Leptin, secreted by peripheral adipocytes, binds the leptin receptor (Lepr) in the hypothalamus, thereby contributing to the regulation of satiety and body weight. Lepr is expressed in the embryonic brain as early as embryonic day 12.5. However, the function of Lepr in neural precursor cells in the brain has not been resolved. To address this issue, we crossed the Leprflox/flox mice with each of Shh-Cre mice (Shh, sonic hedgehog) and Nestin (Nes)-Cre mice. We found that deletion of Lepr specifically in nestin-expressing cells led to extreme obesity, but the conditional null of Lepr in Shh-expressing cells had no obvious phenotype. Moreover, the level of leptin-activated pSTAT3 decreased in the anterior and central subregions of the arcuate hypothalamus of Shh-Cre; Leprflox/flox mice compared with the controls. By contrast, in Nes-Cre; Leprflox/flox mice, the level of leptin-activated pSTAT3 decreased in all subregions including the anterior, central, and posterior arcuate hypothalamus as well as the dorsomedial, ventromedial, and median eminence of the hypothalamus, revealing that the extensive lack of Lepr in the differentiated neurons of the hypothalamus in the conditional null mice. Notably, conditional deletion of Lepr in nestin-expressing cells enhanced the differentiation of neural precursor cells into neurons and oligodendroglia but inhibited differentiation into astrocytes early in postnatal development of hypothalamus. Our results suggest that Lepr expression in neural precursor cells is essential for maintaining normal body weight as well as the differentiation of neural precursor cells to the neural/glial fate in the hypothalamus shortly after birth.

中文翻译：

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有条件地敲除神经干细胞中的瘦素受体会导致小鼠肥胖，并在出生后早期影响下丘脑的神经元分化。

由周围脂肪细胞分泌的瘦素与下丘脑中的瘦素受体（Lepr）结合，从而有助于调节饱腹感和体重。Lepr最早在胚胎第12.5天在胚胎脑中表达。但是，Lepr在大脑神经前体细胞中的功能尚未得到解决。为了解决这个问题，我们将Leprflox / flox小鼠与Shh-Cre小鼠（Shh，声波刺猬）和Nestin（Nes）-Cre小鼠杂交。我们发现，在巢蛋白表达细胞中Lepr的缺失会导致极端肥胖，但是在Shh表达细胞中Lepr的条件无效没有明显的表型。此外，Shh-Cre弓状下丘脑的前部和中央亚区域中，瘦素激活的pSTAT3水平降低；Leprflox / flox小鼠与对照组比较。相比之下，在Nes-Cre中；在Leprflox / flox小鼠中，瘦素激活的pSTAT3的水平在所有子区域（包括前弓形，中央弓形和后弓形下丘脑以及下丘脑的背侧，腹侧和中间隆起）均降低，这表明在小鼠中广泛缺乏Lepr条件空小鼠下丘脑的分化神经元。值得注意的是，表达巢蛋白的细胞中有条件的Lepr缺失增强了神经前体细胞向神经元和少突胶质细胞的分化，但抑制了下丘脑出生后早期向星形胶质细胞的分化。我们的结果表明，Lepr在神经前体细胞中的表达对于维持正常体重以及出生后不久下丘脑中神经前体细胞向神经/神经胶质命运的分化至关重要。在所有子区域，包括弓状下丘脑的前部，中央和后部以及下丘脑的背体，腹膜和中位隆高，瘦素激活的pSTAT3的水平均降低，这表明在下丘脑的分化神经元中广泛缺乏Lepr在条件空小鼠中。值得注意的是，表达巢蛋白的细胞中有条件的Lepr缺失增强了神经前体细胞向神经元和少突胶质细胞的分化，但抑制了下丘脑出生后早期向星形胶质细胞的分化。我们的结果表明，Lepr在神经前体细胞中的表达对于维持正常体重以及出生后不久下丘脑中神经前体细胞向神经/神经胶质命运的分化至关重要。在所有子区域，包括弓状下丘脑的前部，中央和后部以及下丘脑的背体，腹膜和中位隆高，瘦素激活的pSTAT3的水平均降低，这表明在下丘脑的分化神经元中广泛缺乏Lepr在条件空小鼠中。值得注意的是，巢蛋白表达细胞中有条件的Lepr缺失增强了神经前体细胞向神经元和少突胶质细胞的分化，但抑制了下丘脑出生后早期向星形胶质细胞的分化。我们的结果表明，Lepr在神经前体细胞中的表达对于维持正常体重以及出生后不久下丘脑中神经前体细胞向神经/神经胶质命运的分化至关重要。