Background
During lactation, the mammary gland undergoes significant structural and functional changes to produce milk, which is essential for neonatal nutrition and early immune development. Traditional viewpoints suggest that n-3 polyunsaturated fatty acids (such as DHA) primarily enhance mammary function indirectly through anti-inflammatory actions; however, the potential molecular mechanisms underlying this effect remain unclear. G protein-coupled receptors (GPCRs) are a central family of transmembrane signaling molecules involved in metabolism, secretion, migration, differentiation, and immune responses. G protein-coupled receptor 120 (GPR120) and GPR40, in particular, sense long-chain fatty acids and mitigate inflammation via the GPR120–β-arrestin2 pathway, it is not yet clear whether its role in lactation depends solely on this anti-inflammatory effect or also involves other signaling pathways that govern mammary gland development and mammary lipogenesis. Meanwhile, although GPR40 exhibits important functions in various tissues, its specific role in the mammary gland, particularly in mammary lipogenesis and mammary gland development, remains to be determined.

Research Progress
The research team found that the supplementation of n-3 fatty acids significantly enhances lactation performance even in non-inflammatory states, suggesting the existence of an unexplored direct regulatory mechanism. Subsequently, the research team identified that GPR120 is specifically highly expressed in mammary tissues during lactation, with its expression level progressively increasing throughout the lactation process. Further mechanistic investigations revealed that n-3 fatty acids activate the GPR120 receptor on the membrane of mammary epithelial cells, triggering a Gαs-mediated cAMP signaling cascade, which operates completely independently of classical inflammatory regulation pathways.

In terms of molecular mechanisms, the effector molecule EPAC forms a bifurcated regulatory network: at the level of lipid metabolism, EPAC activates the chromatin structural protein CTCF to drive the PPARγ/C/EBPα transcriptional hub, significantly upregulating the expression of fatty acid synthase (FASN) and fatty acid transport protein (CD36), thereby promoting the synthesis of milk fat and the accumulation of lipid droplets. At the level of mammary development, EPAC induces mammary epithelial cells to autonomously secrete the chemokine CXCL14, establishing a CXCL14-CXCR4 autocrine regulatory loop. This, in turn, guides the polarized migration of epithelial cells and the formation of acinar structures through the activation of the AKT/ERK signaling axis.

This study not only clarifies, for the first time, the core role of the "GPR120-EPAC dual axis" in the regulation of mammary function but also innovatively reveals the key physiological function of autocrine CXCL14 and its signaling loop in the development of the acini during lactation.

Future Prospects
Overall, this study emphasizes the critical role of GPR120 in mediating the effects of n-3 polyunsaturated fatty acids on mammary function. It comprehensively elucidates how the GPR120–Gαs–cAMP–EPAC signaling axis and its downstream pathways influence lactation. These insights provide potential clinical targets for enhancing maternal lactational ability and ensuring the healthy development of offspring.

The complete study is accessible via DOI: 10.34133/research.0767