Alharithi, Y. J. | Search bioRxiv

bioRxiv2024

Metabolomic and transcriptomic remodeling of bone marrow myeloid cells in response to maternal obesity

Maternal obesity puts the offspring at high risk of developing obesity and cardio-metabolic diseases in adulthood. Here, using a mouse model of maternal high-fat diet (HFD)-induced obesity, we show that whole body fat content of the offspring of HFD-fed mothers (Off-HFD) increases significantly from very early age when compared to the offspring regular diet-fed mothers (Off-RD). We have previously shown significant metabolic and immune perturbations in the bone marrow of newly-weaned offspring of obese mothers. Therefore, we hypothesized that lipid metabolism is altered in the bone marrow Off-HFD in newly-weaned offspring of obese mothers when compared to the Off-RD. To test this hypothesis, we investigated the lipidomic profile of bone marrow cells collected from three-week-old offspring of regular and high fat diet-fed mothers. Diacylgycerols (DAGs), triacylglycerols (TAGs), sphingolipids and phospholipids, including plasmalogen, and lysophospholipids were remarkably different between the groups, independent of fetal sex. Levels of cholesteryl esters were significantly decreased in offspring of obese mothers, suggesting reduced delivery of cholesterol to bone marrow cells. This was accompanied by age-dependent progression of mitochondrial dysfunction in bone marrow cells. We subsequently isolated CD11b+ myeloid cells from three-week-old mice and conducted metabolomics, lipidomics, and transcriptomics analyses. The lipidomic profiles of these bone marrow myeloid cells were largely similar to that seen in bone marrow cells and included increases in DAGs and phospholipids alongside decreased TAGs, except for long-chain TAGs, which were significantly increased. Our data also revealed significant sex-dependent changes in amino acids and metabolites related to energy metabolism. Transcriptomic analysis revealed altered expression of genes related to major immune pathways including macrophage alternative activation, B-cell receptor signaling, TGF{beta} signaling, and communication between the innate and adaptive immune systems. All told, this study revealed lipidomic, metabolomic, and gene expression abnormalities in bone marrow cells broadly, and in bone marrow myeloid cells particularly, in the newly-weaned offspring of obese mothers, which might at least partially explain the progression of metabolic and cardiovascular diseases in their adulthood.

molecular biology↗

bioRxiv2023

Metabolic abnormalities in the bone marrow cells of young offspring born to obese mothers

Intrauterine metabolic reprogramming occurs in obese mothers during gestation, putting the offspring at high risk of developing obesity and associated metabolic disorders even before birth. We have generated a mouse model of maternal high-fat diet-induced obesity that recapitulates the metabolic changes seen in humans. Here, we profiled and compared the metabolic characteristics of bone marrow cells of newly weaned 3-week-old offspring of dams fed either a high-fat (Off-HFD) or a regular diet (Off-RD). We utilized a state-of-the-art targeted metabolomics approach coupled with a Seahorse metabolic analyzer. We revealed significant metabolic perturbation in the offspring of HFD-fed vs. RD-fed dams, including utilization of glucose primarily via oxidative phosphorylation, and reduction in levels of amino acids, a phenomenon previously linked to aging. Furthermore, in the bone marrow of three-week-old offspring of high-fat diet-fed mothers, we identified a unique B cell population expressing CD19 and CD11b, and found increased expression of Cyclooxygenase-2 (COX-2) on myeloid CD11b, and on CD11bhi B cells, with all the populations being significantly more abundant in offspring of dams fed HFD but not a regular diet. Altogether, we demonstrate that the offspring of obese mothers show metabolic and immune changes in the bone marrow at a very young age and prior to any symptomatic metabolic disease.

physiology↗