Mendelian randomization and experimental IUGR reveal the adverse effect of low birth weight on lung structure and function

Kuiper-Makris, Celien; Zanetti, Daniela; Vohlen, Christina; Fahle, L. M.; Müller, Marion; Odenthal, Margarete; Felderhoff-Müser, Ursula; Dötsch, Jörg; Alcázar, Miguel A. Alejandre

doi:10.1038/s41598-020-79245-7

Cited by 10 publications

(13 citation statements)

References 42 publications

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“…However, these data refer to childhood obesity and can only be used as a surrogate for maternal or perinatal obesity. Moreover, consistent with our findings, previous Mendelian randomization analyses indicated a causal effect between birth weight and reduced lung function in adulthood 58 . In addition, previous experimental and clinical studies identified metabolic disorders such as hyperinsulinemia as risk factors for PAH 59 , 60 .…”

Section: Discussionsupporting

confidence: 93%

Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 93%

Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

et al. 2022

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“…Moreover, infants with catch-up growth after IUGR have a higher risk to become overweight or obese and to develop metabolic disorders later in life ( 4 , 153 ). These clinical findings have been supported by experimental models of IUGR ( 154 – 157 ).…”

Section: The Impact Of Perinatal Nutritive Deficiency On the Origins Of Chronic Lung Diseasementioning

confidence: 59%

“…Multiple animal studies have shown that IUGR impairs alveolar formation and lung growth, leading to reduced lung function ( 155 , 174 – 179 ). In addition, a recent study from our group has demonstrated that IUGR also negatively influences angiogenesis and extracellular matrix formation ( 157 ). The intimate link between angiogenesis and alveologenesis has been shown in various animal studies, where alveolar formation was reduced after blocking angiogenesis ( 180 – 182 ).…”

Section: The Impact Of Perinatal Nutritive Deficiency On the Origins Of Chronic Lung Diseasementioning

confidence: 99%

“…An important molecular link between nutrient status, insulin/leptin signaling and metabolic outcome is the mTOR pathway, controlling cell growth in response to its environment (e.g., stress, oxygen, nutrient status) through protein synthesis as well as lipid, nucleotide, and glucose metabolism ( 211 , 212 ). A study from our group has shown that nutrient sensing via the mTOR signaling pathway is dysregulated in lungs from a rat model of nutrient deprivation-induced IUGR ( 157 ). Recent reports demonstrated that the mTOR signaling pathway is also altered in the placenta of humans and in experimental IUGR studies, enforcing adaptive mechanisms from both the maternal nutrient supply and the fetus's energy demands ( 213 , 214 ).…”

Section: The Impact Of Perinatal Nutritive Deficiency On the Origins Of Chronic Lung Diseasementioning

confidence: 99%

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Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases

et al. 2021

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Lung development is not completed at birth, but expands beyond infancy, rendering the lung highly susceptible to injury. Exposure to various influences during a critical window of organ growth can interfere with the finely-tuned process of development and induce pathological processes with aberrant alveolarization and long-term structural and functional sequelae. This concept of developmental origins of chronic disease has been coined as perinatal programming. Some adverse perinatal factors, including prematurity along with respiratory support, are well-recognized to induce bronchopulmonary dysplasia (BPD), a neonatal chronic lung disease that is characterized by arrest of alveolar and microvascular formation as well as lung matrix remodeling. While the pathogenesis of various experimental models focus on oxygen toxicity, mechanical ventilation and inflammation, the role of nutrition before and after birth remain poorly investigated. There is accumulating clinical and experimental evidence that intrauterine growth restriction (IUGR) as a consequence of limited nutritive supply due to placental insufficiency or maternal malnutrition is a major risk factor for BPD and impaired lung function later in life. In contrast, a surplus of nutrition with perinatal maternal obesity, accelerated postnatal weight gain and early childhood obesity is associated with wheezing and adverse clinical course of chronic lung diseases, such as asthma. While the link between perinatal nutrition and lung health has been described, the underlying mechanisms remain poorly understood. There are initial data showing that inflammatory and nutrient sensing processes are involved in programming of alveolarization, pulmonary angiogenesis, and composition of extracellular matrix. Here, we provide a comprehensive overview of the current knowledge regarding the impact of perinatal metabolism and nutrition on the lung and beyond the cardiopulmonary system as well as possible mechanisms determining the individual susceptibility to CLD early in life. We aim to emphasize the importance of unraveling the mechanisms of perinatal metabolic programming to develop novel preventive and therapeutic avenues.

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“…Intrauterine growth restriction (IUGR) is defined as pathological outcomes due to insufficient nutrition resulting in a body weight that is in the lowest tenth percentile of gestational age. Population-based IUGR studies have identified a series of associated postnatal complications, including disordered skeletal muscle maturation, cerebral injuries, metabolic dysfunction, elevated risk of diabetes, and cardiovascular diseases (4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15). Exposure to an adverse intrauterine environment also leads to a higher incidence of neonatal mortality and morbidity, which are reportedly associated with metabolic disorders.…”

Section: Introductionmentioning

confidence: 99%

Intrauterine Growth Restriction Induces Adulthood Chronic Metabolic Disorder in Cardiac and Skeletal Muscles

Lan

et al. 2022

Front. Nutr.

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ObjectiveAlthough population-based studies of intrauterine growth restriction (IUGR) demonstrated a series of postnatal complications, several studies identified that IUGR could definitely cause dysfunction of metabolism of cardiac and skeletal muscles in the perinatal period and early life. However, it is still unknown if such metabolic alternation would remain for long term or not, and whether normal protein diet administration postnatally would protect the IUGR offsprings from a “catch-up growth” and be able to reverse the premature metabolic remodeling.Materials and MethodsWe established an IUGR rat model with pregnant rats and a low-protein diet, and the developmental phenotypes had been carefully recorded. The cardiac and skeletal muscles had been collected to undergo RNA-seq.ResultsAccording to a series of comparisons of transcriptomes among various developmental processes, programmed metabolic dysfunction and chronic inflammation activity had been identified by transcriptome sequencing in IUGR offsprings, even such rats presented a normal developmental curve or body weight after normal postnatal diet feeding.ConclusionThe data revealed that IUGR had a significant adverse impact on long-term cardiovascular function in rats, even they exhibit good nutritional status. So that, the fetal stage adverse events would encode the lifelong disease risk, which could hide in young age. This study remaindered that the research on long-term molecular changes is important, and only nutrition improvement would not totally reverse the damage of IUGR.

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Mendelian randomization and experimental IUGR reveal the adverse effect of low birth weight on lung structure and function

Cited by 10 publications

References 42 publications

Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

Maternal and perinatal obesity induce bronchial obstruction and pulmonary hypertension via IL-6-FoxO1-axis in later life

Perinatal Nutritional and Metabolic Pathways: Early Origins of Chronic Lung Diseases

Intrauterine Growth Restriction Induces Adulthood Chronic Metabolic Disorder in Cardiac and Skeletal Muscles

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