de Luca Carl, Kowalski Timothy J, Zhang Yiying, Elmquist Joel K, Lee Charlotte, Kilimann Manfred W, Ludwig Thomas, Liu Shun-Mei, Chua Streamson C
Department of Medicine, Division of Preventative Medicine, Columbia University, New York, New York, USA.
J Clin Invest. 2005 Dec;115(12):3484-93. doi: 10.1172/JCI24059. Epub 2005 Nov 10.
We have generated mice that carry a neuron-specific leptin receptor (LEPR) transgene whose expression is driven by the rat synapsin I promoter synapsin-LEPR B (SYN-LEPR-B). We have also generated mice that are compound hemizygotes for the transgenes SYN-LEPR-B and neuron-specific enolase-LEPR B (NSE-LEPR-B). We observed a degree of correction in db/db mice that are hemizygous (Syn db/db) and homozygous (Syn/Syn db/db) for the SYN-LEPR-B transgene similar to that previously reported for the NSE-LEPR-B transgene. We also show complete correction of the obesity and related phenotypes of db/db mice that are hemizygous for both NSE-LEPR-B and SYN-LEPR-B transgenes (Nse+Syn db/db). Body composition, insulin sensitivity, and cold tolerance were completely normalized in Nse+Syn db/db mice at 12 weeks of age compared with lean controls. In situ hybridization for LEPR B isoform expression in Nse+Syn db/db mice showed robust expression in the energy homeostasis-relevant regions of the hypothalamus. Expression of 3 neuropeptide genes, agouti-related peptide (Agrp), neuropeptide Y (Npy), and proopiomelanocortin (Pomc), was fully normalized in dual transgenic db/db mice. The 2 transgenes in concert conferred normal fertility to male and female db/db mice. Male mice with partial peripheral deletion of Lepr, induced in the periweaning phase, did not show alterations in body composition or mass. In summary, we show that brain-specific leptin signaling is sufficient to reverse the obesity, diabetes, and infertility of db/db mice.
我们已经培育出携带神经元特异性瘦素受体（LEPR）转基因的小鼠，其表达由大鼠突触素I启动子驱动，即突触素-LEPR B（SYN-LEPR-B）。我们还培育出了转基因SYN-LEPR-B和神经元特异性烯醇化酶-LEPR B（NSE-LEPR-B）的复合半合子小鼠。我们观察到，对于SYN-LEPR-B转基因半合子（Syn db/db）和纯合子（Syn/Syn db/db）的db/db小鼠，其肥胖症状有一定程度的改善，类似于先前报道的NSE-LEPR-B转基因小鼠。我们还发现，对于同时携带NSE-LEPR-B和SYN-LEPR-B转基因的db/db小鼠（Nse+Syn db/db），其肥胖及相关表型得到了完全改善。与瘦素对照相比，12周龄的Nse+Syn db/db小鼠的身体组成、胰岛素敏感性和耐寒性完全恢复正常。对Nse+Syn db/db小鼠中LEPR B亚型表达的原位杂交显示，在下丘脑与能量稳态相关的区域有强烈表达。在双转基因db/db小鼠中，3种神经肽基因，即刺鼠相关肽（Agrp）、神经肽Y（Npy）和阿片-促黑素细胞皮质素原（Pomc）的表达完全恢复正常。这两个转基因共同赋予了雄性和雌性db/db小鼠正常的生育能力。在断奶期诱导产生部分外周Lepr缺失的雄性小鼠，其身体组成或体重没有变化。总之，我们表明脑特异性瘦素信号足以逆转db/db小鼠的肥胖、糖尿病和不育症。
