Role of metformin in epigenetic regulation of placental mitochondrial biogenesis in maternal diabetes

Adverse maternal environments, such as diabetes and obesity, impair placental mitochondrial function, which affects fetal development and offspring long-term health. The underlying mechanisms and effective interventions to abrogate such effect remain unclear. Our previous studies demonstrated impaired mitochondrial biogenesis in male human placenta of diabetic mothers. In the present studies, epigenetic marks possibly related to mitochondrial biogenesis in placentae of women with diabetes (n = 23) and controls (n = 23) were analyzed. Effects of metformin were examined in human placental explants from a subgroup of diabetic women and in a mouse model of maternal high fat diet feeding. We found that maternal diabetes was associated with epigenetic regulation of mitochondrial biogenesis in human placenta in a fetal sex-dependent manner, including decreased histone acetylation (H3K27 acetylation) and increased promoter methylation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). In male placenta, the levels of H3K27 acetylation and PGC-1α promoter methylation correlated significantly with the activity of AMP-activated protein kinase (AMPK). Metformin treatment on male diabetic placental explant activated AMPK and stimulated PGC-1α expression, concomitant with increased H3K27 acetylation and decreased PGC-1α promoter methylation. In vivo, we show that maternal metformin treatment along with maternal high fat diet significantly increased mouse placental abundance of PGC-1α expression and downstream mitochondrial transcription factor A (TFAM) and inhibited maternal high fat diet-impaired placental efficiency and glucose tolerance in offspring. Together, these findings suggest the capability of metformin to stimulate placental mitochondrial biogenesis and inhibit the aberrant epigenetic alterations occurring in maternal diabetes during pregnancy, conferring protective effects on offspring.