Department of Genetics and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Mol Metab. 2013 Aug 24;2(4):447-56. doi: 10.1016/j.molmet.2013.08.005. eCollection 2013.
Cytokine signaling has been connected to regulation of metabolism and energy balance. Numerous cytokine gene expression changes are stimulated by accumulation of bile acids in livers of young Foxa2 liver-conditional null mice. We hypothesized that bile acid-induced inflammation in young Foxa2 mutants, once chronic, affects metabolic homeostasis. We found that loss of Foxa2 in the liver results in a premature aging phenotype, including significant weight gain, reduced food intake, and decreased energy expenditure. We show that Foxa2 antagonizes the mammalian target of rapamycin (mTOR) pathway, resulting in increased hepatic lipogenesis and adiposity. While much prior work has focused on adipose tissue in obesity, we discovered a novel age-onset obesity phenotype in a model where gene deletion occurs only in the liver, underscoring the importance of the role hepatic lipogenesis plays in the development of obesity.
细胞因子信号与代谢和能量平衡的调节有关。在年轻的 Foxa2 肝条件性缺失小鼠肝脏中，胆汁酸的积累会刺激许多细胞因子基因表达的改变。我们假设，一旦慢性发生，胆汁酸诱导的年轻 Foxa2 突变体炎症会影响代谢稳态。我们发现，肝脏中 Foxa2 的缺失会导致早衰表型，包括体重显著增加、食物摄入减少和能量消耗减少。我们表明，Foxa2 拮抗哺乳动物雷帕霉素靶蛋白 (mTOR) 通路，导致肝内脂肪生成增加和肥胖。虽然之前的许多工作都集中在肥胖症的脂肪组织上，但我们在一种仅在肝脏中发生基因缺失的模型中发现了一种新的与年龄相关的肥胖表型，这突显了肝内脂肪生成在肥胖症发展中的重要作用。
