Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis

Abstract

Epidemiological studies in humans suggest that maternal undernutrition, obesity and diabetes during gestation and lactation can all produce obesity in offspring. Animal models have allowed us to investigate the independent consequences of altering the pre-versus post-natal environments on a variety of metabolic, physiological and neuroendocrine functions as they effect the development in the offspring of obesity, diabetes, hypertension and hyperlipidemia (the 'metabolic syndrome'). During gestation, maternal malnutrition, obesity, type 1 and type 2 diabetes and psychological, immunological and pharmacological stressors can all promote offspring obesity. Normal post-natal nutrition can reduce the adverse impact of some of these pre-natal factors but maternal high-fat diets, diabetes and increased neonatal access to food all enhance the development of obesity and the metabolic syndrome in offspring. The outcome of these perturbations of the perinatal environmental is also highly dependent upon the genetic background of the individual. Those with an obesity-prone genotype are more likely to be affected by factors such as maternal obesity and high-fat diets than are obesity-resistant individuals. Many perinatal manipulations appear to promote offspring obesity by permanently altering the development of central neural pathways, which regulate food intake, energy expenditure and storage. Given their strong neurotrophic properties, either excess or an absence of insulin and leptin during the perinatal period are likely to be effectors of these developmental changes. Because obesity is associated with an increased morbidity and mortality and because of its resistance to treatment, prevention is likely to be the best strategy for stemming the tide of the obesity epidemic. Such prevention should begin in the perinatal period with the identification and avoidance of factors which produce permanent, adverse alterations in neural pathways which control energy homeostasis.

Serotonin controlling feeding and satiety

“…The impact of the nutritional environment during early development is a wellestablished fact [370][371][372][373][374]. 5-HT could possibly have a twofold role here, as 5-HT synthesis depends on tryptophan of nutritional origin, but then the 5-HT satiety system controls feeding itself.…”

“…Evidence has accumulated over the last decades that the nutritional environment during early developmental periods has a significant impact on physiology and pathophysiology in adult age [372,373,385,386]. In this context, the aforementioned role of 5-HT in neural development leads to the question how the developing serotonergic system interacts with the early nutritional environment.…”

Gestational weight gain in relation to offspring body mass index and obesity from infancy through adulthood

“…All childhood BMI measurements were transformed to BMI Z-scores (BMI-Z), using the British 1990 growth references 20 for gender and exact age. For adults (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34) and 42 years), internal sex-specific BMI-Z was created to compare the results with those obtained in children. Analyses, including BMI at the draft board (16-23 years) and the first adult follow-up examination (20-34 years), were adjusted for current age.…”

Relevance of animal models to human eating disorders and obesity

“…For example, rat pups from mothers fed a high-fat diet during gestation cross fostered to dams consuming a low-fat diet during lactation became more obese than pups whose mothers consumed a low-fat diet during gestation and were cross fostered to female rats consuming a high-fat diet during lactation (Levin 2006). Animal studies have revealed that malnutrition (Jones et al 1984), insulin injections (Jones et al 1996), and maternal stress, such as injection of endotoxins and immunosuppressants during gestation, also predispose offspring to adult obesity (Levin 2006). The composition and volume of maternal milk are also important determinants of the development of metabolic regulation (Levin 2006).…”

“…Animal studies have revealed that malnutrition (Jones et al 1984), insulin injections (Jones et al 1996), and maternal stress, such as injection of endotoxins and immunosuppressants during gestation, also predispose offspring to adult obesity (Levin 2006). The composition and volume of maternal milk are also important determinants of the development of metabolic regulation (Levin 2006). Milk volume is experimentally increased by reducing the number of pups that a mother feeds.…”