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The non-canonical hepatic androgen receptor regulates glucagon sensitivity in female mice by operating a PGC-1α/ERRα/mitochondria axis

ABSTRACT: The hormone glucagon plays a crucial role in maintaining normal blood glucose levels and recently has also been found with synergistic effects on liver lipid catabolism in both clinic and basic research studies. However, the mechanisms by which glucagon signaling synchronizes glucose and lipid metabolism in the liver are not yet fully 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 glucagon stimulation of gluconeogenesis and lipid catabolism in hepatocytes. Notably, female mouse hepatocytes express up to four times more AR than their male littermates, and consistently respond to glucagon to a much greater extent in producing glucose and catabolizing lipid. Moreover, liver-specific AR knockout impairs glucagon induction of blood glucose and increases liver fat deposit, 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. Overall, our findings shed light on the role of hepatic AR in mediating glucagon signaling to orchestrate glucose and lipid metabolism, particularly in female mice, which may help elucidate the factors responsible for sex differences in glucagon sensitivity and the development of fatty liver diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE236551 | GEO | 2025/01/01

REPOSITORIES: GEO

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