Evidence for the existence of distinct central appetite, energy expenditure, and ghrelin stimulation pathways as revealed by hypothalamic site-specific leptin gene therapy
Evidence for the existence of distinct central appetite, energy expenditure, and ghrelin stimulation pathways as revealed by hypothalamic site-specific leptin gene therapy
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DOI：
10.1210/en.2002-220505
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发表时间：
2002-11-01
期刊：
影响因子：
4.8
通讯作者：
Kalra, SP
中科院分区：
文献类型：
--
作者：
Bagnasco, M;Dube, MG;Kalra, SP
为了确定特定的下丘脑网站，瘦素的行为，以减少能量摄入和/或增加能量消耗，重组腺相关病毒载体编码瘦素被显微注射到雌性大鼠双侧下丘脑的四个网站之一。腹内侧核和室旁核中的瘦素转基因表达诱导每日食物摄入量（FI; 18-20%）和体重（BW; 26-29%）的相当的降低，伴随着血清瘦素（81-97%）、胰岛素（92-93%）、游离脂肪酸（35-36%）和正常血糖的急剧降低。弓状核（ARC）中的瘦素转基因表达使BW增加（21%）和FI（11%）降低至较小范围，但代谢激素被抑制至相同程度。在内侧视前区（MPOA）的瘦素转基因表达降低BW和代谢激素，而不降低FI。最后，瘦素转基因表达在所有四个网站增加血清胃饥饿素和产热能量消耗，解偶联蛋白-1在棕色脂肪组织的mRNA表达所示。前阿黑皮素基因表达的ARC上调瘦素表达在所有四个网站，但神经肽Y基因表达的ARC中的瘦素转基因表达的ARC，但不是在MPOA抑制。因此，尽管室旁核、腹内侧核或ARC中的瘦素表达通过减少能量摄入和增加能量消耗来抑制肥胖和胰岛素，但在MPOA中，它通过单独增加能量消耗来抑制这些变量。
To identify the specific hypothalamic sites in which leptin acts to decrease energy intake and/or increase energy expenditure, recombinant adeno-associated virus vector-encoding leptin was microinjected bilaterally into one of four hypothalamic sites in female rats. Leptin transgene expression in the ventromedial nucleus and paraventricular nucleus induced comparable decreases in daily food intake (FI; 18-20%) and body weight (BW; 26-29%), accompanied by drastic reductions in serum leptin (81-97%), insulin (92-93%), free fatty acids (35-36%), and normoglycemia. Leptin transgene expression in the arcuate nucleus (ARC) decreased BW gain (21%) and FI (11%) to a lesser range, but the metabolic hormones were suppressed to the same extent. Leptin transgene expression in the medial preoptic area (MPOA) decreased BW and metabolic hormones without decreasing FI. Finally, leptin transgene expression in all four sites augmented serum ghrelin and thermogenic energy expenditure, as shown by uncoupling protein-1 mRNA expression in brown adipose tissue. Proopiomelanocortin gene expression in the ARC was up-regulated by leptin expression in all four sites, but neuropeptide Y gene expression in the ARC was suppressed by leptin transgene expression in the ARC but not in the MPOA. Thus, whereas leptin expression in the paraventricular nucleus, ventromedial nucleus, or ARC suppresses adiposity and insulin by decreasing energy intake and increasing energy expenditure, in the MPOA it suppresses these variables by increasing energy expenditure alone.