The rapid development of new concepts and tools has led to a change in the way in which researchers carry out nutrition-related research. Obesity is determined by the interaction between predisposing genetic and environmental aspects, but at present the gene–gene and gene–environment interactions contributing to the development of this complex disease cannot be analysed in detail. The purpose of the present paper is to provide some examples of the knowledge that is available in the field of obesity genetics, and also the new strategies being developed that are aimed at studying the relative contribution of numerous genes to obesity and their responses to environmental changes. In the rare cases of monogenic obesities in which a major gene is the cause the molecular approach has proved extremely powerful in the identification of the genes responsible and in defining new syndromes. However, in the common forms of obesity (polygenic obesity) most studies have analysed genotype–phenotype associations without sometimes taking into account the influence of environmental factors (diet, sedentary lifestyle). Among the aspects limiting this integrated approach to obesity are the difficulty of having large enough samples and the expansion of biocomputing tools developed for accessing the question of multiple interactions with no a priori hypotheses. This picture is rapidly changing. Large databases of clinical data and DNA and biological sample banks with more precise environmental information and patient phenotypes are being compiled. The capacity for studying multiple genes simultaneously at the DNA or RNA levels is also possible. Finally, the tremendous progress in biocomputing will allow the integration of these different types of data (relating to environment, phenotype, genotype, gene expression) and will improve the ability to deal with this complex disease.

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The ‘thrifty phenotype’ hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11β-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.

Few researchers would dispute that the pandemic of obesity is caused by a profound mismatch between humanity's present environmental circumstances and those that have moulded evolutionary selection. This concept was first articulated when gestational diabetes was described as being the result of a ‘thrifty genotype rendered detrimental by progress’. More recently, this hypothesis has been extended to the concept of a ‘thrifty phenotype’ to describe the metabolic adaptations adopted as a survival strategy by a malnourished fetus; changes that may also be inappropriate to deal with a later life of affluence. Both the thrifty genotype and the thrifty phenotype hypotheses would predict that populations in some areas of the developing world would be at greater risk of obesity and its co-morbidities; a proposition to be explored in the present paper. To date thrifty genes remain little more than a nebulous concept propagated by the intuitive logic that man has been selected to survive episodic famine and seasonal hungry periods. Under such conditions those individuals who could lay down extra energy stores and use them most efficiently would have a survival advantage. The search for candidate thrifty genes needs to cover every aspect of human energy balance from food-seeking behaviour to the coupling efficiency of oxidative phosphorylation. The present paper will describe examples of attempts to find thrifty genes in three selected candidate areas: maternally-transmitted mitochondrial genes; the uncoupling proteins; apoE4, whose geographical distribution has been linked to a possible thrifty role in lipoprotein and cholesterol metabolism.

Obesity is characterized by an expanded adipose tissue mass. Recent data suggest that adipose tissue is a multi-functional organ rather than simply a passive storage site for excess energy. It has been clearly demonstrated that human adipose tissue produces a variety of secretory factors that exert multiple effects at both the local and the systemic level. To date, >100 products, covering a broad range of protein families as well as many fatty acids and prostaglandins, have been reported to be secreted by adipose tissue. The source of these secreted factors is not only mature fat cells but also poorly-identified cells present in the stromal–vascular fraction including macrophages. Secreted factors of particular interest include many cytokines or chemokines, such as TNF-α, IL-6, IL-8, as well as plasminogen activator inhibitor-1, angiotensin-II, leptin, and adiponectin. In the obese state the expression and secretion of these factors is disturbed. With the exception of adiponectin, most circulating factors are elevated. From this perspective, obesity can be described as a pro-inflammatory condition. In addition, regional differences in adipose expression of many of these factors have been found. There is now growing evidence that many secretory factors play an important role in the pathophysiology of the metabolic and cardiovascular complications of obesity. The question arising from these observations is how the secretory pattern of adipose tissue can be modified by dietary and pharmacological measures to reduce the health risks of obesity.

Conjugated linoleic acid (CLA) is a collective term for a mixture of positional and geometric isomers of conjugated dienoic derivatives of linoleic acid. CLA has received considerable attention as a result of animal experiments that report anti-carcinogenic, anti-atherogenic and anti-diabetic properties, and modulation of body composition and immune function. Several studies of CLA supplementation in human subjects have now been published, but in contrast to animal studies there has been marked variation between reports on the health-related outcomes. The consensus from seventeen published studies in human subjects is that CLA does not affect body weight or body composition. Some detrimental effects of the trans-10,cis-12 CLA isomer have also been reported in terms of altered blood lipid composition and impaired insulin sensitivity. Finally, CLA has only limited effects on immune functions in man. However, there have been reports of some interesting isomer-specific effects of CLA on the blood lipid profile, but not on immune function. These isomer-specific effects need further investigation. Until more is known, CLA supplementation in man should be considered with caution.

Crohn's disease is associated with osteoporosis, malnutrition and altered function of peripheral blood mononuclear cells (PBMC). The responses of circulating immune cells and extra-intestinal manifestations to increased inflammatory activity and to modulation by dietary supplementation are uncertain. The relationships between disease status, bone turnover and body mass and composition, PBMC function and fatty acid availability have been investigated in patients with Crohn's disease. The availability of n-3 and n-6 PUFA is altered in adult patients and interferon (IFN)-γ production by PBMC is lower. Increased inflammatory activity is associated with increased bone resorption in adult patients and decreased body mass in paediatric patients. In healthy male subjects there is a proportionate relationship between supplementary intake of EPA and DHA (0.3–2.0 g as fish oil/d) in combination with antioxidants (vitamins A, C and E and Se) and incorporation into plasma phospholipids and PBMC, and a non-linear relationship with PBMC synthesis of TNF-α, IL-6 and prostaglandin E2 (decrease) and IFN-γ (increase). In adults with Crohn's disease high-dose fish oil (2.7 g EPA+DHA/d) in combination with antioxidants (vitamins A, C and E and Se) increases the EPA and DHA content of PBMC and decreases the production of IFN-γ by PBMC, but is not associated with effects on bone turnover or nutritional status.

Osteoporosis is an important contributor to the global burden of disease, and in the UK alone results in one in three women and one in twelve men aged >50 years experiencing a fragility fracture. Optimising peak bone mass in early adulthood is thought to reduce osteoporosis risk by offsetting bone losses in later life. Ensuring sufficient vitamin D status (measured as 25-hydroxyvitamin D (25OHD) in plasma), among other factors, is believed to facilitate the achievement of optimum peak bone mass. Lower 25OHD is associated with a higher plasma concentration of parathyroid hormone (PTH). As PTH is associated with increased bone turnover and bone loss, maintenance of sufficient 25OHD is thought to have a protective effect on bone health. However, there is a lack of consensus internationally on what constitutes an optimum 25OHD concentration, and values between 30 and 80 nmol/l have been suggested. These values have been based on findings from various studies in adults in which PTH has been observed to plateau at a 25OHD concentration of >30 nmol/l; however, not all studies have found such a plateau. Although studies in younger adolescents (14–16 years) have shown an inverse relationship between PTH and 25OHD, the concentration of 25OHD required for achievement of optimum peak bone mass is unknown. The present review examines the evidence defining vitamin D insufficiency thresholds, and the relevance of such thresholds to adolescent bone health.

Exaggerated postprandial lipaemia may increase the risk of CHD by contributing to both thrombotic and atherogenic processes. Previous research has focused on the quantity and composition of dietary fat, whereas the effect of triacylglycerol (TAG) structure on postprandial lipaemia and clotting factor VII activity has received little attention. TAG with similar fatty acid composition may have different biochemical and physical properties that are dependent on their TAG structure, and these differences may affect lipid metabolism. Recent findings suggest that differences in the physical properties of stearic acid-rich fats are associated with differences in postprandial lipaemia, and may play an important role in determining their rates of digestion and absorption.

Obesity is taking on pandemic proportions. The laws of thermodynamics, however, remain unchanged, as energy will be stored if less energy is expended than consumed; the storage is usually in the form of adipose tissue. Several neural, humeral and psychological factors control the complex process known as appetite. Recently, a close evolutionary relationship between the gut and brain has become apparent. The gut hormones regulate important gastrointestinal functions such as motility, secretion, absorption, provide feedback to the central nervous system on availability of nutrients and may play a part in regulating food intake. Peptide YY (PYY) is a thirty-six amino acid peptide related to neuropeptide Y (NPY) and is co-secreted with glucagon-like peptide 1. Produced by the intestinal L-cells, the highest tissue concentrations of PYY are found in distal segments of the gastrointestinal tract, although it is present throughout the gut. Following food intake PYY is released into the circulation. PYY concentrations are proportional to meal energy content and peak plasma levels appear postprandially after 1 h. PYY3-36 is a major form of PYY in both the gut mucosal endocrine cells and the circulation. Peripheral administration of PYY3-36 inhibits food intake for several hours in both rodents and man. The binding of PYY3-36 to the Y2 receptor leads to an inhibition of the NPY neurones and a possible reciprocal stimulation of the pro-opiomelanocortin neurones. Thus, PYY3-36 appears to control food intake by providing a powerful feedback on the hypothalamic circuits. The effect on food intake has been demonstrated at physiological concentrations and, therefore, PYY3-36 may be important in the everyday regulation of food intake.

The rising tide of obesity has led to a resurgence of interest in dietary strategies to prevent excess weight gain. Data from controlled intervention studies is sparse, but nonetheless evidence from other diverse sources has identified a number of specific dietary factors and aspects of eating behaviour that either promote or protect against obesity. The present paper reviews the evidence in relation to energy density, the macronutrient composition of the diet, including the nature of carbohydrate foods and sugar-rich drinks, portion size and snacking habits. It concludes that there is now sufficient evidence to develop clear dietary guidelines to prevent weight gain that are largely consistent with those for the prevention of CVD and cancer. However, coordinated action across multiple stakeholders is also required if these guidelines are to be translated into sustained changes in eating habits.

Ecological data on temporal trends suggest that the rising prevalence of obesity is, at least in part, attributable to declining population energy expenditure. However, population-level data on trends in physical activity are scarce. In longitudinal cohort studies individuals who report higher levels of leisure-time physical activity tend to be less likely to gain weight, but studies vary in their conclusions because of issues of confounding, reverse causality and measurement error. The majority of studies suggest that low levels of activity are only weakly associated with future weight gain. Questions about dose–response can only be properly addressed by studies including objective measures of activity with known measurement error. The observational studies leave uncertainties about the direction of causality, as individuals who are overweight are less likely to stay active. Adjustment for confounding can diminish the impact of known confounders, but only randomisation can deal with issues of unmeasured confounding. Although there are a large number of clinical trials on the treatment of individuals with obesity or the prevention of weight regain among weight losers, the updated review of trials to prevent weight gain de novo only reveals six trials published since 2000 in adults and eleven in children. Not only are these trials relatively few in number but, for various methodological reasons, they are uncertain in their conclusions about whether increasing activity will be effective in preventing obesity. Whilst efforts should continue to enhance the evidence base it is wise, in the meantime, to stick to the consensus public health advice of advocating 45–60 min moderate intensity activity daily to prevent obesity.

There have been only a few controlled studies on the prevention of overweight and obesity in children and adolescents. These studies differ in relation to strategy, setting, duration, focus, variables of outcome and statistical power, and therefore do not allow general conclusions to be made about the value of preventive measures. All school-based interventions aimed at the prevention of overweight and obesity show some improvement of health knowledge and health-related behaviours. Short-term effects on nutritional state seem to be more pronounced in girls than in boys. School-based interventions can reduce the incidence of overweight. There is evidence that families of intermediate and high socio-economic status as well as intact families benefit more from treatment than families sharing other characteristics. Selected prevention in obese children is most successful when children are treated together with their parents. However, there are social barriers limiting the success of family-based interventions. Although some positive effects have been reported, simple interventions in a single area (e.g. a school health education programme) are unlikely to work on their own. The development of effective preventive interventions probably requires strategies that affect multiple settings simultaneously. At present there is no concerted action, rather many strategies in health promotion that are followed in isolation. Faced with the epidemic of overweight there is a need for national campaigns and action plans on childhood overweight and obesity. It is tempting to speculate that this strategy will also increase the value of isolated approaches (e.g. in schools and families).

Obesity is a serious public health problem that has important social, economic and health consequences. The prevalence of obesity is rising rapidly throughout the world in both rich and poor countries, and it affects all sections of society. There are several important reasons for addressing the prevention of obesity, rather than its treatment or management. The prevention of weight gain (or the reversal of small gains) and the maintenance of a healthy weight are likely to be easier, less expensive and potentially more effective than the treatment of obesity after it has fully developed. A structured planning framework for the identification of potential interventions for the promotion of healthy weight and the prevention of weight gain is clearly required. However, detailed reviews of the scientific literature have revealed that the body of research is too small to provide firm guidance on consistently-effective interventions for adults or children. Ultimately, a broader approach to evidence of effectiveness needs to be adopted. The present paper proposes a structured planning approach that utilises the portfolio model and allows the selection of interventions to be based on the best available evidence, while not excluding untried but promising strategies.

The prevalence of obesity in the general population is high and it is inevitable that artificial feeding will be needed from time to time in the obese patient, particularly in the critical care setting. Against a background of generous endogenous stores of energy as adipose tissue and the ability of obese individuals to survive starvation longer than non-obese individuals, emphasis is placed on preserving lean body mass and optimizing physiological function. Insulin resistance is typical of the obese individual and is exacerbated by stress; overfeeding is dangerous, particularly if it results in hyperglycaemia. Refeeding syndrome also has to be avoided. Weight may be difficult to measure and lean body mass difficult to assess. Calculation of energy requirements is therefore problematic in practice in the obese individual and there is substantial evidence from controlled clinical trials of the safety of feeding at or below resting energy expenditure. If this approach is taken it is wise to provide a more generous than normal protein intake and to beware of patients with a very high baseline urinary N excretion.