Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fak/fak) rats
Arcuate nucleus-specific leptin receptor gene therapy attenuates the obesity phenotype of Koletsky (fak/fak) rats
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DOI：
10.1210/en.2002-0115
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发表时间：
2003-05-01
期刊：
影响因子：
4.8
通讯作者：
Schwartz, MW
中科院分区：
文献类型：
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作者：
Morton, GJ;Niswender, KD;Schwartz, MW
据推测，下丘脑弓状核 (ARC) 中的瘦素信号传导在能量稳态中发挥重要作用。为了研究仅限于该大脑区域的瘦素信号传导是否足以减少食物摄入和体重，我们使用腺病毒基因疗法在瘦素受体缺陷的Koletsky (fa(k)/fa(k))大鼠的ARC中表达瘦素受体的信号同工型lepr(b)。通过原位杂交记录了含有 lepr(b) 的腺病毒 (Ad-lepr(b)) 在 ARC 中的成功表达。使用实时 PCR，我们进一步证明，将 Ad-lepr(b) 双侧显微注射到 ARC 中可将下丘脑的 lepr(b) mRNA 水平恢复到接近野生型 (Fa(k)/Fa(k)) 对照的值。与注射对照腺病毒 (Ad-lacZ) 的 fa(k)/fa(k) 大鼠相比，ARC 中瘦素受体表达恢复后，平均每日食物摄入量（减少 13%）和体重增加（增加 33%）均减少，下丘脑阿黑皮素原 mRNA 增加 65%，同时神经肽 Y mRNA 水平降低 30%（P
Leptin signaling in the hypothalamic arcuate nucleus (ARC) is hypothesized to play an important role in energy homeostasis. To investigate whether leptin signaling limited to this brain area is sufficient to reduce food intake and body weight, we used adenoviral gene therapy to express the signaling isoform of the leptin receptor, lepr(b), in the ARC of leptin receptor-deficient Koletsky (fa(k)/fa(k)) rats. Successful expression of adenovirus containing lepr(b) (Ad-lepr(b)) selectively in the ARC was documented by in situ hybridization. Using real-time PCR, we further demonstrated that bilateral microinjection of Ad-lepr(b) into the ARC restored low hypothalamic levels of lepr(b) mRNA to values approximating those of wild-type (Fa(k)/Fa(k)) controls. Restored leptin receptor expression in the ARC reduced both mean daily food intake (by 13%) and body weight gain (by 33%) and increased hypothalamic proopiomelanocortin mRNA by 65% while decreasing neuropeptide Y mRNA levels by 30%, relative to fa(k)/fa(k) rats injected with a control adenovirus (Ad-lacZ) (P