Insulin resistance is associated with mammary mitochondrial dysfunction at the onset of human lactation
Xin Meng, Taha Elajnaf, Hussam Rostom, Michelle Ma, Annalee Furst, Bryony R. Davies, Isabella R. Honess, Gaurav Pandey, Isadora C. Furigo, Craig L. Doig, Jayne F. Martin Carli, Rajesh V. Thakker, Lars Bode, Kelsey E. Johnson, Fadil M. Hannan
Xin Meng, Taha Elajnaf, Hussam Rostom, Michelle Ma, Annalee Furst, Bryony R. Davies, Isabella R. Honess, Gaurav Pandey, Isadora C. Furigo, Craig L. Doig, Jayne F. Martin Carli, Rajesh V. Thakker, Lars Bode, Kelsey E. Johnson, Fadil M. Hannan
View: Text | PDF
Research Article Endocrinology Metabolism Reproductive biology

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

Abstract

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 more than 200 mammary mitochondrial genes. These alterations were absent on postpartum days 3–5. Cultured mammary epithelial cells 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.

Authors

Xin Meng, Taha Elajnaf, Hussam Rostom, Michelle Ma, Annalee Furst, Bryony R. Davies, Isabella R. Honess, Gaurav Pandey, Isadora C. Furigo, Craig L. Doig, Jayne F. Martin Carli, Rajesh V. Thakker, Lars Bode, Kelsey E. Johnson, Fadil M. Hannan

×

Figure 2

Association of IR with the MFG transcriptome during SA.

Options: View larger image (or click on image) Download as PowerPoint
Association of IR with the MFG transcriptome during SA. (A) MFG RNA-seq ...
(A) MFG RNA-seq protocol. TG, triglyceride; MEC, mammary epithelial cell. (B) Number of differentially expressed genes (DEGs) from high vs. low and medium vs. low IR groups on postpartum days 2–5. Day 2 samples were collected at 45 ± 1.5 hours postpartum, day 3 samples at 72 ± 1.3 hours postpartum, day 4 samples at 96 ± 1.2 hours postpartum, and day 5 samples at 120 ± 1.4 hours postpartum. No significant differences in sample collection time were observed between low, medium, and high IR groups (Kruskal-Wallis test). (C) Volcano plot showing upregulated (red) and downregulated (blue) genes from high vs. low IR groups on postpartum day 2. Horizontal and vertical dashed lines indicate meta-q = 0.05 and log2 expression fold-change = 0.5, respectively. (D) GSEA showing top upregulated (red) and downregulated (blue) processes from high vs. low IR groups on postpartum day 2. Circle size represents number of genes. Circle color represents FDR-adjusted P value (meta-q) obtained from fast GSEA (FGSEA) and single-sample GSEA (ssGSEA). (E) Inflammatory gene network upregulated in the high IR group on postpartum day 2. Network comprises nodes representing genes and edges representing functional gene interactions. Node size corresponds to number of connections to other nodes. (F and G) Serum C-reactive protein (CRP) measured at (F) 36 weeks’ gestation and (G) postpartum day 2 in low, medium, and high IR groups. *P < 0.05 (1-way ANOVA). (H) Schematic of lactating MEC showing processes altered in the high IR group on postpartum day 2. Upregulated (red) and downregulated (blue) genes and proteins are shown. Unaltered genes and proteins are shown in white. (I) Mitochondrial processes altered in the high IR group on postpartum day 2. Numbers of upregulated and downregulated genes are shown in red and blue, respectively.