Early-Life Nutrition and Metabolic Disorders in Later Life: A New Perspective on Energy Metabolism
The global epidemic of type 2 diabetes mellitus (T2DM) and other metabolic disorders has become a significant public health concern. Despite extensive research, the pathogenesis of these conditions remains largely unclear, and effective prevention and treatment strategies are still limited. While environmental factors during adulthood, such as obesity, high-calorie diets, and physical inactivity, are well-known contributors to metabolic disorders, emerging evidence suggests that early-life nutrition plays a crucial role in shaping long-term metabolic health. This review explores the concept of fetal programming and investigates the effects of early-life nutrition on energy metabolism in later life, with a focus on the potential epigenetic mechanisms involved.
Introduction
Metabolic disorders, particularly T2DM, have reached pandemic proportions. According to the World Health Organization, high blood glucose is the third leading global risk factor for mortality, following high blood pressure and tobacco use. In 2019, the International Diabetes Federation estimated that approximately 463 million adults aged 20 to 79 years had diabetes, accounting for 9.3% of the global adult population. If current trends continue, this number is projected to rise to 700.2 million by 2050, posing a significant economic burden worldwide. China, in particular, has the largest number of diabetic patients globally, with the prevalence of diabetes continuing to rise rapidly.
Traditionally, genetic factors and adult lifestyle choices have been considered the primary contributors to metabolic disorders. However, recent clinical and experimental studies have highlighted the importance of early-life nutrition in influencing the risk of metabolic abnormalities in adulthood. The Developmental Origins of Health and Disease (DOHaD) hypothesis emphasizes the link between early life stages, including the perinatal period and infancy, and the development of metabolic disorders later in life. This hypothesis suggests that the fetus or newborn adapts to the early-life nutritional environment to ensure immediate survival, but these adaptations may lead to a mismatch with postnatal conditions, increasing the risk of chronic diseases in adulthood.
Early-Life Undernutrition and Metabolic Disorders in Later Life
Epidemiological studies and animal models have demonstrated that early-life undernutrition can have lasting effects on energy metabolism and increase the risk of metabolic disorders in adulthood. The “thrifty phenotype” hypothesis, proposed by Barker, suggests that maternal undernutrition during pregnancy and early postpartum programs offspring to adapt to a thrifty environment, leading to various dysfunctions later in life.
Clinical Evidence
Famine studies provide valuable insights into the effects of early-life undernutrition on metabolic health. The Dutch Hunger Winter Families Study, which examined individuals born during the Dutch famine of 1944-1945, found that maternal undernutrition during pregnancy was associated with a higher prevalence of T2DM and lipid profile disorders in adult offspring. Similarly, the Great Chinese Famine cohort studies revealed that maternal undernutrition during pregnancy and lactation significantly increased the risks of metabolic syndrome, non-alcoholic fatty liver disease, and visceral fat dysfunction in adult offspring.
Animal Models
Animal studies have further validated the link between early-life undernutrition and metabolic disorders. For example, maternal food restriction in mice resulted in lower birth weight, impaired glucose tolerance, and increased adipocyte size in adult offspring. Interestingly, postnatal catch-up growth exacerbated these metabolic abnormalities, supporting the “metabolic memory” hypothesis. Maternal low-protein diets have also been shown to program increased risks of glucose intolerance and lipid metabolic disorders in offspring.
Overnutrition in Early Life and Energy Metabolism in Later Life
While undernutrition has been extensively studied, the impact of early-life overnutrition on metabolic health has gained increasing attention in recent years.
Clinical Evidence
Maternal obesity during pregnancy and lactation is a significant risk factor for metabolic disorders in offspring. The Helsinki Birth Cohort Study found that maternal body mass index (BMI) during pregnancy was positively associated with cardiovascular disease and T2DM in offspring. Similarly, the Generation R Study demonstrated that maternal obesity during pregnancy increased the risks of childhood obesity and adverse cardiometabolic outcomes, such as higher systolic blood pressure and insulin levels.
Animal Models
Animal studies have provided mechanistic insights into the effects of maternal overnutrition on offspring metabolic health. Maternal high-fat diet (HFD) intake during pregnancy and lactation has been shown to increase body weight, adiposity, and the risk of metabolic disorders in offspring. These effects are mediated by alterations in the insulin signaling pathway, islet structure, and gut microbiota. Maternal HFD has also been associated with changes in brain insulin receptors and glucose uptake, predisposing offspring to metabolic-neurodegenerative diseases.
Role of Epigenetics in Mediating Metabolic Programming
Epigenetic mechanisms, including DNA methylation, histone modifications, and non-coding RNAs (ncRNAs), play a crucial role in mediating the effects of early-life nutrition on metabolic health.
DNA Methylation
DNA methylation is a well-studied epigenetic mechanism that regulates gene expression. Changes in DNA methylation of metabolic-associated genes have been linked to early-life nutritional exposure. For example, elevated methylation levels in the insulin-like growth factor 2 (IGF2) gene were associated with exposure to the Chinese Great Famine and increased total cholesterol levels in late adulthood. Maternal obesity has also been shown to alter DNA methylation patterns in the placenta, umbilical cord, and offspring tissues.
miRNAs
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the post-transcriptional level. Dysregulation of miRNAs has been implicated in insulin sensitivity, glucose homeostasis, and metabolic disorders. Maternal undernutrition and overnutrition have been shown to alter miRNA expression in offspring, affecting key metabolic pathways.
Histone Modifications
Histone modifications, such as acetylation and methylation, regulate chromatin structure and gene expression. Maternal nutritional exposure has been shown to alter histone modifications in offspring, influencing metabolic gene expression and long-term metabolic health.
Early-Life Interventions and Metabolic Health
Given the critical role of early-life nutrition in shaping metabolic health, early-life interventions have emerged as a promising strategy for preventing metabolic disorders.
Lifestyle Modifications
Lifestyle interventions, such as dietary management and physical activity during pregnancy, have shown potential in improving maternal and offspring metabolic health. However, the effectiveness of these interventions varies, and further research is needed to optimize their implementation.
Dietary Bioactive Compounds
Dietary bioactive compounds, such as resveratrol and genistein, have been shown to counteract the adverse effects of maternal malnutrition on offspring metabolic health. Maternal resveratrol supplementation during pregnancy and lactation has been associated with improved glucose tolerance, lipid metabolism, and gut microbiota in offspring.
Nutritional Interventions
Nutritional interventions, including folic acid supplementation, have been explored for their potential to prevent metabolic disorders. While some studies have shown beneficial effects, the impact of these interventions may depend on maternal baseline health and nutritional status.
Conclusion and Future Prospects
This review highlights the critical role of early-life nutrition in shaping long-term metabolic health. Both maternal undernutrition and overnutrition during pregnancy and lactation can program increased risks of metabolic disorders in offspring. Epigenetic mechanisms, including DNA methylation, miRNAs, and histone modifications, mediate these effects. Early-life interventions, such as lifestyle modifications, dietary bioactive compounds, and nutritional interventions, offer promising strategies for preventing metabolic disorders.
Characterizing the early-life nutritional factors that reshape metabolic disease trajectories may yield novel targets for early prevention and intervention. By extending the focus on metabolic health to early life stages, we can potentially reduce the global burden of T2DM and other metabolic disorders. Future research should aim to elucidate the specific mechanisms underlying the effects of early-life nutrition on metabolic health and optimize early-life interventions for maximum benefit.
doi.org/10.1097/CM9.0000000000000976
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