Omega-3 Fatty Acids Regulate Mammary Gland Lipogenesis and Development via Gα _s -Mediated cAMP–EPAC Signaling Pathway

G protein-coupled receptor 120 (GPR120) plays a pivotal role in regulating lactation, yet its underlying mechanisms remain unclear. In mouse models, GPR120 expression in the mammary gland increases markedly during lactation. Under inflammatory conditions, both n-3 polyunsaturated fatty acids (n-3 PUFAs) and GPR120 agonists markedly reduced inflammatory responses and enhanced lipogenesis and migration in HC11 mammary epithelial cells. These benefits were also observed under non-inflammatory conditions and were diminished when GPR120 was knocked down. Furthermore, the regulatory function of GPR120 under non-inflammatory conditions in in vivo and in vitro models is explored. We discovered that the GPR120-Gα_s-cyclic adenosine monophosphate (cAMP)-exchange protein directly activated by cAMP (EPAC) signaling axis is critical for lipogenesis and migration in mammary epithelial cells. Through transcriptomic analyses, the EPAC-CCCTC-binding factor (CTCF)-peroxisome proliferator-activated receptor γ (PPARγ)/CCAAT enhancer-binding protein α (C/EBPα) pathway was identified to primarily govern lipogenesis, while the EPAC-C-X-C motif chemokine ligand 14 (CXCL14)/C-X-C chemokine receptor type 4 (CXCR4) autocrine loop regulates migration of mammary epithelial cells. Overall, these findings suggest that GPR120, which can be activated by n-3 PUFAs, improves mammary gland performance by alleviating inflammation and directly modulating mammary lipogenesis and mammary gland development through the CTCF-PPARγ/C/EBPα and CXCL14-CXCR4 pathways. Thus, GPR120 and its downstream signaling targets may represent an important clinical target for enhancing maternal lactation.