Androgen-PDH axis modulates sexual dimorphism of mitochondrial respiration in visceral fat

Sex-dimorphic adipose mitochondrial function (lower activity in males) correlates with visceral adiposity and metabolic risk, yet the underlying mechanisms remain elusive. We find that androgen–androgen receptor (AR) signaling suppresses mitochondrial respiration and thermogenesis in visceral adipose tissue (VAT), promoting visceral fat accumulation. Mechanistically, androgen–AR signaling represses transcription of Pdhb, which encodes a pyruvate dehydrogenase (PDH) subunit, thereby reducing PDH activity, acetyl-CoA levels, H3K27 acetylation, and chromatin accessibility at the promoters of mitochondrial respiration-related genes. Notably, Pdhb overexpression largely reverses these alterations and restores mitochondrial function. Furthermore, sodium dichloroacetate, a PDH activator, enhances mitochondrial respiration and reduces visceral fat in male mice. Multi-omics analyses reveal that the androgen–PDH axis orchestrates a male-specific chromatin-based transcriptional landscape that encompasses mitochondrial and metabolic pathways in visceral adipocytes. Collectively, this study identifies the androgen–PDH axis as a key regulator of sexual dimorphism in mitochondrial metabolism and adipose homeostasis in VAT.