Sahu A
Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
J Neuroendocrinol. 2002 Oct;14(10):796-804. doi: 10.1046/j.1365-2826.2002.00840.x.
Leptin regulates food intake and body weight by acting primarily in the hypothalamus. In humans and rodents, obesity is associated with hyperleptinaemia, suggesting a possible state of leptin resistance. Thus, to begin to examine the mechanisms of leptin resistance, we developed a rat model in which chronic central leptin infusion results in the development of resistance to leptin's satiety action. Adult male rats were infused chronically into the lateral cerebroventricle with leptin (160 ng/h) or phosphate-buffered saline via Alzet pumps for 28 days, followed by artificial cerebrospinal fluid infusion for 3 weeks. After the initial decrease in food intake, rats developed resistance to the satiety action of leptin, and withdrawal of the chronic leptin infusion resulted in hyperphagia. During leptin infusion, body weight was gradually decreased to reach a nadir on day 12, and thereafter, body weight was sustained at a reduced level throughout the entire 28-day infusion, despite normalization in food intake. Body weight was mostly normalized by day 22 postleptin. Since neuropeptide Y (NPY) neurones are one of the targets of leptin signalling in the hypothalamus, we next examined whether the development of resistance to the satiety action of leptin was due to altered NPY gene expression. On day 3-4 of infusion, hypothalamic NPY mRNA levels, as determined by RNAse protection assay (RPA), were significantly decreased in leptin treated rats compared to controls. By contrast, on day 16 of infusion, NPY mRNA levels in the leptin treated group had returned to control levels. In situ hybridization study confirmed the results obtained with RPA and showed further that the effect of chronic leptin infusion on NPY mRNA levels was restricted to the rostral and middle parts of the arcuate nucleus. Overall, the finding that the action of continuous leptin exposure on NPY neurones was not sustained suggests that NPY neurones may be involved in the development of leptin resistance to the satiety action of leptin in the hypothalamus.
瘦素主要通过在下丘脑发挥作用来调节食物摄入和体重。在人类和啮齿动物中，肥胖与高瘦素血症相关，这表明可能存在瘦素抵抗状态。因此，为了开始研究瘦素抵抗的机制，我们建立了一种大鼠模型，其中慢性中枢性瘦素输注会导致对瘦素饱腹感作用产生抵抗。成年雄性大鼠通过Alzet泵经侧脑室慢性输注瘦素（160 ng/h）或磷酸盐缓冲盐水，持续28天，随后输注人工脑脊液3周。在食物摄入量最初减少后，大鼠对瘦素的饱腹感作用产生了抵抗，停止慢性瘦素输注会导致食欲亢进。在瘦素输注期间，体重逐渐下降，在第12天达到最低点，此后，尽管食物摄入量恢复正常，但在整个28天的输注过程中体重一直维持在较低水平。瘦素输注后第22天体重基本恢复正常。由于神经肽Y（NPY）神经元是下丘脑瘦素信号传导的靶点之一，接下来我们研究了对瘦素饱腹感作用的抵抗的产生是否是由于NPY基因表达的改变。在输注的第3 - 4天，通过核糖核酸酶保护分析（RPA）测定，与对照组相比，瘦素处理的大鼠下丘脑NPY mRNA水平显著降低。相比之下，在输注的第16天，瘦素处理组的NPY mRNA水平已恢复到对照水平。原位杂交研究证实了RPA获得的结果，并进一步表明慢性瘦素输注对NPY mRNA水平的影响仅限于弓状核的头端和中部。总体而言，持续瘦素暴露对NPY神经元的作用不能持续这一发现表明，NPY神经元可能参与了下丘脑对瘦素饱腹感作用的抵抗的形成。
