Endocrine Abstracts

Physiological onset of lactation occurs 24-72 hours after childbirth and is characterised by increased mammary cell metabolism to support milk synthesis. Obesity is associated with delayed lactation onset and causes mitochondrial dysfunction in metabolically active tissues. We hypothesised that obesity may impair lactation through adverse effects on mammary mitochondria. To investigate this, we recruited n = 27 obese pregnant women (mean BMI=34±0.7 kg/m²) intending to breastfeed, following informed consent, and compared them to n = 87 matched controls (BMI<25 kg/m²) during postpartum days 1-5. First, we assessed the timing of lactation onset, through participant self-reporting of milk coming in, and found that obese mothers had delayed lactation onset compared to controls (3.4±0.1 vs 2.8±0.1 days postpartum, P < 0.001). We assessed if this is associated with altered mammary metabolic gene expression. RNA sequencing was performed on mammary cell RNA isolated from postpartum day 1-5 milk samples (n = 11 obese mothers and n = 62 controls). Gene expression analysis revealed significant downregulation (>0.8-fold decrease in obese vs control, P < 0.05) of mammary genes encoding mitochondrial complex I (NDUFA2, NDUFA12), complex III (UQCRC2), complex IV (COX1, COX3), ATP synthase (ATP6, ATP8), and mitochondrial translation initiation and transcription factors (MTIF3, TFB1M), consistent with mammary mitochondrial dysfunction. We then investigated if this was caused by insulin resistance, which is reported to induce mitochondrial dysfunction in tissues such as skeletal muscle. We assessed the plasma leptin/adiponectin ratio (LAR), a non-fasting insulin resistance measure, and compared the transcriptome of n = 22 insulin-resistant (LAR>3) with n = 38 control (LAR<1) mothers. This showed an inflammatory mammary phenotype in insulin-resistant mothers with increased expression of pro-inflammatory cytokine receptors e.g. IL6R (1.7-fold increase, P < 0.05) and enrichment of inflammatory processes. However, mitochondrial gene expression was not altered in insulin-resistant mothers. Thus, our findings indicate that obesity may cause mammary mitochondrial dysfunction and delayed lactation onset by insulin-resistance independent mechanisms.