Transcription profiling by array of livers from Foxa2 -/- knockout mice and wild-type mice to study bile acid-induced cytokine inflammatory signaling in response to the lack of Foxa2

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 genetic deletion occurs only in the liver, underscoring the importance of the role hepatic lipogenesis plays in the development of obesity.细胞因子信号通路（Cytokine signaling）与代谢及能量平衡的调控密切相关。年轻Foxa2肝脏条件性敲除小鼠（Foxa2 liver-conditional null mice）的肝脏内胆汁酸（bile acids）蓄积可诱导大量细胞因子基因表达发生改变。本研究推测，年轻Foxa2突变体中由胆汁酸诱导的炎症若发展为慢性状态，会影响代谢稳态。研究发现，肝脏中Foxa2的缺失会引发早衰表型，包括显著体重增加、食物摄入减少以及能量消耗降低。本研究证实，Foxa2可拮抗哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin, mTOR）通路，进而导致肝脏脂肪生成增加及体脂堆积。尽管此前多数研究均聚焦于肥胖中的脂肪组织，本研究在仅肝脏存在基因敲除的模型中发现了一种全新的年龄相关性肥胖表型，这突显了肝脏脂肪生成在肥胖发生发展中的关键作用。