Major advances have occurred in food production during the last 30 years as a result of the adoption of ‘green revolution’ technology. The price of rice and wheat is 40 % lower than it was in the 1950s. This lower price has helped the poorer sections of society, who spend 50–60 % of their income on food. The proportion of the population in the developing world that is malnourished fell from 46·5 % in the early 1960s to 31 % in 1995. However, there are still 1·3 billion of the population who go to bed hungry every day. Deficiencies of micronutrients such as Fe, Zn and vitamin A affect millions of the population in the developing world. The world population is increasing at the rate of 1·4 %, or an increase of eighty million per year. It is estimated that we will have to produce 50 % more food grains by 2025. Various strategies for meeting this challenge exist, including the development of cereal varieties with a higher yield potential and yield stability, and farmer-friendly public policies. In order to tackle hidden hunger, efforts are underway to develop crop varieties with higher concentrations of Fe and Zn. Recently, a breakthrough has occurred in the introduction of the genes for the pathway leading to the biosynthesis of β-carotene, a precursor of vitamin A, in rice. Various conventional approaches and modern tools of biotechnology are being employed in the development of crop varieties with higher yields and higher levels of micronutrients.

Metabolism is one of the corner stones of nutritional science. As biology enters the post-genomic era and with functional genomics beginning to take off, we anticipate that the study of metabolism will play an increasingly important role in helping to link advances made via the reductionist paradigm, that has been so successful in molecular and cellular biology, with those emerging from observational studies in animals and human subjects. A reconstructive metabolically-focused approach offers a timely paradigm for enhancing the elegance of nutritional science. Here we give particular attention to the use of tracers as phenotyping tools and discuss the application of our metaprobe concepts with respect to some novel features of metabolism, including ‘underground metabolism’, ‘metabolic hijacking’, ‘catalytic promiscuity’ and ‘moonlighting proteins’. The opportunities for enhancing the study of metabolism by new and emerging technologies, and the importance of the interdisciplinary research enterprise are also touched upon. We conclude that: (1) the metaprobe concepts and approach, discussed herein, potentially yield a quantitative physiological (metabolic) phenotype against which to elaborate partial or focused genotypes; (2) physiological (metabolic) phenotypes which have a whole-body or kinetically-discernible inter-organ tissue-directed metabolic signature are an ideal target for this directed tracer-based definition of the ‘functional’ genotype; (3) metabolism, probed with tracer tool kits suitable for measuring rates of turnover, change and conversion, becomes in the current sociology of the ‘Net’, like AOL, Yahoo, Alta Vista, Lycos or Ask Jeeves, the portal for an exploration of the metabolic characteristics of the ‘Genomics Internet’.

The present review addresses the relative contribution of diet and genotype to variability in human bone growth and mineralisation in the context of the aetiology of osteoporosis. Heritability studies indicate that 60–70 % of the variability in bone mineral mass or bone mineral density (BMD) can be accounted for by genetic variation. Cross-trait analyses suggest that a proportion of this variation reflects genetic influences on bone and body size, such as height and lean body mass. Candidate-gene studies have demonstrated associations between several genetic polymorphisms and bone mineral mass but, as yet, genotype determinations have proved unhelpful in identifying individuals at increased risk of osteoporosis. Variations in diet and other environmental factors contribute 30–40 % to total phenotypic variance in bone mineral mass or BMD. Correlations between intakes of individual nutrients and BMD have been reported, but these relationships are subject to confounding due to size. However, no specific dietary factor has been identified from prospective and twin studies as making a significant contribution to environmental variability in BMD or bone loss. This finding may reflect the difficulties in quantifying environmental exposures, both current and over a lifetime. In addition, the influence of diet on bone health may depend on the genotype of the individual. Optimisation of nutrition and lifestyle remains an attractive strategy for the reduction of fracture risk, but more research is required to fully define optimal dietary requirements.

Population-based studies of human pregnancies show that periconceptional folate supplementation has a significant protective effect for embryos during early development, resulting in a significant reduction in developmental defects of the face, the neural tube, and the cono-truncal region of the heart. These results have been supported by experiments with animal models. An obvious quality held in common by these three anatomical regions is that the normal development of each region depends on a set of multi-potent cells that originate in the mid-dorsal region of the neural epithelium. However, the reason for the sensitive dependence of these particular cells on folic acid for normal development has not been obvious, and there is no consensus about the biological basis of the dramatic rescue with periconceptional folate supplementation. There are two principal hypotheses for the impact of folate insufficiency on development; each of these hypotheses has a micronutrient component and a genetic component. In the first hypothesis the effect of low folate is direct, limiting the availability of folic acid to cells within the embryo itself; thus compromising normal function and limiting proliferation. The second hypothetical effect is indirect: low folate disrupts methionine metabolism; homocysteine increases in the maternal serum; homocysteine induces abnormal development by inhibiting the function of N-methyl-D-aspartate (NMDA) receptors in the neural epithelium. There are three general families of genes whose level of expression may need to be considered in the context of these two related hypotheses: folate-receptor genes; genes that regulate methionine– homocysteine metabolism; NMDA-receptor genes.

Nutrition profoundly alters the phenotypic expression of a given genotype, particularly during fetal and postnatal development. Many hormones act as nutritional signals and their receptors play a key role in mediating the effects of nutrition on numerous genes involved in differentiation, growth and metabolism. Polypeptide hormones act on membrane-bound receptors to trigger gene transcription via complex intracellular signalling pathways. By contrast, nuclear receptors for lipid-soluble molecules such as glucocorticoids (GC) and thyroid hormones (TH) directly regulate transcription via DNA binding and chromatin remodelling. Nuclear hormone receptors are members of a large superfamily of transcriptional regulators with the ability to activate or repress many genes involved in development and disease. Nutrition influences not only hormone synthesis and metabolism but also hormone receptors, and regulation is mediated either by specific nutrients or by energy status. Recent studies on the role of early environment on development have implicated GC and their receptors in the programming of adult disease. Intrauterine growth restriction and postnatal undernutrition also induce striking differences in TH-receptor isoforms in functionally-distinct muscles, with critical implications for gene transcription of myosin isoforms, glucose transporters, uncoupling proteins and cation pumps. Such findings highlight a mechanism by which nutritional status can influence normal development, and modify nutrient utilization, thermogenesis, peripheral sensitivity to insulin and optimal cardiac function. Diet and stage of development will also influence the transcriptional activity of drugs acting as ligands for nuclear receptors. Potential interactions between nuclear receptors, including those for retinoic acid and vitamin D, should not be overlooked in intervention programmes using I or vitamin A supplementation of young and adult human populations.

Like most essential nutrients, Fe needs to be maintained in the body at a defined level for optimal health, with appropriate adaptation to varying Fe needs and supply. The primary mechanism for controlling Fe level is the regulation of Fe absorption. Several different proteins have been identified as contributors to the process. Despite a complex regulatory system, Fe disorders (both Fe deficiency and Fe overload) occur. Fe deficiency is a common problem worldwide, resulting from inadequate dietary Fe and blood loss. Complications include pre-term labour, developmental delay, and impaired work efficiency. No specific genetic syndromes causing isolated Fe deficiency have been described, but animal studies and clinical observations suggest that such a relationship may be a possibility. Conversely, the known causes of Fe overload are genetic. Fe overload is less common than Fe deficiency, but can result in serious medical complications, including cirrhosis, primary liver cancer, diabetes, cardiomyopathy and arthritis. The most common and best characterized syndrome of Fe overload is hereditary haemochromatosis (HHC), an autosomal recessive disorder. Mutations in the HFE protein cause HHC, but the clinical presentation is variable. Of particular interest is the factor that some HFE genotypes appear to be associated with protection from Fe deficiency. Other genetic variants in the regulatory pathway may influence the likelihood of Fe deficiency and Fe overload. Studies of genetic variants in HFE and other regulatory proteins provide important tools for studying the biological processes in Fe regulation. This work is likely to lead to new insights into Fe disorders and potentially to new therapeutic approaches. It will not be complete, however, until coordinated study of both genetic and nutritional factors is undertaken.

Energy balance can affect the risk for hormone-related cancers by altering sex hormone levels. Energy intake and expenditure are difficult to measure in epidemiological studies, but a chronic excess of intake relative to expenditure leads to a high BMI, which can be accurately measured. In premenopausal women obesity has little effect on the serum concentration of oestradiol, but causes an increase in the frequency of anovular menstrual cycles and thus a reduction in progesterone levels; these changes lead to a large increase in the risk for endometrial cancer, but little change, or a small decrease, in the risk for breast cancer. In post-menopausal women oestradiol levels are not regulated by negative feedback, and obesity causes an increase in the serum concentration of bioavailable oestradiol; this factor causes increases in the risk for both endometrial cancer and breast cancer. The development of ovarian cancer appears to be related more strongly to the frequency of ovulation than to direct effects of circulating levels of sex hormones, and BMI is not clearly associated with the risk for ovarian cancer. In men, increasing BMI has little effect on bioavailable androgen levels, and any effect of obesity on prostate cancer risk is small.

Recent theories propose that a Western lifestyle may increase cancer risk through alterations in the metabolism of insulin and insulin-like growth factors (IGF; McKeown-Eyssen, 1994; Giovannucci, 1995; Kaaks, 1996; Werner & LeRoith, 1996). Insulin regulates energy metabolism, and increases the bioactivity of IGF-I, by enhancing its synthesis, and by decreasing several of its binding proteins (IGFBP; IGFBP-1 and -2). Insulin and IGF-I both stimulate anabolic processes as a function of available energy and elementary substrates (e.g. amino acids). The anabolic signals by insulin or IGF-I can promote tumour development by inhibiting apoptosis, and by stimulating cell proliferation. Furthermore, both insulin and IGF-I stimulate the synthesis of sex steroids, and inhibit the synthesis of sex hormone-binding globulin (SHBG), a binding protein that regulates the bioavailability of circulating sex steroids to tissues. The present paper reviews epidemiological findings relating the risk of cancers of the colo-rectum, pancreas, breast, endometrium and prostate to body size (obesity, height) and physical activity, and discusses the relationships between obesity and physical activity and plasma levels of insulin, IGF-I and IGFBP. Subsequent sections review epidemiological findings relating cancer risk to indices of chronic hyperinsulinaemia, and to plasma levels of IGF-I and IGFBP. Conclusions are that chronic hyperinsulinaemia may be a cause of cancers of the colon, pancreas and endometrium, and also possibly of the breast. On the other hand, elevated plasma IGF-I, as total concentrations or relative to levels of IGFBP-3, appears to be related to an increased risk of prostate cancer, breast cancer in young women, and possibly colo-rectal cancer. For cancers of the endometrium, breast and prostate, these findings are discussed in the context of relationships between insulin and IGF-I and levels of bioavailable sex steroids.

Evidence is accumulating that high levels of physical activity are associated with a reduced risk of some cancers. This evidence is most consistent for colon cancer, which is reduced by 40–50 % among the most active individuals, compared with the least active. The effect is evident in men and women, and appears to be independent of important confounding factors. However, there may be important interactions with body fatness; a high BMI has been reported to be associated with an increased risk of colon cancer in sedentary men but not in physically-active men. Whilst the evidence on breast cancer is less consistent, case–control studies typically suggest a reduction of 25–30 % among the most active women, although several studies have found no effect. Potential mechanisms include systemic influences and others relevant only to site-specific cancers. One unifying hypothesis is that physical inactivity reduces insulin sensitivity, leading to a growth-promotional environment which may facilitate neoplasia. The non-specific immune system may be improved by physical activity, possibly through the summative effects of repeated exercise bouts. Regular exercise, even at a recreational level, probably reduces exposure to oestrogen and thus decreases the risk of breast cancer. Increased colonic peristalsis, and thus reduced bowel transit time, might partly explain the lower risk of colon cancer in active people. Physical activity emerges as one of the few modifiable risk factors for some cancers and, as such, justifies further study.

Selection in commercial populations on aspects of output, such as for growth rate in poultry, against fatness and for growth rate in pigs, and for milk yield in cows, has had very large effects on such outputs over the past 50 years. Partly because of the cost of recording intake, there has been little or no selection for food intake or feeding behaviour. In order to predict the effects of such past, and future, selection on intake it is necessary to have some suitable theoretical framework. Intake needs to be predicted in order to make rational feeding and environmental decisions. The idea that an animal will eat ‘to meet its requirements’ has proved useful and continues to be fruitful. An important part of the idea is that the animal (genotype) can be described in a way that is sufficient for the accurate prediction of its outputs over time. Such descriptions can be combined with a set of nutritional constants to calculate requirements. There appears to have been no change in the nutritional constants under selection for output. Under such selection it is simplest to assume that changes in intake follow from the changes in output rates, so that intake changes become entirely predictable. It is suggested that other ways that have been proposed for predicting intake cannot be successful in predicting the effects of selection. Feeding behaviour is seen as being the means that the animal uses to attain its intake rather than being the means by which that intake can be predicted. Thus, the organisation of feeding behaviour can be used to predict neither intake nor the effects of selection on it.

The hypothalamus is a major regulatory centre involved in the control of many important physiological axes. One of these axes is the regulation of ingestive behaviour. Recent work using a combination of genetic-mutant mouse models together with targeted gene deletions has contributed much to our understanding of how neural pathways of the hypothalamus are involved in the regulation of energy balance in animals. These pathways are also relevant to human energy homeostasis, as mutations in key genes are correlated with obesity. Many of the genes identified mediate the effects of leptin, and are therefore primarily involved in sensing and responding to peripheral signals. In seasonal animals, such as the Siberian hamster (Phodopus sungorus), there is evidence for a higher level of regulation. The systems involved regulate body weight around an apparent 'set-point' through the action of photoperiod via the neurohormone, melatonin. The ability to manipulate energy balance through photoperiod (and melatonin) in the seasonal-animal model offers novel opportunities to identify further fundamental aspects of the control mechanisms involved in the central control of energy homeostasis and body weight.

Certain dietary risk factors for physical ill health are also risk factors for depression and cognitive impairment. Although cholesterol lowering has been suggested to increase vulnerability to depression, there is better support for an alternative hypothesis that intake of n-3 long-chain polyunsaturated fatty acids can affect mood (and aggression). Possible mechanisms for such effects include modification of neuronal cell membrane fluidity and consequent impact on neurotransmitter function. Stronger evidence exists concerning a role for diet in influencing cognitive impairment and cognitive decline in older age, in particular through its impact on vascular disease. For example, cognitive impairment is associated with atherosclerosis, type 2 diabetes and hypertension, and findings from a broad range of studies show significant relationships between cognitive function and intakes of various nutrients, including long-chain polyunsaturated fatty acids, antioxidant vitamins, and folate and vitamin B12. Further support is provided by data on nutrient status and cognitive function. Almost all this evidence, however, comes from epidemiological and correlational studies. Given the problem of separating cause and effect from such evidence, and the fact that cognitive impairment and cognitive decline (and depression) are very likely to be significant factors contributing to the consumption of a poor diet, greater emphasis should now be placed on conducting intervention studies. An efficient approach to this problem could be to include assessments of mood and cognitive function as outcome measures in studies designed primarily to investigate the impact of dietary interventions on markers of physical health.

The purpose of the present paper is to review recent theoretical developments in food intake modelling applied to animal science and ecology. The models are divided into those that have been developed for intensive agricultural systems, and those which consider more extensive systems and natural systems. For the most part the present paper discusses models that predict the food intake of herbivores. The mechanisms of each model are discussed, along with a brief mention of the experimental support for the most popular models. We include a discussion of models that approach the study of food intake behaviour from an evolutionary perspective, and suggest that lifetime models are especially useful when food intake carries an intrinsic cost. These long timescale evolutionary models contrast with the more common food intake models, whose timescale is usually much shorter. We conclude that the ‘eating to requirements’ model highlights an important food intake mechanism that provides an accurate predictive tool for intensive agricultural systems. The mechanisms of food intake regulation in extensive systems are less certain, and closer links between the ideas of animal science and ecology will be helpful for improving our understanding of food intake regulation.