Early-onset obesity dysregulates pulmonary adipocytokine/insulin signaling and induces asthma-like disease in mice.

Childhood obesity is a risk factor for asthma, but the molecular mechanisms linking both remain elusive. Since obesity leads to chronic low-grade inflammation and affects metabolic signaling we hypothesized that postnatal hyperalimentation (pHA) induced by maternal high-fat-diet during lactation leads to early-onset obesity and dysregulates pulmonary adipocytokine/insulin signaling, resulting in metabolic programming of asthma-like disease in adult mice. Offspring with pHA showed at postnatal day 21 (P21): (1) early-onset obesity, greater fat-mass, increased expression of IL-1ß, IL-23, and Tnf-α, greater serum leptin and reduced glucose tolerance than Control (Ctrl); (2) less STAT3/AMPKα-activation, greater SOCS3 expression and reduced AKT/GSK3ß-activation in the lung, indicative of leptin resistance and insulin signaling, respectively; (3) increased lung mRNA of IL-6, IL-13, IL-17A and Tnf-α. At P70 body weight, fat-mass, and cytokine mRNA expression were similar in the pHA and Ctrl, but serum leptin and IL-6 were greater, and insulin signaling and glucose tolerance impaired. Peribronchial elastic fiber content, bronchial smooth muscle layer, and deposition of connective tissue were not different after pHA. Despite unaltered bronchial structure mice after pHA exhibited significantly increased airway reactivity. Our study does not only demonstrate that early-onset obesity transiently activates pulmonary adipocytokine/insulin signaling and induces airway hyperreactivity in mice, but also provides new insights into metabolic programming of childhood obesity-related asthma.

Running Exercise in Obese Pregnancies Prevents IL-6 Trans-signaling in Male Offspring.

PURPOSE: Maternal obesity is known to predispose the offspring to impaired glucose metabolism and obesity associated with low-grade inflammation and hypothalamic dysfunction. Because preventive approaches in this context are missing to date, we aimed to identify molecular mechanisms in the offspring that are affected by maternal exercise during pregnancy. METHODS: Diet-induced obese mouse dams were divided into a sedentary obese (high-fat diet [HFD]) group and an obese intervention (HFD-running intervention [RUN]) group, which performed voluntary wheel running throughout gestation. Male offspring were compared with the offspring of a sedentary lean control group at postnatal day 21. RESULTS: HFD and HFD-RUN offspring showed increased body weight and white adipose tissue mass. Glucose tolerance testing showed mild impairment only in HFD offspring. Serum interleukin-6 (IL-6) levels, hypothalamic and white adipose tissue IL-6 gene expressions, and phosphorylation of signal transducer and activator of transcription 3 in HFD offspring were significantly increased, whereas HFD-RUN was protected against these changes. The altered hypothalamic global gene expression in HFD offspring showed partial normalization in HFD-RUN offspring, especially with respect to IL-6 action. CONCLUSION: Maternal exercise in obese pregnancies effectively reduces IL-6 trans-signaling and might be the underlying mechanism for the amelioration of glucose metabolism at postnatal day 21 independent of body composition.

Developmental regulation of inflammatory cytokine-mediated Stat3 signaling: the missing link between intrauterine growth restriction and pulmonary dysfunction?

Intrauterine growth restriction (IUGR) is a risk factor for impairment of lung function in adolescence and adulthood. Inflammatory and proliferative processes linking IUGR and perturbed extracellular matrix (ECM) as an underlying mechanism have not been addressed so far. Therefore, in this study, we aimed to investigate the developmental regulation of inflammatory and profibrotic processes in the lung subsequent to IUGR. IUGR was induced in rats by isocaloric protein restriction during gestation. Lung function was assessed with direct plethysmography at postnatal day (P) 28 and P70. Lungs were obtained at P1, P42, and P70 for assessment of mRNA, protein expression, immunohistochemistry, and gelatinolytic activity. Both respiratory system resistance and compliance were impaired subsequent to IUGR at P28 and this impairment was even more pronounced at P70. In line with these results, the expression of ECM components and metabolizing enzymes was deregulated. The deposition of collagen was increased at P70. In addition, the expression of inflammatory cytokines and both the activity and the expression of target genes of Stat3 signaling were dynamically regulated, with unaltered or decreased expression at P1 and significantly increased expression art P70. Taken together, these data give evidence for an age-dependent impairment of lung function as a result of a developmentally regulated increase in inflammatory and profibrotic processes subsequent to IUGR.

Inhibition of TGF-ß signaling and decreased apoptosis in IUGR-associated lung disease in rats.

Intrauterine growth restriction is associated with impaired lung function in adulthood. It is unknown whether such impairment of lung function is linked to the transforming growth factor (TGF)-ß system in the lung. Therefore, we investigated the effects of IUGR on lung function, expression of extracellular matrix (ECM) components and TGF-ß signaling in rats. IUGR was induced in rats by isocaloric protein restriction during gestation. Lung function was assessed with direct plethysmography at postnatal day (P) 70. Pulmonary activity of the TGF-ß system was determined at P1 and P70. TGF-ß signaling was blocked in vitro using adenovirus-delivered Smad7. At P70, respiratory airway compliance was significantly impaired after IUGR. These changes were accompanied by decreased expression of TGF-ß1 at P1 and P70 and a consistently dampened phosphorylation of Smad2 and Smad3. Furthermore, the mRNA expression levels of inhibitors of TGF-ß signaling (Smad7 and Smurf2) were reduced, and the expression of TGF-ß-regulated ECM components (e.g. collagen I) was decreased in the lungs of IUGR animals at P1; whereas elastin and tenascin N expression was significantly upregulated. In vitro inhibition of TGF-ß signaling in NIH/3T3, MLE 12 and endothelial cells by adenovirus-delivered Smad7 demonstrated a direct effect on the expression of ECM components. Taken together, these data demonstrate a significant impact of IUGR on lung development and function and suggest that attenuated TGF-ß signaling may contribute to the pathological processes of IUGR-associated lung disease.

Persistent changes within the intrinsic kidney-associated NPY system and tubular function by litter size reduction.

BACKGROUND: Intrauterine growth restriction (IUGR) is associated with an increased risk of renal diseases in adulthood. However, while low-birth-weight-infants often undergo accelerated postnatal growth, the impact of postnatal environmental factors such as nutrition and early postnatal stressors on renal development and function remains unclear. In this context, Neuropeptide Y (NPY) may act as a critical factor. NPY is a sympathetic coneurotransmitter involved in blood pressure regulation and tubular function. Yet, little is known about the expression and function of endogenous NPY in the kidney and the functional relevance for the transmission of persistent postnatal-induced effects. METHODS: (1) IUGR was induced in Wistar rats by isocaloric protein restriction in pregnant dams. (2) Litter size was reduced to 6 (LSR6) or 10 (LSR10) male neonates. To differentiate the effect of postnatal nutrition and stressors, we additionally included home-cage-control animals without any postnatal manipulation. Animals were sacrificed at Day 70. RESULTS: Litter size reduction (LSR) to 6 but not IUGR increased messenger RNA expression of endogenous NPY and down-regulated the NPY-receptors Y1 and Y2. Furthermore, dipeptidylpeptidase IV (DPPIV)--an enzyme that cleaves NPY--was decreased after LSR. Expression and the phosphorylation of mitogen-activated protein kinase 42/44 (intracellular signalling pathway of the receptor Y1) were altered. An impaired renal function with pronounced kaliuresis and natriuresis was observed at Day 70 after LSR. CONCLUSIONS: Postnatal nutrition and stressors such as LSR lead to dysregulated signalling of NPY. These data demonstrate that factors in the early postnatal environment exert important changes in the tubular function, which may predispose to corresponding pathology.