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 4

Effect of Akt knockdown on insulin-mediated differential gene expression.

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Effect of Akt knockdown on insulin-mediated differential gene expression...
(A) Capillary protein electrophoresis blot showing phosphorylated and total Akt in MCF-12A cells following 30 minutes of 0, 10, or 100 nM insulin and 100 nM insulin with Akt-targeted siRNA treatments. (B and C) Quantitative analysis of (B) total Akt shown as percentage compared with control (0 nM insulin) and (C) p-Akt normalized to total Akt and shown as a fold-change compared with control (0 nM insulin). Data shown as mean ± SEM (n = 4–6 biological replicates). ***P < 0.001 and ****P < 0.0001 compared with untreated cells. ##P < 0.01 and ###P < 0.001 in cells treated with 100 nM insulin and Akt-targeted siRNA compared with cells treated with 100 nM insulin alone (1-way ANOVA). (D) Number of DEGs at 1, 4, and 8 hours following 100 nM insulin ± Akt-targeted siRNA. (E) Interaction analysis between Akt expression and 100 nM insulin at 4 hours. Scatterplot shows the relationship between the expression of insulin-induced DEGs that are attenuated (red dots) or enhanced (blue dots) by Akt knockdown. X axis shows log2 expression fold-change from 100 nM insulin alone, and the y axis shows the log2 expression fold-change from 100 nM insulin + Akt-targeted siRNA. (F) Top enriched biological processes following 100 nM insulin ± Akt-targeted siRNA treatment. Circle size represents number of genes involved per process. Processes no longer enriched after Akt knockdown are shown in red.