Perinatal obesity interferes with sphingolipid pathway signaling leading to premature cardiopulmonary aging

<bold>Background:</bold> Obesity is associated with cardiopulmonary diseases. Maternal obesity induces a transient metabolic phenotype with overactive adipose tissue, causing arrest of alveolarization and aging-associated processes. The sphingolipid pathway (SLP) is linked to obesity, cardiopulmonary health and aging. Given the converging pathways of obesity and SLP, we investigated the effect of perinatal obesity on alveolarization and heart function via aberrant SLP, through activation of DNA damage response (DDR). <bold>Methods:</bold> (1) At P21 and P70 the offspring of female wildtype mice, fed a high-fat diet (HFD) or standard-diet prior to mating, during pregnancy and lactation, were analyzed. SLP, lungs and hearts were studied. (2) We established a neonatal mouse model with increased sphinganine (SPH) by treatment with Fumonisin b1 (Fb1). (3) Murine alveolar epithelial cells (MLE12) and precision-cut lung slices (PCLS) were exposed to WAT-conditioned medium (CM^HFD), Fb1 and to SPH. <bold>Results:</bold> (1) Perinatal obesity causes alveolar simplification with increased DDR in lungs and hearts at P21 and P70 which is linked to increased SPH. (2) Fb1 elevated SPH, reduced alveolarization, and depleted AT2. In hearts, Fb1 induced a right ventricular-specific hypertrophy and increased DDR. Echocardiography showed right ventricular dysfunction with a decreased heart function, indicating pulmonary hypertension (PH). (3) The exposure of MLE12 or PCLS to CM^HFD, Fb1 and SPH induced apoptosis, DDR and reduced cell survival. <bold>Conclusion:</bold> We identified SPH as a novel mediator of the WAT-lung axis that could cause premature cardiopulmonary aging and increases susceptibility to chronic lung diseases and PH later in life.