4.6 Article

Investigating the complex interplay between genotype and high-fat-diet feeding in the lactating mammary gland using the Tph1 and Ldlr knockout models

出版社

AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00456.2020

关键词

high-fat diet; lactation; mammary gland; obesity; serotonin

资金

  1. U.S. Department of Agriculture (USDA), Agriculture Research Service (Dairy Forage Research Center) [5090-31000-026-00-D]
  2. National Cancer Institute [R01-CA-227542]
  3. Karos Pharmaceuticals [USDA-Hatch MSN158160]
  4. University of Wisconsin, Madison Graduate School Fall Competition Grant [MSN215653]

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The study investigated the impact of diet and genotype on lactation, finding that obesity and genotype can affect milk composition and immune system at different stages, illustrating the complexities in understanding the intersection of these parameters.
Obesity is a prevailing problem across the globe. Women who are obese have difficulty initiating and sustaining lactation. However, the impact of genetics and diet on breastfeeding outcomes is understudied. Here we explore the effect of diet and genotype on lactation. We utilized the low-density lipoprotein receptor (Ldlr-KO) transgenic mouse model as an obesity and hypercholesterolemia model. Additionally, we used the tryptophan hydroxylase 1 (Tph1-KO) mouse, recently identified as a potential anti-obesogenic model, to investigate if addition of Tph1-KO could ameliorate negative effects of obesity in Ldlr-KO mice. We created a novel transgenic mouse line by combining the Ldlr and Tph1 [double knockout (DKO)] mice to study the interaction between the two genotypes. Female mice were fed a low-fat diet (LFD; 10% fat) or high-fat diet (HFD; 60% fat) from 3 wk of age through early [lactation day 3 (L3)] or peak lactation [lactation day 11 (L11)]. After 4 wk of consuming either LFD or HFD, female mice were bred. On L2 and L10, dams were milked to investigate the effect of diet and genotype on milk composition. Dams were euthanized on L3 or L11. There was no impact of diet or genotype on milk protein or triglycerides (TGs) on L2; however, by L10, Ldlr-KO and DKO dams had increased TG levels in milk. RNA-sequencing of L11 mammary glands demonstrated Ldlr-KO dams fed HFD displayed enrichment of genes involved in immune system pathways. Interestingly, the DKO may alter vesicle budding and biogenesis during lactation. We also quantified macrophages by immunostaining for F4/80thorn cells at L3 and L11. Diet played a significant role on L3 (P = 0.013), but genotype played a role at L11 (P < 0.0001) on numbers of F4/80thorn cells. Thus the impact of diet and genotype on lactation differs depending on stage of lactation, illustrating complexities of understanding the intersection of these parameters. NEW & NOTEWORTHY We have created a novel mouse model that is focused on understanding the intersection of diet and genotype on mammary gland function during lactation.

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