Identification of targets of leptin action in rat hypothalamus
Identification of targets of leptin action in rat hypothalamus
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DOI：
10.1172/jci118891
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发表时间：
1996-09-01
影响因子：
15.9
通讯作者：
Baskin, DG
中科院分区：
文献类型：
--
作者：
Schwartz, MW;Seeley, RJ;Baskin, DG
瘦素（OB蛋白）在下丘脑中起作用以减少食物摄入和体重的假设主要基于瘦素缺乏的ob/ob小鼠的证据。为了研究瘦素是否在正常动物中发挥类似的作用，我们给Long-Evans大鼠脑室注射瘦素。与赋形剂处理的对照组相比，在夜间进食开始时给予瘦素（3.5 μ g冰）在1小时和4小时分别减少了50%和42%的食物摄入（均P < 0.05）。为了研究这种效应的基础，我们使用原位杂交（ISH）来确定瘦素是否改变参与能量稳态的下丘脑神经肽的表达。在40小时禁食期间注射两次瘦素（3.5 μ g冰）显著降低了弓状核中神经肽Y（NPY，其刺激食物摄入）的mRNA水平（-24%），并增加了室旁核中促肾上腺皮质激素释放激素（CRH，食物摄入抑制剂）的mRNA水平（38%）（均P < 0.05，与赋形剂处理的对照组相比）。为了研究这些效应的解剖学基础，我们使用与所有瘦素受体剪接变体的mRNA互补的探针，通过ISH测量了大鼠脑中瘦素受体基因的表达。瘦素受体mRNA密集地集中在弓状核中，在腹内侧核和背内侧核以及参与能量平衡的其他脑区中存在较低水平。这些结果表明，瘦素在大鼠下丘脑的作用涉及改变关键神经肽基因的表达，并牵连瘦素在下丘脑对禁食的反应。
The hypothesis that leptin (OB protein) acts in the hypothalamus to reduce food intake and body weight is based primarily on evidence from leptin-deficient, ob/ob mice. To investigate whether leptin exerts similar effects in normal animals, we administered leptin intracerebroventricularly (icy) to Long-Evans rats. Leptin administration (3.5 mu g icy) at the onset of nocturnal feeding reduced food intake by 50% at 1 h and by 42% at 4 h, as compared with vehicle-treated controls (both P < 0.05). To investigate the basis for this effect, we used in situ hybridization (ISH) to determine whether leptin alters expression of hypothalamic neuropeptides involved in energy homeostasis. Two injections of leptin (3.5 mu g icy) during a 40 h fast significantly decreased levels of mRNA for neuropeptide Y (NPY, which stimulates food intake) in the arcuate nucleus (-24%) and increased levels of mRNA for corticotrophin releasing hormone (CRH, an inhibitor of food intake) in the paraventricular nucleus (by 38%) (both P < 0.05 vs. vehicle-treated controls). To investigate the anatomic basis for these effects, we measured leptin receptor gene expression in rat brain by ISH using a probe complementary to mRNA for all leptin receptor splice variants. Leptin receptor mRNA was densely concentrated in the arcuate nucleus, with lower levels present in the ventromedial and dorsomedial hypothalamic nuclei and other brain areas involved in energy balance. These findings suggest that leptin action in rat hypothalamus involves altered expression of key neuropeptide genes, and implicate leptin in the hypothalamic response to fasting.