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
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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

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Figure 1

Association of IR with the timing of SA and circulating hormone concentrations.

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Association of IR with the timing of SA and circulating hormone concentr...
(A) Study protocol. (B) Timing of SA as assessed by participant daily self-reporting of breast fullness. *P < 0.05 compared with medium and low IR groups (χ2 test). (C–E) Milk concentrations of (C) lactose, (D) Na+, and (E) K+. (F) Milk Na+/K+ ratio. *P < 0.05, **P < 0.01 (2-way ANOVA). (G–I) Plasma concentrations of (G) leptin and (H) adiponectin and (I) leptin/adiponectin ratio (LAR). *P < 0.05, **P < 0.01, ***P < 0.001 (2-way ANOVA). All participants were stratified into low (black), medium (blue), or high IR (red) categories based on plasma LAR values. Sample sizes are shown below graphs in C–I. Day 1 samples were collected at 21 ± 1.0 hours postpartum, day 2 samples at 46 ± 1.0 hours postpartum, day 3 samples at 71 ± 1.0 hours postpartum, and day 4 samples at 96 ± 1.0 hours postpartum. No significant differences in sample collection time were observed between low, medium, and high IR groups (Kruskal-Wallis test). Red and blue asterisks represent P values for high vs. low IR group comparisons and medium vs. low IR group comparisons, respectively. D, postpartum day.