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Short Term Changes in Dietary Fat Content and Metformin Treatment During Lactation Impact Milk Composition and Mammary Gland Morphology

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Abstract

Maternal health and diet can have important consequences for offspring nutrition and metabolic health. During lactation, signals are communicated from the mother to the infant through milk via macronutrients, hormones, and bioactive molecules. In this study we designed experiments to probe the mother-milk-infant triad in the condition of normal maternal health and upon exposure to high fat diet (HFD) with or without concurrent metformin exposure. We examined maternal characteristics, milk composition and offspring metabolic parameters on postnatal day 16, prior to offspring weaning. We found that lactational HFD increased maternal adipose tissue weight, mammary gland adipocyte size, and altered milk lipid composition causing a higher amount of omega-6 (n6) long chain fatty acids and lower omega-3 (n3). Offspring of HFD dams were heavier with more body fat during suckling. Metformin (Met) exposure decreased maternal blood glucose and several milk amino acids. Offspring of met dams were smaller during suckling. Gene expression in the lactating mammary glands was impacted to a greater extent by metformin than HFD, but both metformin and HFD altered genes related to muscle contraction, indicating that these genes may be more susceptible to lactational stressors. Our study demonstrates the impact of common maternal exposures during lactation on milk composition, mammary gland function and offspring growth with metformin having little capacity to rescue the offspring from the effects of a maternal HFD during lactation.

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RNA seq data is available and has been linked to this manuscript.

Change history

  • 31 October 2023

    Updated the name tagging of the 3rd author as follows given name is "Noura" and last name is "El Habbal".

References

  1. Bartol FF, Wiley AA, Bagnell CA. Epigenetic programming of porcine endometrial function and the lactocrine hypothesis. Reprod Domest Anim. 2008;43(Suppl 2):273–9. https://doi.org/10.1111/j.1439-0531.2008.01174.x.

    Article  PubMed  Google Scholar 

  2. Bode L, et al. Understanding the mother-breastmilk-infant “triad.” Science. 2020;367(6482):1070–2. https://doi.org/10.1126/science.aaw6147.

    Article  CAS  PubMed  Google Scholar 

  3. Ellsworth L, et al. Lactational programming of glucose homeostasis: a window of opportunity. Reproduction. 2018;156(2):R23–42. https://doi.org/10.1530/REP-17-0780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Hafner H, et al. Lactational High-Fat Diet Exposure Programs Metabolic Inflammation and Bone Marrow Adiposity in Male Offspring. Nutrients. 2019;11(6). https://doi.org/10.3390/nu11061393.

  5. Liang X, et al. Maternal high-fat diet during lactation impairs thermogenic function of brown adipose tissue in offspring mice. Sci Rep. 2016;6:34345. https://doi.org/10.1038/srep34345.

  6. Masuyama H, Hiramatsu Y. Additive effects of maternal high fat diet during lactation on mouse offspring. PLoS ONE. 2014;9(3): e92805. https://doi.org/10.1371/journal.pone.0092805.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Carlson Z, et al. Lactational metformin exposure programs offspring white adipose tissue glucose homeostasis and resilience to metabolic stress in a sex-dependent manner. Am J Physiol Endocrinol Metab. 2020;318(5):E600–12. https://doi.org/10.1152/ajpendo.00473.2019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Dos Santos CO, et al. An epigenetic memory of pregnancy in the mouse mammary gland. Cell Rep. 2015;11(7):1102–9. https://doi.org/10.1016/j.celre2015.04.015.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ellsworth L, et al. Impact of maternal overweight and obesity on milk composition and infant growth. Matern Child Nutr. 2020;16(3): e12979. https://doi.org/10.1111/mcn.12979.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Kuhn NJ, Lowenstein JM. Lactogenesis in the rat. Changes in metabolic parameters at parturition. Biochem J. 1967;105(3):995–1002. https://doi.org/10.1042/bj1050995.

  11. Arthur G, Smith M, Hartmann E. Milk lactose, citrate, and glucose as markers of lactogenesis in normal and diabetic women. J Pediatr Gastroenterol Nutr. 1989;9(4):488–96. https://doi.org/10.1097/00005176-198911000-00016.

    Article  CAS  PubMed  Google Scholar 

  12. Harvey I, et al. Glucocorticoid-Induced Metabolic Disturbances Are Exacerbated in Obese Male Mice. Endocrinology. 2018;159(6):2275–87. https://doi.org/10.1210/en.2018-00147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Parlee SD, et al. Quantifying size and number of adipocytes in adipose tissue. Methods Enzymol. 2014;537:93–122. https://doi.org/10.1016/B978-0-12-411619-1.00006-9.

  14. Patro R, et al. Salmon provides fast and bias-aware quantification of transcript expression. Nat Methods. 2017;14(4):417–9. https://doi.org/10.1038/nmeth.4197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Love MI, et al. Tximeta: Reference sequence checksums for provenance identification in RNA-seq. PLoS Comput Biol. 2020;16(2): e1007664. https://doi.org/10.1371/journal.pcbi.1007664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Soneson C, Love MI, Robinson MD. Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Res. 2015;4:1521. https://doi.org/10.12688/f1000research.7563.2.

  17. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550. https://doi.org/10.1186/s13059-014-0550-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Subramanian A, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50. https://doi.org/10.1073/pnas.0506580102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Mootha VK, et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 2003;34(3):267–73. https://doi.org/10.1038/ng1180.

    Article  CAS  PubMed  Google Scholar 

  20. R: The R Project for Statistical Computing. Available from: www.r-project.org.

  21. Newburg DS, Woo JG, Morrow AL. Characteristics and potential functions of human milk adiponectin. J Pediatr. 2010;156(2 Suppl):S41–6. https://doi.org/10.1016/j.jpeds.2009.11.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yamauchi T, et al. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med. 2001;7(8):941–6. https://doi.org/10.1038/90984.

    Article  CAS  PubMed  Google Scholar 

  23. Hernandez LL, et al. High fat diet alters lactation outcomes: possible involvement of inflammatory and serotonergic pathways. PLoS ONE. 2012;7(3): e32598. https://doi.org/10.1371/journal.pone.0032598.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Silverman J, Stone DW, Powers JD. The lipid composition of milk from mice fed high or low fat diets. Lab Anim. 1992;26(2):127–31. https://doi.org/10.1258/002367792780745832.

    Article  CAS  PubMed  Google Scholar 

  25. Monks J, et al. Maternal obesity during lactation may protect offspring from high fat diet-induced metabolic dysfunction. Nutr Diabetes. 2018;8(1):18. https://doi.org/10.1038/s41387-018-0027-z.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ramos P, Martin-Hidalgo A, Herrera E. Insulin-induced up-regulation of lipoprotein lipase messenger ribonucleic acid and activity in mammary gland. Endocrinology. 1999;140(3):1089–93. https://doi.org/10.1210/endo.140.3.6565.

  27. Patterson E, et al. Health implications of high dietary omega-6 polyunsaturated Fatty acids. J Nutr Metab. 2012;2012:539426. https://doi.org/10.1155/2012/539426.

  28. Scorletti E, Byrne CD. Omega-3 fatty acids, hepatic lipid metabolism, and nonalcoholic fatty liver disease. Annu Rev Nutr. 2013;33:231–48. https://doi.org/10.1146/annurev-nutr-071812-161230.

  29. Mohammad MA, Sunehag AL, Haymond MW. Effect of dietary macronutrient composition under moderate hypocaloric intake on maternal adaptation during lactation. Am J Clin Nutr. 2009;89(6):1821–7. https://doi.org/10.3945/ajcn.2008.26877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nasser R, et al. The effect of a controlled manipulation of maternal dietary fat intake on medium and long chain fatty acids in human breast milk in Saskatoon, Canada. Int Breastfeed J. 2010;5: 3. https://doi.org/10.1186/1746-4358-5-3.

  31. Jonsson K, et al. Fat intake and breast milk fatty acid composition in farming and nonfarming women and allergy development in the offspring. Pediatr Res. 2016;79(1–1):114–23. https://doi.org/10.1038/pr.2015.187.

    Article  CAS  PubMed  Google Scholar 

  32. Koletzko B, et al. Infant feeding and later obesity risk. Adv Exp Med Biol. 2009;646:15–29. https://doi.org/10.1007/978-1-4020-9173-5_2.

  33. Casper D, Schingoethe DJ. Model to describe and alleviate milk protein depression in early lactation dairy cows fed a high fat diet. J Dairy Sci. 1989;72(12):3327–35. https://doi.org/10.3168/jds.S0022-0302(89)79494-7.

    Article  CAS  PubMed  Google Scholar 

  34. Beauchamp GK, Mennella JA. Flavor perception in human infants: development and functional significance. Digestion. 2011;83(Suppl 1):1–6. https://doi.org/10.1159/000323397.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Davis TA, et al. Amino acid composition of human milk is not unique. J Nutr. 1994;124(7):1126–32. https://doi.org/10.1093/jn/124.7.1126.

    Article  CAS  PubMed  Google Scholar 

  36. Ventura AK, Beauchamp GK, Mennella JA. Infant regulation of intake: the effect of free glutamate content in infant formulas. Am J Clin Nutr. 2012;95(4):875–81. https://doi.org/10.3945/ajcn.111.024919.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Tomlinson C, et al. Arginine is synthesized from proline, not glutamate, in enterally fed human preterm neonates. Pediatr Res. 2011;69(1):46–50. https://doi.org/10.1203/PDR.0b013e3181fc6ab7.

    Article  CAS  PubMed  Google Scholar 

  38. Shulman RJ. Effect of enteral administration of insulin on intestinal development and feeding tolerance in preterm infants: a pilot study. Arch Dis Child Fetal Neonatal Ed. 2002;86(2):F131–3. https://doi.org/10.1136/fn.86.2.f131.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shehadeh N, Sukhotnik I, Shamir R. Gastrointestinal tract as a target organ for orally administered insulin. J Pediatr Gastroenterol Nutr. 2006;43(3):276–81. https://doi.org/10.1097/01.mpg.0000226377.03247.fb.

    Article  CAS  PubMed  Google Scholar 

  40. Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes. 2017;18(1):10–6. https://doi.org/10.1111/pedi.12473.

    Article  PubMed  Google Scholar 

  41. Polianskyte-Prause Z, et al. Metformin increases glucose uptake and acts renoprotectively by reducing SHIP2 activity. FASEB J. 2019;33(2):2858–69. https://doi.org/10.1096/fj.201800529RR.

    Article  CAS  PubMed  Google Scholar 

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Funding

BG is supported by K08 DK102526, R56 DK121787, and the Amendt-Heller Award for Newborn Research. DB is supported by R01 DK107535. Amino acid and long-chain fatty acid levels were analyzed at the Michigan Regional Comprehensive Metabolomics Resource Core (MRC2) supported by grant DK097153 to the University of Michigan. We would also like to acknowledge the White Adipose Tissue Core, which is a part of the Michigan Nutrition and Obesity Center (P30 DK089503) for instruction in adipocyte size analysis. Body composition measurements were done with the assistance of the Mouse Metabolic Phenotyping Center (U2CDK110768). Histology was performed by the Rogel Cancer Center Histology Core (P30 CA04659229). RNA Sequencing was performed by the University of Michigan Advanced Genomics Core. ZC was funded by an internship through the Momentum Center of the University of Michigan.

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Authors and Affiliations

  1. Department of Pediatrics, Division of Diabetes, Endocrinology and Metabolism, University of Michigan Medicine, Ann Arbor, MI, USA

    Zach Carlson, Hannah Hafner, Emma Harman, Stephanie Liu, Nathalie Botezatu, Cecilia Rivet, Holly Reynolds, Haijing Sun & Brigid Gregg

  2. Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA

    Noura El Habbal, Nyahon Both, Dave Bridges & Brigid Gregg

  3. Department of Pediatrics, University of Michigan, Ann Arbor, MI, USA

    Emma Harman

  4. University of Michigan Flint Campus, Flint, MI, USA

    Masa Alharastani

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  1. Zach Carlson
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Contributions

BG was responsible for the study design and conceived the original idea. ZC, BG, HH, NEH, EH, SL, NB, MA, CR, and HR carried out the experiments. ZC, HH, NB, BG, NEH and DB performed data analysis. Manuscript preparation was done by HH, BG, ZC, NEH, and DB. Manuscript editing was completed by ZC, EH, SL, NB, MA, CR, and HR. Input and approval on the final manuscript was provided by all authors.

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Correspondence to Brigid Gregg.

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Carlson, Z., Hafner, H., El Habbal, N. et al. Short Term Changes in Dietary Fat Content and Metformin Treatment During Lactation Impact Milk Composition and Mammary Gland Morphology. J Mammary Gland Biol Neoplasia 27, 1–18 (2022). https://doi.org/10.1007/s10911-022-09512-y

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