Identification of targets of leptin action in rat hypothalamus

被引:1293
作者
Schwartz, MW
Seeley, RJ
Campfield, LA
Burn, P
Baskin, DG
机构
[1] UNIV WASHINGTON,DEPT MED,SEATTLE,WA 98108
[2] UNIV WASHINGTON,DEPT PSYCHOL,SEATTLE,WA 98108
[3] UNIV WASHINGTON,DEPT BIOL STRUCT,SEATTLE,WA 98108
[4] HOFFMANN LA ROCHE INC,MET DIS UNIT,NUTLEY,NJ 07110
关键词
D O I
10.1172/JCI118891
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
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.
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页码:1101 / 1106
页数:6
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