Insulin resistance is associated with mammary mitochondrial dysfunction at the onset of human lactation

Insulin resistance (IR) has emerged as a risk factor for lactation insufficiency and delays the onset of milk secretion after childbirth, termed secretory activation (SA). This may cause inadequate infant weight gain and early breastfeeding cessation. However, the mechanisms underlying delayed SA in insulin resistant women are unknown. To investigate this, we characterized the mammary transcriptomes and IR-related hormones of 75 breastfeeding women with healthy term infants during postpartum days 1-5. Participants were divided into IR tertiles based on plasma leptin-to-adiponectin ratio measurements. Those in the highest tertile had later SA onset with greater neonatal weight loss during postpartum days 1-5. Transcriptomic analysis on postpartum day 2 (n=4 high IR vs. n=8 low IR participants) showed transient suppression of mammary insulin and prolactin signaling genes, increased pro-inflammatory gene expression and altered expression of >200 mammary mitochondrial genes. These alterations were absent on postpartum days 3-5. Cultured mammary epithelial cells (MECs) treated with insulin showed upregulation of prolactin signaling and oxidative phosphorylation (OXPHOS) genes, with imaging and bioenergetic studies demonstrating that insulin promotes mitochondrial biogenesis and OXPHOS. Thus, our findings delineate roles for insulin in mammary bioenergetics and highlight mitochondrial dysfunction as a mechanism for delayed SA in insulin resistant women.