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 6

Effect of insulin on mitochondrial volume and morphology in cultured mammary cells.

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Effect of insulin on mitochondrial volume and morphology in cultured mam...
(A) Protocol for mitochondrial volume and morphology analysis in HC11 cells. (B) Representative images of mitochondria in cells treated with insulin (0, 10, 100, or 1,000 nM) for 24 hours, shown as maximum z projections. Scale bar = 10 μm. (C–F) Quantitative analysis of mitochondrial parameters: (C) volume, (D) length, (E) number of branches, and (F) sphericity in insulin-treated cells. On average, 7,000–10,000 mitochondria were analyzed per image from each condition (n = 5–10 images per condition). Data in C–F are shown as mean ± SEM (n = 7–10 biological replicates). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 (1-way ANOVA).