Obesity is a pre-disposing condition for chronic obstructive pulmonary disease, asthma, and pulmonary arterial hypertension. Accumulating evidence suggests that metabolic influences during development can determine chronic lung diseases (CLD). We demonstrate that maternal obesity causes early metabolic disorder in the offspring. Here, interleukin-6 induced bronchial and microvascular smooth muscle cell (SMC) hyperproliferation and increased airway and pulmonary vascular resistance. The key anti-proliferative transcription factor FoxO1 was inactivated via nuclear exclusion. These findings were confirmed using primary SMC treated with interleukin-6 and pharmacological FoxO1 inhibition as well as genetic FoxO1 ablation and constitutive activation. In vivo, we reproduced the structural and functional alterations in offspring of obese dams via the SMC-specific ablation of FoxO1. The reconstitution of FoxO1 using IL-6-deficient mice and pharmacological treatment did not protect against metabolic disorder but prevented SMC hyperproliferation. In human observational studies, childhood obesity was associated with reduced forced expiratory volume in 1 s/forced vital capacity ratio Z-score (used as proxy for lung function) and asthma. We conclude that the interleukin-6-FoxO1 pathway in SMC is a molecular mechanism by which perinatal obesity programs the bronchial and vascular structure and function, thereby driving CLD development. Thus, FoxO1 reconstitution provides a potential therapeutic option for preventing this metabolic programming of CLD.

Maternal obesity predisposes for hepato-metabolic disorders early in life. However, the underlying mechanisms causing early onset dysfunction of the liver and metabolism remain elusive. Since obesity is associated with subacute chronic inflammation and accelerated aging, we test the hypothesis whether maternal obesity induces aging processes in the developing liver and determines thereby hepatic growth. To this end, maternal obesity was induced with high-fat diet (HFD) in C57BL/6N mice and male offspring were studied at the end of the lactation [postnatal day 21 (P21)]. Maternal obesity induced an obese body composition with metabolic inflammation and a marked hepatic growth restriction in the male offspring at P21. Proteomic and molecular analyses revealed three interrelated mechanisms that might account for the impaired hepatic growth pattern, indicating prematurely induced aging processes: (1) Increased DNA damage response (γH2AX), (2) significant upregulation of hepatocellular senescence markers (Cdnk1a, Cdkn2a); and (3) inhibition of hepatic insulin/insulin-like growth factor (IGF)-1-AKT-p38-FoxO1 signaling with an insufficient proliferative growth response. In conclusion, our murine data demonstrate that perinatal obesity induces an obese body composition in male offspring with hepatic growth restriction through a possible premature hepatic aging that is indicated by a pathologic sequence of inflammation, DNA damage, senescence, and signs of a possibly insufficient regenerative capacity.

Chronic Kidney Disease (CKD), a global health burden, is strongly associated with age-related renal function decline, hypertension, and diabetes, which are all frequent consequences of obesity. Despite extensive studies, the mechanisms determining susceptibility to CKD remain insufficiently understood. Clinical evidence together with prior studies from our group showed that perinatal metabolic disorders after intrauterine growth restriction or maternal obesity adversely affect kidney structure and function throughout life. Since obesity and aging processes converge in similar pathways we tested if perinatal obesity caused by high-fat diet (HFD)-fed dams sensitizes aging-associated mechanisms in kidneys of newborn mice. The results showed a marked increase of γH2AX-positive cells with elevated 8-Oxo-dG (RNA/DNA damage), both indicative of DNA damage response and oxidative stress. Using unbiased comprehensive transcriptomics we identified compartment-specific differentially-regulated signaling pathways in kidneys after perinatal obesity. Comparison of these data to transcriptomic data of naturally aged kidneys and prematurely aged kidneys of genetic modified mice with a hypomorphic allele of Ercc1, revealed similar signatures, e.g., inflammatory signaling. In a biochemical approach we validated pathways of inflammaging in the kidneys after perinatal obesity. Collectively, our initial findings demonstrate premature aging-associated processes as a consequence of perinatal obesity that could determine the susceptibility for CKD early in life.

Background: Obesity contributes to lung diseases and regeneration. Prior studies from our group showed that perinatal and maternal obesity induces bronchial and vascular remodeling in later life. However, the impact of obesity on alveolarization and the alveolar regenerative niche remains uncertain. Aims: (1) To investigate the impact of maternal and perinatal obesity on alveolar formation and on alveolar epithelial type II cells (ATII) as alveolar progenitor cells; (2) To study the effect of white adipose tissue (WAT) and its adipocytokines on ATII. Methods: 1) Female mice were fed with high-fat diet (HFD) or standard-diet (SD) prior mating, and during pregnancy and lactation. The offspring’s lungs were analyzed at postnatal day 21 (P21). (2) Murine lung epithelial cells (MLE12) were exposed to WAT conditioned medium (CM^WAT), Interleukin 6 (IL-6) or Leptin. Results: (1) Lung RNAseq transcriptomic profiling at P21 followed by KEGG pathway analysis identified in the HFD-group pathways involved in cell survival and lung development. Quantitative histomorphometry demonstrated an increased alveolar surface and a reduced radial alveolar count (RAC) in the HFD when compared to the SD-group, indicating reduced alveolarization. Immunofluorescence staining for surfactant protein C, an ATII marker, showed reduction of ATII by 52 %, suggesting that perinatal obesity depletes alveolar regenerative capacity. (2) Exposure of MLE12 to CM^WAT IL‑6, or Leptin induced cellular senescence and reduced cell survival. Conclusion: We identified a novel adipose tissue-lung axis linking perinatal overactive adipose tissue secretome to depletion of alveolar progenitor cells and reduced alveolar formation.

Obesity is associated with cardiopulmonary diseases. Despite Obesity and aging converging in similar pathways, specifically inflammation-associated genomic instability, their interdependency remains unclear. We recently demonstrated that perinatal obesity triggers bronchial/vascular remodeling through Interleukin 6 (IL-6). We investigated if and how perinatal obesity induces early genomic instability in alveolar epithelial cells type 2 (AT2) leading to alveolar simplification. Lungs of offspring of high-fat diet- or standard-diet-fed dams were analyzed at postnatal day 21 (P21), P70, P365 and after 1.5years, including global and AT2-specific transcriptomic and epigenetic profiling. Cultured AT2, precision-cut lung slices and bronchioalveolar lung organoids were used for ex vivo studies. Perinatal obesity induced a life-long emphysema-like lung structure with a reduction of AT2, increased DDR (γH2AX+) and senescence (p21+). Global and AT2-specific RNA-Seq together with AT2-specific ATAC-Seq identified DNA damage and repair processes together with transcriptional stress and aging-associated pathways after perinatal obesity. Cultured AT2, PCLS and BALOs demonstrated that WAT secretome inhibits growth and induces DDR, senescence and loss of AT2 through IL-6. IL-6 null mice and mice with pharmacological inhibition of IL-6 signaling were protected from DDR and alveolar growth arrest after perinatal obesity. Finally, human lungs with emphysema showed increased DDR and AT2 loss. Our data demonstrate that perinatal obesity induces genomic instability in AT2 with life-long emphysema-like lung structure, a process that is in part mediated by WAT derived IL-6.

Background: 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). Methods: (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. Results: (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. Conclusion: 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.