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

Abstract The hormone glucagon plays a crucial role in maintaining normal blood glucose levels and has recently been found to promote liver lipid catabolism in both clinical and basic research studies. However, the mechanisms by which glucagon signaling synchronizes glucose and lipid metabolism in the liver remain poorly understood. Here, we report that hepatic androgen receptor (AR) functions as a critical mediator of glucagon signaling, contributing to sexual dimorphism in hepatic glucagon sensitivity. The inhibition of AR, either through chemical or genetic means, impairs the ability of glucagon to stimulate gluconeogenesis and lipid catabolism in primary hepatocytes. Notably, female mouse hepatocytes express up to three times more AR than their male littermates. Consequently, they respond to glucagon to a much greater extent in terms of glucose production and lipid catabolism outcomes. Moreover, liver-specific AR knockout impairs the effect of glucagon in inducing blood glucose production, especially in female mice. Mechanistically, we demonstrate that hepatic AR drives a PGC1α/ERRα-mitochondria axis to promote lipid catabolism for liver glucose production in response to glucagon treatment. Together, our study sheds light on the role of hepatic AR in mediating glucagon activity in orchestrating glucose and lipid metabolism, particularly in female mice. These findings may help elucidate the factors responsible for sex differences in glucagon sensitivity and the development of fatty liver disease.