Investigation into the mechanisms by which maternal diet impacts on offspring health the role of programmed changes in the leptin axis

The diet of an individual has important health issues at any stage of life. However there is evidence to suggest that the diet of pregnant and lactating women is particularly important as it has major long-term implications on the health of their babies. It has been shown that individuals with a low birth weight are not only less likely to survive delivery but are also at substantially increased risk of developing obesity as adults. In contrast breast-fed infants, who are known to grow more slowly than bottle-fed infants, are less likely to become obese later in life. The underlying causes of the relationship between early growth and later obesity are not known but we believe that the quality of the diet of women during pregnancy and during breast-feeding is critically important. We have shown in a rodent model that if pregnant animals have too little protein during pregnancy their babies are small at birth and are more likely to become obese in adulthood. We think this is because these animals eat more and exercise less. In contrast in our rodent model where animals grow slowly during lactation because their mothers are eating a diet low in protein, the animals do not get fat even when offered a highly palatable diet. We have identified an important gene in the brain that is expressed at higher levels in animals that are resistant to obesity. We think this makes these animals more responsive to a protein leptin. This protein is produced by fat cells and signals to the brain to suppress appetite and to increase energy expenditure. In this proposal we will test this idea by giving obesity-prone and obesity-resistant animals leptin and thenmeasure their food intake and energy expenditure. We will also study the brains of these animals further to identify other genes that are expressed at different levels. We will study the DNA from the brains of our animals to determine why particular genes are not expressed properly. Understanding these processes will enable us to both identify at risk individuals and to develop intervention strategies to improve the health of both pregnant and breast-feeding women and their offspring.

Fetal and early life nutrition has long-term consequences for adult health. Poor fetal nutrition leads to a 'thrifty' phenotype that appears beneficial when postnatal nutrition is poor, but maladaptive, increasing susceptibility to obesity, when postnatal nutrition is adequate or excessive. In contrast reduced nutrition during the lactation period is protective against subsequent obesity risk. We have developed models in which rats are cross-fostered between mothers fed normal (20 %) or low (8%) protein diets. Control rats are the offspring of dams fed a normal diet. Offspring of low protein fed dams that are cross-fostered to normally fed dams during lactation ('recuperated') are more susceptible to obesity. In contrast control offspring that are suckled by low protein fed dams ('postnatal low protein' or PNLP rats) are less susceptible to diet-induced obesity. Preliminary data suggests that PNLP rats have increased expression of the leptin receptor in the arcuate nucleus of the hypothalamus and increased energy expenditure, whereas recuperated rats have decreased energy expenditure. We aim to establish the molecular mechanisms that link maternal diet with susceptibility to obesity in later life by investigating programmed changes in leptin sensitivity. We shall measure food intake and energy expenditure following peripheral and central administration of leptin in the rat models. We will compare the effects of leptin on the expression of genes involved in its signalling in the arcuate nucleus of the hypothalamus in these three groups by in situ hybridisation and immunohistochemistry. We shall identify genes that are differentially expressed in the arcuate nucleus of control, recuperated and PNLP rats, using laser capture microscopy and microarrays and use bioinformatic tools to identify novel drug targets among these genes. Finally, we shall assess DNA methylation profiles of six of these genes to see whether this contributes to their differential expression. (Joint with Ozanne BB/E00797X/1)