Although it is clear that increased risk of chronic disease and obesity are associated with exposure to both deficiencies and excesses of energy and nutrients in utero and in early life , there has been very little examination of the role of nutrients in the development of food intake regulatory mechanisms in the etiology of metabolic disease. As with many physiological systems, the development of intake control mechanisms would be expected to occur both in utero and in the early life of the offspring.
The interaction among nutrients and development of regulatory systems in determining effects in later life is complex and there are likely multiple mechanisms to explain the outcome. Altered gene expression is a likely factor. In addition, the development of regulatory systems in the GI tract continues after birth and depending on the composition of the food may have long-lasting effects.
Altered expression of genes regulating insulin has been offered as an explanation of the development of obesity through loss of intake control early in life. Insulin is intimately involved in both long- and short-term intake control and the actions of both insulin and leptin are modified by malnutrition. Programmed development of obesity and adipogenic diabetes in rats has been attributed to a permanent dysregulation of the adipoinsular feedback system, again amplified by a hypercaloric diet, leading to hyperleptinemia, leptin resistance, hyperinsulinemia, and compensatory leptin production by pancreatic 8 cells . The offspring of undernourished mothers (30% of the ad libitum intake of the control mothers), cross-fostered during lactation to the control mothers, had lower birth weights than the offspring of control mothers . After weaning, they exhibited higher food intake, systolic blood pressure, and fasting plasma insulin and leptin concentrations than control pups. These effects were amplified by a hypercaloric diet (30 vs. 5% fat), prompting the authors to conclude that hyperphagia is programmed in fetal development and exacerbated by environmental factors.
Epigenetic effects of nutrients and other dietary factors (e.g. antioxidants) during embryonic development, not gene mutations, have recently provided a plausible link between genetic makeup and susceptibility to development of chronic diseases . DNA methylation is a major modifier of the genome, repressing transcription and thus a 'gene silencing' mechanism. Early in development, the genes are not methylated, but this process is thought to occur after implantation of the zygote. Methylation occurs through the action of the DNA methyltransferase, a process in which many vitamins participate. Therefore, certain dietary supplements given during pregnancy and early postnatal life may have an unintended silencing or deleterious effect on gene expression  as shown by the effect of feeding a diet high in vitamins involved in methyl group metabolism on the expression of coat color in the viable yellow Agouti mouse (Avy). The expression of the Agouti gene is characterized by a yellow coat color, obese, diabetic and cancer-prone phenotype. A 3- to 5-fold higher intake of methyl donors and methylation cofactors in the form of choline, betaine, B12 and folate during pregnancy led to a shift towards offspring with the brown coat color phenotype, indicating an epige-netic regulation of the Avy gene through methylation . The resulting phe-notype is characterized by a brown coat color, lean body weight, and normoinsulinemia .
The development of the gene expression of gut hormones involved in the regulation of food intake is at present unknown, as is the influence of the composition of food consumed in early life, but this requires exploration. The ability to potentially modify different populations of enteroendocrine cells may become an important therapeutic strategy for treating and/or preventing excessive food intake and obesity .
Preliminary data support the importance of epigenetic events in the development of intake control mechanisms [39, 40]. Increasing the vitamin content of the diet fed to Wistar rats, only during pregnancy and after implementation of the zygote, predisposes the offspring to impairment of intake control, altered gut hormone response, insulin resistance and obesity. Altered pheno-typic expression due to epigenetic changes appears to be a likely explanation.
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