Wan Yihong, Saghatelian Alan, Chong Ling-Wa, Zhang Chun-Li, Cravatt Benjamin F, Evans Ronald M
Howard Hughes Medical Institute, Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, California 92037, USA.
Genes Dev. 2007 Aug 1;21(15):1895-908. doi: 10.1101/gad.1567207. Epub 2007 Jul 24.
Lactation is a highly demanding lipid synthesis and transport process that is crucial for the development of newborn mammals. While PPAR gamma is known to promote adipogenesis and lipogenesis in adipose tissue, its role in the lactating mammary gland is unexplored. Here, we report that a targeted deletion of PPAR gamma in mice results in the production of "toxic milk" containing elevated levels of inflammatory lipids. Surprisingly, ingestion of this "toxic milk" causes inflammation, alopecia, and growth retardation in the nursing neonates. Genomic profiling reveals that PPAR gamma deficiency leads to increased expression of lipid oxidation enzymes in the lactating mammary gland. Consistently, metabolomic profiling detects increased levels of oxidized free fatty acids in the pups nursed by PPAR gamma-deficient mothers. Therefore, maternal PPAR gamma is pivotal for maintaining the quality of milk and protecting the nursing newborns by suppressing the production of inflammatory lipids in the lactating mammary gland.
泌乳是一个对脂质合成和运输要求极高的过程，对新生哺乳动物的发育至关重要。虽然已知过氧化物酶体增殖物激活受体γ（PPARγ）可促进脂肪组织中的脂肪生成和脂质生成，但其在泌乳乳腺中的作用尚未得到探索。在此，我们报告，在小鼠中靶向缺失PPARγ会导致产生含有高水平炎性脂质的“有毒乳汁”。令人惊讶的是，摄入这种“有毒乳汁”会导致哺乳新生仔出现炎症、脱发和生长发育迟缓。基因组分析表明，PPARγ缺乏会导致泌乳乳腺中脂质氧化酶的表达增加。同样，代谢组学分析检测到由PPARγ缺陷型母亲哺育的幼崽中氧化游离脂肪酸水平升高。因此，母体PPARγ对于维持乳汁质量和通过抑制泌乳乳腺中炎性脂质的产生来保护哺乳新生儿至关重要。
