Loss of CREB Coactivator CRTC1 in SF1 Cells Leads to Hyperphagia and Obesity by High-fat Diet But Not Normal Chow Diet
Loss of CREB Coactivator CRTC1 in SF1 Cells Leads to Hyperphagia and Obesity by High-fat Diet But Not Normal Chow Diet
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DOI：
10.1210/endocr/bqab076
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发表时间：
2021-04-12
期刊：
影响因子：
4.8
通讯作者：
Inoue, Kazuo
中科院分区：
文献类型：
--
作者：
Matsumura, Shigenobu;Ishikawa, Fuka;Inoue, Kazuo
环磷酸腺苷反应元件结合蛋白-1调节转录共激活因子-1（CRTC 1）是一种细胞质共激活因子，可响应环磷酸腺苷转移至细胞核。Crtc 1的全身敲除导致肥胖，导致食物摄入增加和能量消耗减少。CRTC 1在大脑中高度表达，因此，它可能通过神经元途径在能量代谢中发挥重要作用。然而，CRTC 1调节能量代谢的确切机制仍然未知。在这里，我们发现缺乏CRTC 1的小鼠，特别是在类固醇生成因子-1表达细胞（SF 1细胞）中，对高脂饮食（HFD）诱导的肥胖敏感，表现出摄食过多和体重增加。SF 1细胞中CRTC 1的缺失损害了糖代谢。与全身CRTC 1敲除小鼠不同，SF 1细胞特异性CRTC 1缺失不影响正常食物喂养中的体重增加或食物摄入。因此，SF 1细胞中的CRTC 1是HFD喂养小鼠正常食欲调节所必需的。CRTC 1主要在大脑中表达。下丘脑对食欲调节起着重要作用，而SF 1细胞仅存在于下丘脑腹内侧。对显微切割的下丘脑腹内侧样本进行RNA测序分析，结果显示CRTC 1的缺失显著改变了某些基因的表达水平。我们的研究结果揭示了CRTC 1在SF 1细胞中对膳食代谢失衡的重要保护作用。
Cyclic adenosine monophosphate responsive element-binding protein-1-regulated transcription coactivator-1 (CRTC1) is a cytoplasmic coactivator that translocates to the nucleus in response to cyclic adenosine monophosphate. Whole-body knockdown of Crtc1 causes obesity, resulting in increased food intake and reduced energy expenditure. CRTC1 is highly expressed in the brain; therefore, it might play an important role in energy metabolism via the neuronal pathway. However, the precise mechanism by which CRTC1 regulates energy metabolism remains unknown. Here, we showed that mice lacking CRTC1, specifically in steroidogenic factor-1 expressing cells (SF1 cells), were sensitive to high-fat diet (HFD)-induced obesity, exhibiting hyperphagia and increased body weight gain. The loss of CRTC1 in SF1 cells impaired glucose metabolism. Unlike whole-body CRTC1 knockout mice, SF1 cell-specific CRTC1 deletion did not affect body weight gain or food intake in normal chow feeding. Thus, CRTC1 in SF1 cells is required for normal appetite regulation in HFD-fed mice. CRTC1 is primarily expressed in the brain. Within the hypothalamus, which plays an important role for appetite regulation, SF1 cells are only found in ventromedial hypothalamus. RNA sequencing analysis of microdissected ventromedial hypothalamus samples revealed that the loss of CRTC1 significantly changed the expression levels of certain genes. Our results revealed the important protective role of CRTC1 in SF1 cells against dietary metabolic imbalance.