Department of Internal Medicine, University of Michigan, Ann Arbor, MI.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI.
Diabetes. 2018 Jun;67(6):1093-1104. doi: 10.2337/db17-1395. Epub 2018 Mar 13.
Leptin acts via its receptor (LepRb) to modulate gene expression in hypothalamic LepRb-expressing neurons, thereby controlling energy balance and glucose homeostasis. Despite the importance of the control of gene expression in hypothalamic LepRb neurons for leptin action, the transcriptional targets of LepRb signaling have remained undefined because LepRb cells contribute a small fraction to the aggregate transcriptome of the brain regions in which they reside. We thus employed translating ribosome affinity purification followed by RNA sequencing to isolate and analyze mRNA from the hypothalamic LepRb neurons of wild-type or leptin-deficient ( mice treated with vehicle or exogenous leptin. Although the expression of most of the genes encoding the neuropeptides commonly considered to represent the main targets of leptin action were altered only following chronic leptin deprivation, our analysis revealed other transcripts that were coordinately regulated by leptin under multiple treatment conditions. Among these, acute leptin treatment increased expression of the transcription factor in LepRb neurons. Furthermore, ablation of from LepRb neurons (Atf3KO mice) decreased leptin efficacy and promoted positive energy balance in mice. Thus, this analysis revealed the gene targets of leptin action, including , which represents a cellular mediator of leptin action.
瘦素通过其受体 (LepRb) 作用于下丘脑表达 LepRb 的神经元中的基因表达，从而控制能量平衡和葡萄糖稳态。尽管瘦素作用于下丘脑 LepRb 神经元中基因表达的控制非常重要，但 LepRb 信号的转录靶标仍然未被定义，因为 LepRb 细胞对其所在脑区的总转录组的贡献很小。因此，我们采用翻译核糖体亲和纯化结合 RNA 测序，从野生型或瘦素缺乏型（用载体或外源性瘦素处理的小鼠）的下丘脑 LepRb 神经元中分离和分析 mRNA。尽管大多数编码通常被认为是瘦素作用主要靶点的神经肽的基因的表达仅在慢性瘦素剥夺后发生改变，但我们的分析还揭示了其他在多种处理条件下受瘦素协调调节的转录本。其中，急性瘦素处理增加了 LepRb 神经元中转录因子 的表达。此外，从 LepRb 神经元中剔除 （Atf3KO 小鼠）降低了瘦素的功效并促进了小鼠的正能量平衡。因此，这项分析揭示了瘦素作用的基因靶点，包括 ，它代表了瘦素作用的细胞介导物。
