Disruption of the circadian clock component BMAL1 elicits an endocrine adaption impacting on insulin sensitivity and liver disease.
Disruption of the circadian clock component BMAL1 elicits an endocrine adaption impacting on insulin sensitivity and liver disease.
复制标题
DOI：
10.1073/pnas.2200083119
复制
发表时间：
2022-03-08
影响因子：
11.1
通讯作者：
Gachon F
中科院分区：
文献类型：
--
作者：
Jouffe C;Weger BD;Martin E;Atger F;Weger M;Gobet C;Ramnath D;Charpagne A;Morin-Rivron D;Powell EE;Sweet MJ;Masoodi M;Uhlenhaut NH;Gachon F
虽然越来越多的证据表明昼夜节律的破坏与病理状况有关，包括肥胖、2型糖尿病和非酒精性脂肪性肝病（NAFLD），但涉及的机制仍然缺乏描述。在这里，我们表明，在人类和小鼠中，NAFLD的发病机制与生物钟的破坏以及生长激素和性激素途径的扰动有关。然而，虽然这种情况可以保护小鼠免受纤维化和胰岛素抵抗的发展，但它与人类纤维化的增加有关。这表明，生物钟的扰动及其相关的生长激素和性激素通路的破坏对代谢和肝脏疾病的发病机制至关重要。肥胖和肝脏疾病与协调哺乳动物生理以优化营养代谢和储存的生物钟的破坏有关。在这里，我们发现昼夜节律时钟调节器脑和肌肉芳烃受体核易位样1 （BMAL1）的活性在人类肝纤维化期间受到干扰。为了了解BMAL1扰动对肥胖和肝脏疾病的影响，我们评估了高脂肪饮食或瘦素缺乏对BMAL1基因敲除小鼠的影响。虽然Bmal1基因敲除小鼠容易肥胖，但它们可以防止胰岛素抵抗、肝脂肪变性、炎症和纤维化。此外，为了指导BMAL1对代谢程序的转录调节，我们发现生长激素和性激素通路的破坏在这种保护中起着关键作用。类似的内分泌干扰与人类肝纤维化的发展相关，但在肝细胞特异性Bmal1敲除小鼠中不存在。这表明，与BMAL1活性的整体破坏相关的全身内分泌扰动对代谢性和肝脏疾病的发病机制至关重要。
While increasing evidence associates the disruption of circadian rhythms with pathologic conditions, including obesity, type 2 diabetes, and nonalcoholic fatty liver diseases (NAFLD), the involved mechanisms are still poorly described. Here, we show that, in both humans and mice, the pathogenesis of NAFLD is associated with the disruption of the circadian clock combined with perturbations of the growth hormone and sex hormone pathways. However, while this condition protects mice from the development of fibrosis and insulin resistance, it correlates with increased fibrosis in humans. This suggests that the perturbation of the circadian clock and its associated disruption of the growth hormone and sex hormone pathways are critical for the pathogenesis of metabolic and liver diseases. Obesity and liver diseases are associated with the disruption of the circadian clock that orchestrates mammalian physiology to optimize nutrient metabolism and storage. Here, we show that the activity of the circadian clock regulator Brain and Muscle Aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1) is perturbed during liver fibrosis in humans. To understand the impact of BMAL1 perturbation in obesity and liver diseases, we assessed the impact of a high fat diet or leptin deficiency on Bmal1 knockout mice. While Bmal1 knockout mice were prone to obesity, they were protected against insulin resistance, hepatic steatosis, inflammation, and fibrosis. In addition, to direct the transcriptional regulation of metabolic programs by BMAL1, we show that the disruption of the growth hormone and sex hormone pathways plays a critical role in this protection. Similar endocrine perturbations correlate with the development of liver fibrosis in humans but were absent in hepatocyte-specific Bmal1 knockout mice. This suggests that systemic endocrine perturbation associated with the global disruption of BMAL1 activity is critical for the pathogenesis of metabolic and liver diseases.
登录
查看更多内容
影响因子：
4
作者：
Chakrabarti A;Membrez M;Morin-Rivron D;Siddharth J;Chou CJ;Henry H;Bruce S;Metairon S;Raymond F;Betrisey B;Loyer C;Parkinson SJ;Masoodi M
通讯作者：
Masoodi M
影响因子：
8.1
作者：
Dyar KA;Ciciliot S;Wright LE;Biensø RS;Tagliazucchi GM;Patel VR;Forcato M;Paz MI;Gudiksen A;Solagna F;Albiero M;Moretti I;Eckel-Mahan KL;Baldi P;Sassone-Corsi P;Rizzuto R;Bicciato S;Pilegaard H;Blaauw B;Schiaffino S
通讯作者：
Schiaffino S
雌激素可保护雄性小鼠免受肥胖并发症的影响，并影响糖皮质激素代谢。
DOI：
10.1038/ijo.2015.102
发表时间：
2015-10
期刊：
International journal of obesity (2005)
影响因子：
--
作者：
Dakin RS;Walker BR;Seckl JR;Hadoke PW;Drake AJ
通讯作者：
Drake AJ
影响因子：
4.8
作者：
Coschigano, KT;Holland, AN;Kopchick, JJ
通讯作者：
Kopchick, JJ
影响因子：
2.7
作者：
Benjamini, Yoav;Krieger, Abba M.;Yekutieli, Daniel
通讯作者：
Yekutieli, Daniel