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首页> 外文期刊>American Journal of Physiology >Investigating the complex interplay between genotype and high-fat-diet feeding in the lactating mammary gland using the Tph1 and Ldlr knockout models
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Investigating the complex interplay between genotype and high-fat-diet feeding in the lactating mammary gland using the Tph1 and Ldlr knockout models

机译：使用TPH1和LDLR敲除模型调查哺乳乳腺基因型和高脂饮食之间的复杂相互作用

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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 F4/80+ 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 F4/80+ 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.
机译：肥胖是全球普遍存在的问题。肥胖女性难以开始和维持哺乳。然而，基因和饮食对母乳喂养结果的影响尚不清楚。在这里，我们探讨了饮食和基因型对泌乳的影响。我们利用低密度脂蛋白受体（Ldlr-KO）转基因小鼠模型作为肥胖和高胆固醇血症模型。此外，我们使用色氨酸羟化酶1（Tph1-KO）小鼠（最近被确定为潜在的抗肥胖模型）来研究添加Tph1-KO是否可以改善Ldlr-KO小鼠肥胖的负面影响。我们通过结合Ldlr和Tph1[双敲除（DKO）]小鼠来研究这两种基因型之间的相互作用，建立了一个新的转基因小鼠系。从3周龄到早期[哺乳第3天（L3）]或哺乳高峰[哺乳第11天（L11）]，雌性小鼠喂食低脂饮食（LFD；10%脂肪）或高脂饮食（HFD；60%脂肪）。在食用LFD或HFD 4周后，培育雌性小鼠。在L2和L10，对母鼠挤奶，以研究饮食和基因型对牛奶成分的影响。母鼠在L3或L11被安乐死。饮食或基因型对乳蛋白或甘油三酯（TGs）对L2没有影响；然而，到了L10，Ldlr-KO和DKO母鼠已经提高了牛奶中的TG水平。L11乳腺的RNA测序表明，喂食HFD的Ldlr-KO母鼠表现出丰富的免疫系统途径相关基因。有趣的是，DKO可能会在哺乳期改变囊泡出芽和生物发生。我们还通过对L3和L11的F4/80+细胞进行免疫染色来量化巨噬细胞。饮食对L3有显著影响（P=0.013），但基因型在L11对F4/80+细胞数量有影响（P<0.0001）。因此，饮食和基因型对哺乳期的影响因哺乳期的不同而不同，说明了理解这些参数交叉点的复杂性。新的和值得注意的是，我们创建了一个新的小鼠模型，重点是了解哺乳期饮食和基因型对乳腺功能的影响。

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