Divergent Regulation of Mammary Lipogenesis by trans-10, cis-12 and cis-9, trans-11 CLA Isomers Is Determined by Receptor-Specific Signaling

Conjugated linoleic acid (CLA) isomers exhibit distinct biological activities in lipid metabolism, yet their roles in regulating mammary lipogenesis remain poorly understood. Understanding how individual CLA isomers influence lipid synthesis is essential for improving milk fat quality and developing targeted nutritional strategies. We assessed the effects of <i>trans</i>-10, <i>cis</i>-12 (t10c12-CLA) and <i>cis</i>-9, <i>trans</i>-11 (c9t11-CLA) isomers on lipid synthesis in goat mammary epithelial cells and investigated fatty acid receptor involvement. t10c12-CLA significantly suppressed key lipogenic proteins (FASN, ACACA, and SREBP-1) and impaired mitochondrial activity, as evidenced by reduced mitochondrial membrane potential, ATP/ADP ratio, and PGC-1α expression. Both isomers paradoxically increased lipid droplet accumulation; for t10c12-CLA, this phenomenon resulted from compensatory metabolic shifts due to weakened mitochondrial function. Critically, GPR40 inhibition reversed the antilipogenic effects and mitochondrial impairment caused by t10c12-CLA, establishing GPR40 as the key mediator. In contrast, c9t11-CLA had milder effects and preserved mitochondrial activity, with no definitive receptor dependence established. Transcriptomic analysis confirmed isomer-specific gene expression patterns, with t10c12-CLA broadly affecting lipid metabolism and mitochondrial pathways in a GPR40-dependent manner. These findings reveal that the divergent effects of CLA isomers are dictated by differential receptor engagement, providing insights for precision nutritional strategies in dairy production.