Jun and cyclic AMP response element-binding protein (CREB); however, activation of signal transducer and activator of transcription 3 was reduced in the cortex and unchanged in the hippocampus and suppressor of cytokine signaling 3 remained unchanged in these areas. In addition, the leptin antagonist L39A/D40A/F41A blocked the leptin-induced changes in SRIF receptors, leptin signaling and CREB activation. In conclusion, increased activation of insulin signaling after leptin infusion is related to acute up-regulation of the SRIF receptor-effector system that may antagonize short-term leptin actions in the rat brain.
瘦素和生长抑素 (SRIF) 对摄食行为具有相反的作用，其部分功能受额顶叶皮质和海马体调节。虽然已知瘦素急性抑制摄食作用会随时间而减弱，但对抗调节机制仍不清楚。我们的目的是分析急性中枢性瘦素输注对这些区域中 SRIF 受体-效应系统的影响，以及相关细胞内信号机制在这种反应中的作用。我们研究了 20 只成年雄性 Wistar 大鼠，包括对照组和脑室注射 5μg 瘦素的实验组，1 或 6 小时后处死。1 小时时 SRIF 受体密度无变化，而瘦素在 6 小时时增加了 SRIF 受体密度，这与两种区域中 SRIF 抑制 forskolin刺激的腺苷酸环化酶活性的能力升高有关。两种脑区的 G 抑制蛋白 αi1 和 αi2 亚基的细胞膜水平不变，表明 SRIF 受体的功能能力不变。SRIF 受体密度的增加是由于 SRIF 受体亚型 2 (sst2) 蛋白水平的升高，这与该受体的 mRNA 水平升高有关。sst2 mRNA 水平的这些变化与胰岛素信号、c-Jun 和环磷酸腺苷反应元件结合蛋白 (CREB) 的激活增加有关；然而，皮质中信号转导和转录激活因子 3 的激活减少，海马体中不变，这些区域中的细胞因子信号转导抑制因子 3 不变。此外，瘦素拮抗剂 L39A/D40A/F41A 阻断了瘦素诱导的 SRIF 受体、瘦素信号和 CREB 激活的变化。总之，瘦素输注后胰岛素信号的增强与 SRIF 受体-效应系统的急性上调有关，这可能拮抗大鼠脑内短期瘦素作用。
