PDF(Pubmed)
Abstract：
High fructose intake during pregnancy increases insulin resistance (IR) and gestational diabetes mellitus (GDM) risk. IR during pregnancy primarily results from elevated hormone levels. We aim to determine the role of liver carbohydrate response element binding protein (ChREBP) in insulin sensitivity and lipid metabolism in pregnant mice and their offspring. Pregnant C57BL/6J wild-type mice and hepatocyte-specific ChREBP-deficient mice were fed with a high-fructose diet (HFrD) or normal chow diet (NC) pre-delivery. We found that the combination of HFrD with pregnancy excessively activates hepatic ChREBP, stimulating progesterone synthesis by increasing MTTP expression, which exacerbates IR. Increased progesterone levels upregulated hepatic ChREBP via the progesterone-PPARγ axis. Placental progesterone activated the progesterone-ChREBP loop in female offspring, contributing to IR and lipid accumulation. In normal dietary conditions, hepatic ChREBP modestly affected progesterone production and influenced IR during pregnancy. Our findings reveal the role of hepatic ChREBP in regulating insulin sensitivity and lipid homeostasis in both pregnant mice consuming an HFrD and female offspring, and suggest it as a potential target for managing gestational metabolic disorders, including GDM.
摘要：
妊娠期高果糖摄入会增加胰岛素抵抗（IR）和妊娠期糖尿病（GDM）的风险。怀孕期间的IR主要由激素水平升高引起。我们旨在确定肝脏碳水化合物反应元件结合蛋白（ChREBP）在妊娠小鼠及其后代的胰岛素敏感性和脂质代谢中的作用。怀孕的C57BL/6J野生型小鼠和肝细胞特异性ChREBP缺陷型小鼠在分娩前饲喂高果糖饮食（HFrD）或正常饮食（NC）。我们发现HFrD与妊娠的组合过度激活肝ChREBP，通过增加MTTP表达刺激孕酮合成，这加剧了IR。孕酮水平升高通过孕酮-PPARγ轴上调肝脏ChREBP。胎盘孕酮激活了雌性后代的孕酮-ChREBP环，有助于IR和脂质积累。在正常饮食条件下，肝ChREBP适度影响孕酮的产生并影响妊娠期的IR。我们的发现揭示了肝ChREBP在调节消耗HFrD的妊娠小鼠和雌性后代的胰岛素敏感性和脂质稳态中的作用。并建议将其作为管理妊娠期代谢紊乱的潜在目标，包括GDM。
