Omega-3 Fatty Acids Regulate Mammary Gland Lipogenesis and Development via Gαs-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 PU...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
American Association for the Advancement of Science (AAAS)
2025-01-01
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| Series: | Research |
| Online Access: | https://spj.science.org/doi/10.34133/research.0767 |
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| Summary: | 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–Gαs–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. |
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| ISSN: | 2639-5274 |