Non-canonical hepatic androgen receptor mediates glucagon sensitivity in female mice through the PGC1α/ERRα/mitochondria axis. Non-canonical hepatic androgen receptor mediates glucagon sensitivity in female mice through the PGC1α/ERRα/mitochondria axis

Glucagon has recently been found to modulate liver fat content, in addition to its role in regulating gluconeogenesis. However, the precise mechanisms by which glucagon signaling synchronizes glucose and lipid metabolism in the liver remain poorly understood. By employing chemical and genetic approaches, we demonstrate that inhibiting the androgen receptor (AR) impairs the ability of glucagon to stimulate gluconeogenesis and lipid catabolism in primary hepatocytes and female mice. Notably, AR expression in the liver of female mice is up to three times higher than that in their male littermates, accounting for the more pronounced response to glucagon in females. Mechanistically, hepatic AR promotes energy metabolism and enhances lipid breakdown for liver glucose production in response to glucagon treatment through the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α)/estrogen-related receptor alpha (ERRα)-mitochondria axis. Overall, our findings highlight the crucial role of hepatic AR in mediating glucagon signaling and the sexual dimorphism in hepatic glucagon sensitivity. Overall design: mRNA profile of mouse primary hepatocytes treated with shScr±glucagon/shAr±glucagon

近年研究发现，胰高血糖素（Glucagon）除调控糖异生（gluconeogenesis）的经典功能外，还可调节肝脏脂肪含量。然而，胰高血糖素信号通路如何协调肝脏内糖代谢与脂代谢的具体分子机制仍不甚明确。本研究通过化学与遗传学手段证实，抑制雄激素受体（AR）可削弱胰高血糖素在原代肝细胞及雌性小鼠体内促进糖异生与脂解的能力。值得注意的是，雌性小鼠肝脏中AR的表达量最高可达雄性同窝仔鼠的三倍，这解释了雌性个体对胰高血糖素的响应更为显著的现象。从机制层面来看，肝脏AR可通过过氧化物酶体增殖物激活受体γ辅激活因子1α（PGC1α）/雌激素相关受体α（ERRα）-线粒体轴，在胰高血糖素刺激下促进能量代谢并增强脂解以支撑肝脏葡萄糖生成。综上，本研究结果凸显了肝脏AR在介导胰高血糖素信号通路及肝脏胰高血糖素敏感性性别二态性中的核心作用。总体实验设计：对经阴性对照短发夹RNA（shScr）±胰高血糖素、靶向AR的短发夹RNA（shAr）±胰高血糖素处理的小鼠原代肝细胞开展mRNA转录组分析。