Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice.
Hypothalamic ATF3 is involved in regulating glucose and energy metabolism in mice.
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DOI：
10.1007/s00125-013-2879-z
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发表时间：
2013-06
期刊：
影响因子：
8.2
通讯作者：
Kitamura, T.
中科院分区：
文献类型：
--
作者：
Lee, Y. -S.;Sasaki, T.;Kobayashi, M.;Kikuchi, O.;Kim, H. -J.;Yokota-Hashimoto, H.;Shimpuku, M.;Susanti, V. -Y.;Ido-Kitamura, Y.;Kimura, K.;Inoue, H.;Tanaka-Okamoto, M.;Ishizaki, H.;Miyoshi, J.;Ohya, S.;Tanaka, Y.;Kitajima, S.;Kitamura, T.
胰腺和下丘脑对于维持营养和能量稳态至关重要，这些器官的综合紊乱导致了代谢综合征的发生。激活转录因子 3 (ATF3) 是一种适应性反应转录因子。 ATF3 在胰腺中的生理作用一直存在争议，而其在下丘脑中的作用仍不清楚。为了阐明 ATF3 在这些器官中的作用，我们在本研究中培育了胰腺和下丘脑特异性 Atf3 敲除 (PHT-Atf3-KO) 小鼠。我们将携带 floxed Atf3 等位基因的小鼠与 Pdx1-cre 小鼠（其中 cre 在胰腺和下丘脑中特异性表达）进行杂交，并分析了脂肪组织中的代谢变量、胰腺形态、食物摄入、能量消耗和交感神经活动。我们还使用下丘脑细胞系来研究 ATF3 调节刺鼠相关蛋白 (Agrp) 编码基因转录的分子机制。尽管 PHT-Atf3-KO 小鼠表现出更好的葡萄糖耐量，但这些小鼠的血浆胰高血糖素和胰岛素水平均未改变。然而，这些小鼠表现出更高的胰岛素敏感性，同时由于食物摄入量减少和能量消耗增加而导致更瘦的表型。我们还观察到 PHT-Atf3-KO 小鼠下丘脑 Agrp 表达减少。重要的是，ATF3 水平的增加是由下丘脑的禁食或低血糖引起的。我们还表明，ATF3 与 Agrp 启动子上的叉头盒蛋白 O 亚家族 1 (FoxO1) 相互作用，并激活 Agrp 转录。我们的结果表明ATF3通过调节Agrp在控制葡萄糖和能量代谢中发挥重要作用。本文的在线版本 (doi:10.1007/s00125-013-2879-z) 包含经过同行评审但未经编辑的补充材料，可供授权用户使用。
The pancreas and hypothalamus are critical for maintaining nutrient and energy homeostasis, and combined disorders in these organs account for the onset of the metabolic syndrome. Activating transcription factor 3 (ATF3) is an adaptive response transcription factor. The physiological role of ATF3 in the pancreas has been controversial, and its role in the hypothalamus remains unknown. To elucidate the roles of ATF3 in these organs, we generated pancreas- and hypothalamus-specific Atf3 knockout (PHT-Atf3-KO) mice in this study. We crossed mice bearing floxed Atf3 alleles with Pdx1-cre mice, in which cre is specifically expressed in the pancreas and hypothalamus, and analysed metabolic variables, pancreatic morphology, food intake, energy expenditure and sympathetic activity in adipose tissue. We also used a hypothalamic cell line to investigate the molecular mechanism by which ATF3 regulates transcription of the gene encoding agouti-related protein (Agrp). Although PHT-Atf3-KO mice displayed better glucose tolerance, neither plasma glucagon nor insulin level was altered in these mice. However, these mice exhibited higher insulin sensitivity, which was accompanied by a leaner phenotype due to decreased food intake and increased energy expenditure. We also observed decreased hypothalamic Agrp expression in PHT-Atf3-KO mice. Importantly, an increase in ATF3 levels is induced by fasting or low glucose in the hypothalamus. We also showed that ATF3 interacts with forkhead box-containing protein, O subfamily 1 (FoxO1) on the Agrp promoter and activates Agrp transcription. Our results suggest that ATF3 plays an important role in the control of glucose and energy metabolism by regulating Agrp. The online version of this article (doi:10.1007/s00125-013-2879-z) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
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