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.