Physiological signals critical periods and hypothalamic mechanisms underlying neonatal programming of adult hyperphagia by maternal over-nutrition

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Extensive epidemiological and animal-based studies have demonstrated that maternal obesity not only heightens the complications commonly associated with pregnancy, but also increases the long-term risks of metabolic and cardiovascular disease in offspring. This effect is independent of any direct genetic cause. Inheritance of a characteristic which has been acquired by the mother raises important biological issues; consequently, the full significance of this phenomenon extends beyond the immediate context of energy balance. Nevertheless, the immediate implications of these findings provide important perspectives on the escalating problems of obesity, which threaten to overwhelm our healthcare services. We have recently developed an experimental protocol in which female rats or mice are given a highly palatable diet, rich in sugar and fat, before conception and throughout gestation and lactation. This diet results in overt obesity and mimics the obesogenic food which is commonly eaten throughout the western hemisphere. Although the pups of these rodents are raised on a normal diet from weaning, by adulthood they show increased appetite and obesity, with signs of type-2 diabetes and cardiovascular disease. Fifteen years ago a novel hormone secreted by fat cells was discovered and named leptin (from the Greek leptos, meaning thin). When administered in adulthood to normal rodents or to mice which are deficient of this hormone, leptin suppresses feeding. In chronic cases of obesity, however, leptin is ineffective; under such conditions, humans and rodents are said to be leptin-resistant. During the first ten days after birth, rodents produce a surge of leptin in the blood. This enters the brain and promotes the growth of pathways in the hypothalamus, the part of the brain which controls appetite. One of the most striking changes we have found in the rodents programmed for high appetite by maternal over-nutrition is a massively raised and prolonged surge of leptin before weaning. We have also found leptin-resistance in these animals by postnatal day 30 (9 days after weaning), long before they are overtly obese. These animals show a loss of leptin's ability to suppress feeding behaviour, and also a reduction in the cellular activity normally induced by leptin within the appetite-regulating part of the hypothalamus. These findings lead us to hypothesise that chemical signals in the mother's milk promote the abnormal surge of leptin in the pup's blood. We also hypothesise that the consequent over-stimulation of leptin-sensitive circuits in the hypothalamus results in chronic leptin-resistance and a persistently unrestrained appetite. The proposed research will elucidate the chemical signals received from the mother and the critical period during which those signals influence the infant's future appetite by excess secretion of leptin. The therapeutic possibilities of increasing the ratio of beneficial fatty acids in the maternal diet will be addressed. We will also elucidate the processes causing the hypothalamus to become leptin-resistant and the effects on appetite-regulating circuits. These studies will increase our understanding of the biological mechanisms which underlie the ways in which maternal obesity may influence the long-term health of offspring.