Trans -10, cis 12-Conjugated Linoleic Acid-Induced Milk Fat Depression Is Associated with Inhibition of PPAR Signaling and Inflammation in Murine Mammary Tissue
Exogenous trans-10, cis-12-CLA (CLA) reduces lipid synthesis in murine adipose and mammary (MG) tissues. However, genomewide alterations in MG and liver (LIV) associated with dietary CLA during lactation remain unknown. We fed mice ( /diet) control or control？+？trans-10, cis-12-CLA (37？mg/day) between d 6 and d 10 postpartum. The 35,302 annotated murine exonic evidence-based oligo (MEEBO) microarray and quantitative RT-PCR were used for transcript profiling. Milk fat concentration was 44% lower on d 10 versus d 6 due to CLA. The CLA diet resulted in differential expression of 1,496 genes. Bioinformatics analyses underscored that a major effect of CLA on MG encompassed alterations in cellular signaling pathways and phospholipid species biosynthesis. Dietary CLA induced genes related to ER stress (Xbp1), apoptosis (Bcl2), and inflammation (Orm1, Saa2, and Cp). It also induced marked inhibition of PPARγ signaling, including downregulation of Pparg and Srebf1 and several lipogenic target genes (Scd, Fasn, and Gpam). In LIV, CLA induced hepatic steatosis probably through perturbations in the mitochondrial functions and induction of ER stress. Overall, results from this study underscored the role of PPARγ signaling on mammary lipogenic target regulation. The proinflammatory effect due to CLA could be related to inhibition of PPARγ signaling. 1. Introduction Dietary nutrients influence the quantity and composition of milk during lactation. Specifically, dietary lipids regulate milk lipid synthesis and milk fatty acid composition in different species of animals. Recently we showed that trans fatty acids (FA) and, in particular, trans-containing conjugated linoleic acid (CLA) isomers regulate murine mammary lipid metabolism to different extents [1]. CLA isomers are the positional and geometric isomers of linoleic acid, an 18-carbon FA with two double bonds. The conjugated double bonds in the CLA are responsible for their biological and biochemical activities. Of the different CLA isomers, the role of trans-10, cis-12-CLA in decreasing milk fat synthesis is well established. The effects of dietary trans-10, cis-12-CLA on lipid metabolism in adipose and liver have been examined previously [2, 3]. Gene expression profiling studies in rodent adipose [2, 4], liver [5–7], and macrophages [8] have been conducted to help elucidate the molecular mechanisms elicited by trans-10, cis-12-CLA. In adipose and liver, trans-10, cis-12-CLA reduces adipogenesis, increases hepatic steatosis, and leads to insulin resistance, hyperinsulinemia, and inflammation [3, 9]. Studies on the
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