Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes
Hepatic CREB3L3 Controls Whole-Body Energy Homeostasis and Improves Obesity and Diabetes
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DOI：
10.1210/en.2014-1113
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发表时间：
2014-12-01
期刊：
影响因子：
4.8
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Nakagawa, Yoshimi;Satoh, Aoi;Shimano, Hitoshi
肝脏代谢基因的转录调控是饥饿期间维持全身能量稳态的关键。据报道，膜结合转录因子cAMP-responsive element-binding protein 3-like 3 （CREB3L3）在禁食期间被激活并调节甘油三酯代谢。在这里，我们发现CREB3L3在体内对饥饿有广泛的代谢反应。腺病毒和转基因核CREB3L3的过表达诱导全身脂解、肝脏生酮和胰岛素敏感性随着能量消耗的增加，导致体重、血脂水平和血糖水平显著降低。CREB3L3过表达激活基因表达水平和血浆抗糖尿病激素水平，包括成纤维细胞生长因子21和igf结合蛋白2。在几种类型的糖尿病肥胖小鼠中也观察到通过肝脏激活CREB3L3来改善糖尿病。细胞核CREB3L3以自动循环的方式相互激活过氧化物酶体增殖体激活受体(PPAR) α启动子，并且通过与其转录调节因子，过氧化物酶体增殖体激活受体γ辅激活因子-1 α相互作用，对PPAR α的配体转激活至关重要。CREB3L3直接或间接控制成纤维细胞生长因子21的表达及其血浆水平，这至少部分地促进了CREB3L3对全身全身能量稳态的分解代谢作用。因此，CREB3L3是肥胖和糖尿病的治疗靶点。
Transcriptional regulation of metabolic genes in the liver is the key to maintaining systemic energy homeostasis during starvation. The membrane-bound transcription factor cAMP-responsive element-binding protein 3-like 3 (CREB3L3) has been reported to be activated during fasting and to regulate triglyceride metabolism. Here, we show that CREB3L3 confers a wide spectrum of metabolic responses to starvation in vivo. Adenoviral and transgenic overexpression of nuclear CREB3L3 induced systemic lipolysis, hepatic ketogenesis, and insulin sensitivity with increased energy expenditure, leading to marked reduction in body weight, plasma lipid levels, and glucose levels. CREB3L3 overexpression activated gene expression levels and plasma levels of antidiabetic hormones, including fibroblast growth factor 21 and IGF-binding protein 2. Amelioration of diabetes by hepatic activation of CREB3L3 was also observed in several types of diabetic obese mice. Nuclear CREB3L3 mutually activates the peroxisome proliferator-activated receptor(PPAR) alpha promoter in an autoloop fashion and is crucial for the ligand transactivation of PPAR alpha by interacting with its transcriptional regulator, peroxisome proliferator-activated receptor gamma coactivator-1 alpha. CREB3L3 directly and indirectly controls fibroblast growth factor 21 expression and its plasma level, which contributes at least partially to the catabolic effects of CREB3L3 on systemic energy homeostasis in the entire body. Therefore, CREB3L3 is a therapeutic target for obesity and diabetes.