CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms
CREBH Improves Diet-Induced Obesity, Insulin Resistance, and Metabolic Disturbances by FGF21-Dependent and FGF21-Independent Mechanisms
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DOI：
10.1016/j.isci.2020.100930
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发表时间：
2020-03-27
期刊：
影响因子：
5.8
通讯作者：
Shimano, Hitoshi
中科院分区：
文献类型：
--
作者：
Satoh, Aoi;Han, Song-iee;Shimano, Hitoshi
主要在肝脏中过度表达核型CREBH的小鼠(CREBH-TG)显示，高脂高蔗糖(HFHS)饮食诱导的肥胖受到抑制，同时血浆成纤维细胞生长因子21(FGF21)水平增加。CREBH过表达诱导腹股沟白色脂肪组织(WAT)的褐化和全身能量消耗，这在FGF21(-/-)小鼠中被取消。CREBH-TG小鼠体内FGF21的缺失主要抵消了肥胖的改善，但对表皮Wat炎症的抑制、胰岛素抵抗的改善和糖代谢的改善仍在持续。Kissspeptin 1(Kiss1)被确定为CREBH的一个新的激素靶点，以解释CREBH的这些FGF21非依赖性作用。在HFHS喂养的CREBH-TG FGF21(-/-)小鼠中，Kiss1基因的敲除显示部分取消了糖代谢的改善。综上所述，我们认为，肝脏CREBH通过改善FGF21依赖和FGF21非依赖机制中的全身能量代谢，多向性地改善饮食诱导的肥胖介导的外周组织功能障碍。
Mice overexpressing the nuclear form of CREBH mainly in the liver (CREBH-Tg) showed suppression of high-fat high-sucrose (HFHS) diet-induced obesity accompanied by an increase in plasma fibroblast growth factor 21 (FGF21) levels. CREBH overexpression induced browning in inguinal white adipose tissue (WAT) and whole-body energy expenditure, which was canceled in Fgf21(-/-) mice. Deficiency of FGF21 in CREBH-Tg mice mostly canceled the improvement of obesity, but the suppression of inflammation of epidermal WAT, amelioration of insulin resistance, and improvement of glucose metabolism still sustained. Kisspeptin 1 (Kiss1) was identified as a novel hormone target for CREBH to explain these FGF21-independent effects of CREBH. Knockdown of Kiss1 in HFHS-fed CREBH-Tg Fgf21(-/-) mice showed partially canceled improvement of glucose metabolism. Taken together, we propose that hepatic CREBH pleiotropically improves diet-induced obesity-mediated dysfunctions in peripheral tissues by improving systemic energy metabolism in FGF21-dependent and FGF21-independent mechanisms.