Tuesday, April 1, 2025
4/1/2025
Immunometabolic dysregulations in the offspring of obese mothers - Three out of ten women in the US are obese prior to becoming pregnant. Obese pregnant women face increased risk of obesity and metabolic disease in their newborns, thus initiating a vicious trajectory of obesity and its health-related consequences in subsequent generations, a phenomenon called developmental programming. Epidemiological studies show a strong link between maternal obesity and the offspring's increased risk of metabolic and cardiovascular diseases; however, efforts to prevent such programming have been confounded by an incomplete understanding of the underlying mechanisms. We have previously developed and reported a mouse model of maternal high-fat diet (HFD)-induced adiposity that recapitulates cardio-metabolic abnormalities seen in human offspring of obese mothers. We found that metabolic dysregulations including obesity, glucose intolerance, and asthma, progress in the adult offspring of mothers fed a HFD—all despite the offspring eating a regular diet only and having similar food intake and activity levels as the offspring of regular diet-fed mothers. Our new data from this mouse model suggest that in comparison with regular diet-fed dams, pregnant HFD-fed dams present increased inflammation that also includes excessive production of interferon-gamma (IFN-), a pro-inflammatory regulator of macrophages. Furthermore, our metabolomics analysis showed significant metabolic perturbations in bone marrow cells isolated from newly weaned offspring of HFD-fed mothers, similar to those previously reported in aging. Those changes included activation of glycolysis and oxidative phosphorylation and decreased amino acid levels. Furthermore, in the bone marrow of three-week-old offspring of high-fat diet-fed mothers, we found increased expression of COX2 on myeloid cells, and identified a unique B-cell population expressing CD19 and CD11b, that was significantly more abundant than in offspring of a regular diet-fed mothers. Thus, our data indicate that immunometabolic and immune perturbations precede the progression of adult metabolic diseases in the offspring of obese mothers. The finding that inflammation potentially mediates the pathological consequences of maternal obesity in offspring raises the hope of exploiting existing anti-inflammatory drugs to treat individuals with maternal obesity-associated metabolic disorders. Underscoring this potential, administration of low-dose aspirin in pregnant women has been shown to lower the risk of preeclampsia, an inflammatory condition. The overall hypothesis of this study is that increased inflammation in HFD-fed mothers causes early-life immunometabolic reprogramming in offspring, thereby leading to metabolic diseases in later life. Two specific aims are proposed. In Aim 1, we will conduct a pre-clinical trial of using low-dose aspirin in regular and HFD-fed pregnant female mice with the scope of reducing the later life risk of obesity and metabolic diseases in their offspring. In Aim 2, we will determine whether the metabolic dysregulations in bone marrow cells in 3-week-old offspring of obese mothers cause chronic inflammation and metabolic disease in adulthood.
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