Diglycerides, or DAGs, are glycerolipids in which a glycerol backbone carries two fatty acid chains rather than three. The 1,3-isomer in particular has attracted attention because, unlike conventional triglycerides, it appears to inhibit intra-abdominal fat accumulation, reduce postprandial serum triglyceride and cholesterol levels, improve glucose metabolism, and lower thrombosis and atherosclerosis risks in rodent studies. Diets rich in DAG have been shown to reduce weight gain and visceral fat in obese mice and to improve insulin resistance induced by high-fat feeding by inhibiting hepatic gluconeogenesis and stimulating fat oxidation in skeletal muscle. What remained unclear until now was whether these protective effects could cross the placental and lactational bond to influence offspring, and how maternal diet and post-weaning diet might interact in shaping adult metabolic health.

The research team, working with female C57BL/6J mice, divided the animals into three dietary groups before mating: a normal diet providing ten percent of calories from fat, a high-fat diet providing sixty percent of calories from fat, and a DAG diet in which forty percent of the oil in the high-fat feed was replaced with diglyceride oil, yielding an oil content of 34.9 percent. After four weeks of continuous feeding, females were mated with normal-diet males, and the dietary assignments were maintained throughout pregnancy and lactation. From 168 pups born—84 males and 84 females—the investigators tracked lipid abnormalities at weaning and then followed male offspring into adulthood under three post-weaning diets: normal, high-fat, or DAG. Body weight gain, white adipose tissue weights, and serum triglycerides, total cholesterol, LDL-C, and HDL-C were measured in dams, young offspring, and adult offspring.

The results were striking. Compared with obese dams on the high-fat diet, mothers fed the DAG diet showed reduced body weight gain, decreased white adipose tissue weight, and lowered serum triglyceride and total cholesterol levels. At weaning, offspring of high-fat-fed dams exhibited higher body weight gain and a greater proportion of white adipose tissue than offspring of normal-diet dams, but pups nursed by DAG-fed mothers had significantly lower serum triglycerides, total cholesterol, and LDL-C. In adulthood, when offspring were challenged with a post-weaning high-fat diet, those from DAG-fed mothers accumulated less adipose tissue and showed lower serum triglyceride, cholesterol, and LDL-C levels than offspring from high-fat-fed mothers receiving the same post-weaning diet. Notably, HDL-C levels were not restored by the DAG intervention in dams or offspring, remaining significantly lower than in normal-diet groups—a finding the authors interpret cautiously, given ongoing debate about the nonlinear, possibly U-shaped relationship between HDL-C and cardiovascular risk in humans.

Histological and ultrastructural analyses of liver tissue revealed the mechanistic depth of these effects. High-fat feeding produced enlarged and more numerous lipid droplets in maternal hepatocytes, along with blurred mitochondrial membrane structures and incomplete cristae visible under transmission electron microscopy. The DAG diet partially reversed both abnormalities, reducing lipid deposition and maintaining normal mitochondrial morphology. Because mitochondria are the site of fatty acid oxidation, preserving their structure ensures that energy metabolism proceeds smoothly. Consistent with this, the DAG diet improved the expression of lipid metabolism-related genes, including Pparα, Cpt1a, and Acss2, in both mothers and young offspring. PPARα is a crucial regulator of lipid homeostasis, and elevated PPARα and CPT1A levels indicate restoration of the liver’s fatty acid oxidation capacity, while downregulation of ACSS2 suggests reduced production of acetyl-CoA, an important precursor for de novo fatty acid synthesis.

Proton nuclear magnetic resonance spectroscopy of maternal serum added a metabolic dimension. Orthogonal partial least squares discriminant analysis separated the three maternal groups clearly, and pathway analysis identified differential metabolites concentrated in purine metabolism, pyrimidine metabolism, and the interconversion of pentose and glucuronate. Compared with the normal diet, the high-fat diet produced 69 differential metabolites in maternal serum, with 50 trending downward; the DAG diet, relative to the high-fat diet, produced 95 differential metabolites, with 84 trending upward. The DAG intervention partially restored the decreased levels of purine and pyrimidine metabolism induced by high-fat feeding. The investigators also examined the expression of obesity-associated genes previously linked to differential methylation—Miz-1, Sim1, and Mmp9—in maternal liver and adipose tissue, finding that the DAG diet was associated with more stable expression of these genes in both mothers and young offspring, while maintaining normal levels of the DAG-PKC signaling pathway. The authors emphasize that mRNA expression, not DNA methylation, was measured, so whether DAG directly modulates epigenetic marks requires further investigation.

The gut microbiota emerged as a central mediator. Sequencing of 16S rRNA genes from maternal feces showed that both high-fat and DAG diets decreased alpha-diversity indices relative to the normal diet, but the DAG diet improved the ratio of Firmicutes to Bacteroidetes compared with the high-fat diet and corrected the abnormal decrease in relative abundance of Akkermansia and Alloprevotella as well as the abnormal increase of Helicobacter and Dubosiella. Short-chain fatty acid analysis by gas chromatography-mass spectrometry showed that the DAG diet significantly improved the decrease in butyric acid caused by high-fat feeding and corrected abnormal levels of acetic, propionic, valeric, hexanoic, isobutyric, and isovaleric acids. Butyrate is known to enhance CPT1A activity, promote fatty acid oxidation and regulatory T-cell differentiation, and improve the intestinal barrier. In adult offspring, post-weaning high-fat diet led to an abnormal increase in the Firmicutes-to-Bacteroidetes ratio, but offspring of DAG-fed mothers showed an overall lower ratio and greater resistance when facing a high-fat diet, with lower levels of isobutyric and isovaleric acids.

To test whether the microbiota could carry the DAG effect independently of diet, the investigators performed fecal colony mixture transplantation from mice on the three dietary structures into normal-diet recipients. After six weeks, sequencing showed that the gut microbiota structure of mice receiving fecal suspension from DAG-fed donors was closer to that of normal-diet mice, with increased abundance of butyrogenic genera such as Muribaculaceae, Muribaculum, and Prevotella, all closely related to short-chain fatty acid production, especially butyric acid. The Firmicutes-to-Bacteroidetes ratio was higher in recipients of high-fat-donor feces. However, no significant differences in body weight or body fat emerged among the transplant groups, echoing earlier findings that microbiota-dependent benefits may require a metabolic challenge or a specific dietary context to manifest fully in phenotype.

Spearman correlation analysis tied the maternal and offspring effects together. Maternal fecal short-chain fatty acid content was negatively correlated with body weight growth rate, white adipose tissue proportion, total cholesterol, and LDL-C in adult offspring when diet types were matched between mother and offspring. When offspring returned to a normal diet after weaning, these correlations weakened, suggesting that a healthy post-weaning dietary environment helps adult offspring gradually weaken the influence of maternal diet intervention and form a relatively independent growth trend. Conversely, when offspring were exposed to a high-fat diet after weaning, the negative correlation between maternal short-chain fatty acids and offspring adiposity was pronounced, indicating that the protective effect of DAG in early life is most evident when adult offspring face a metabolic challenge.

The authors acknowledge important limitations. Multi-omics profiling—including proton NMR metabolomics, electron microscopy, 16S rRNA sequencing, and short-chain fatty acid analysis—was restricted to three biologically independent animals per group, randomly selected from larger cohorts of six to ten, so the observed alterations should be interpreted as exploratory and hypothesis-generating rather than conclusive. Marked interspecies differences in lipid metabolism, including lipoprotein profiles, bile acid synthesis, and cholesterol homeostasis, limit direct extrapolation of murine findings to human physiology, and rodent cecotrophy—absent in humans—substantially alters gut microbiota composition and short-chain fatty acid bioavailability. Even so, the study provides a coherent picture of a diet-microbiota-host interplay in which maternal diglyceride feeding creates a healthier intrauterine and early developmental environment, promotes fatty acid oxidation capacity, maintains mitochondrial structure, stabilizes the expression of obesity-associated genes, and shapes a founding gut microbiota and short-chain fatty acid profile that confer measurable resistance to metabolic disruption in adult offspring. The findings may inform future preclinical research on diglyceride edible oils as potential healthy fats, though translation to humans will require careful validation in non-cecotrophic models and human cohorts.

Subject of Research: Maternal Diglyceride Diet Attenuates Selected Metabolic Effects of Maternal High‐Fat Feeding in Offspring via Energy Metabolism and Microbiota Modulation

Article Title: Maternal Diglyceride Diet Attenuates Selected Metabolic Effects of Maternal High‐Fat Feeding in Offspring via Energy Metabolism and Microbiota Modulation

Article References: Wu, Q., Li, C., Song, S., Wang, H., Zhao, R., Sun, L., Shang, B., & Geng, Y. (2026). Maternal Diglyceride Diet Attenuates Selected Metabolic Effects of Maternal High‐Fat Feeding in Offspring via Energy Metabolism and Microbiota Modulation. Food Science & Nutrition, 14(10), Article e72427. https://doi.org/10.1002/fsn3.72427

Image Credits: AI Generated

DOI: 10.1002/fsn3.72427

Keywords: Maternal, Diglyceride, Diet, Attenuates, Selected, Metabolic, Effects, High, Feeding, Offspring, Energy, Metabolism