Written by: Alla Katsnelson, Ph.D | Issue # 115 | 2023
- In mice, a fatty acid called γ-linolenic acid, or GLA, that is present in maternal milk switches on a transcription factor called RXR, which is crucial for the maturation of cardiomyocytes.
- The researchers demonstrated the role of GLA in cardiomyocyte function by knocking out the gene in mice and conducting feeding studies in which pregnant dams ate a fat-free diet.
- The importance of GLA in activating RXR has not yet been demonstrated in humans.
Researchers have speculated for decades that one effect of breast milk may be to promote heart maturation in newborns. A recent study has finally confirmed this idea, and has also pinned down the molecular connection. In mice, the study reports, a fatty acid called γ-linolenic acid, or GLA, from maternal milk activates a protein called retinoid X receptor (RXR), which helps heart cells—cardiomyocytes—switch on their pulsing function at birth (1).
“We think the beauty of this study is that it opens up many new avenues of research at the molecular level and also, if relevant in humans, at the clinical level,” says Mercedes Ricote, a molecular biologist at the Spanish National Center for Cardiovascular Research who led the work.
Ricote and her colleagues did not set out to study milk at all. Their lab was investigating how proteins called transcription factors play a role in cardiomyocyte maturation, and in previous work they identified a protein called RXR as one such factor. In this study, they found that mice in which the gene encoding RXR was knocked out survived until birth, but most neonates did not survive past 24 hours. “If there is no RXR signaling after birth, the hearts of these mice stop beating and they die,” says Ana Paredes, a molecular biologist in Ricote’s laboratory and first author on the study.
Neonatal mice undergo a significant change in their metabolic profile. In the fetus, cardiomyocytes are powered by glucose oxidation, but after birth that process falls away, and instead these cells begin relying on fatty acid consumption by mitochondria. Paredes and Ricote reasoned that birth also brings two major physiological challenges: breathing, and ingesting maternal milk. Earlier work from the lab showed that RXR must be activated by a ligand to function (2). The identity of that ligand was unknown, although there were hints in the literature that it came from fatty acids. So the researchers hypothesized that maternal milk might carry it.
To test the idea, Ricote and her colleagues fed dams a specially created diet lacking free fatty acids. Lipidomic studies of the milk these mice produced showed that it lacked omega-6 fatty acids, including GLA. Most neonates suckling from these mothers died within a day or two, just like the pups lacking RXR. The researchers then looked at gene expression in genes regulating fatty acid metabolism and with the help of lipidomics, a method for analyzing multiple fats, found that these genes’ activation depends on the presence of GLA. When they gave GLA to mouse mothers who were fed a fat-free diet, their pups thrived. Conversely, giving GLA directly to pups lacking the RXR gene did not boost their survival—suggesting that GLA activates RXR function.
“Together, these results reveal a molecular signaling pathway whereby nutrients in the milk of female mice activate a gene-expression program that triggers maturation of cardiomyocytes and prepares them for postnatal function,” write Pingzhu Zhou and William T. Pu at Boston Children’s Hospital, in a review article in Nature accompanying the paper (3).
The researchers note that GLA is not naturally present in the body. “GLA is an essential omega-6 fatty acid—it must be ingested because we cannot produce it,” Paredes says. That may partly explain the significance of mother’s milk in terms of evolution, she adds.
Ricote speculates that this milk-governed process takes place not only in the heart but in all organs that have a high-energy requirement. The investigators are currently testing whether and how milk plays a role in maintaining energy levels in the brain and the liver. “We think this is a homeostatic process,” she says.
The work was conducted in mice, and “the relevance of our studies to humans needs further evaluation,” Ricote cautions. Little is known about human variants of the RXR gene, but determining whether premature babies or babies born with cardiac problems have specific variants might provide some hints to whether the mechanism also is present in humans, Paredes says. If so, supplementing such babies’ diets with GLA may help promote their survival, she says.
Ricote also notes that the lab tested an infant milk formula and found that it contained enough GLA precursors to provide this fatty acid—so babies who eat formula instead of breast milk would still get enough GLA. “That is an important point for women who might who read this study and get scared,” she said.
1. Paredes A, Justo-Méndez R, Jiménez-Blasco D, Núñez V, Calero I, Villalba-Orero M, Alegre-Martí A, Fischer T, Gradillas A, Sant’Anna VAR, Were F, Huang Z, Hernansanz-Agustín P, Contreras C, Martínez F, Camafeita E, Vázquez J, Ruiz-Cabello J, Area-Gómez E, Sánchez-Cabo F, Treuter E, Bolaños JP, Estébanez-Perpiñá E, Rupérez FJ, Barbas C, Enríquez JA, Ricote M. γ-Linolenic acid in maternal milk drives cardiac metabolic maturation. Nature. 2023;618(7964):365-373.
2. Rőszer T, Menéndez-Gutiérrez MP, Cedenilla M, Ricote M. Retinoid X receptors in macrophage biology. Trends Endocrinol Metab. 2013;24(9):460-468.
3. Zhou P, Pu WT. Molecule in mothers’ milk nurses pups’ heart muscle cells to maturity. Nature. 2023:618(7964):242-243.