Cost-effective prevention strategies to prevent weight gain and the development of obesity should be based on appropriate knowledge of the determinants of weight gain. The body of evidence on the dietary determinants of weight gain is, however, fragmentary at best, partly because inappropriate research methods are used to study the determinants of obesity under normal circumstances. Evidence from studies using experimental diets have shortcomings because of their short duration and selection of highly-motivated subjects and because the outcomes can be easily influenced by the choice of foods to be used in the intervention. Of the observational studies, many have severe methodological shortcomings, e.g. ecological studies, cross-sectional surveys and classical cohort studies in which the baseline diet is linked to subsequent weight development over long periods of time. Longitudinal studies with repeated measurements in which changes in diet and physical activity are linked to changes in weight are probably the most informative, but these studies are relatively rare. There is a great interest in interventions that are effective and efficient for the prevention of obesity. Many countries and research funding agencies seem to show a strong tendency to develop interventions for children and adolescents exclusively. It can be easily shown, however, that intervention programmes are much more likely to be cost-effective in older adults than in children, which indicates that adults should not be neglected as target populations for obesity prevention. Obesity prevention should follow a life-course approach, as currently recommended for non-communicable diseases in general by the WHO.

Obesity is a risk factor for the development of type 2 diabetes and CVD. Is adipose tissue the culprit in the relationship between obesity and metabolic disease? It iscertainly possible to argue that adipose tissue function is disturbed in obesity in sucha way that adverse consequences may follow. For instance, lipolysis is down regulated, the sensitivity of lipolysis to insulin is reduced and there are disturbances in the regulation of adipose tissue blood flow. However, when examined critically these changes canbe seen as adaptations to the increased adipose tissue mass, making the situation betterrather than worse. In terms of the many peptide and other factors now known to be secreted from adipose tissue, it is easier to argue that adipose tissue is the culprit. However, for no single ‘adipokine’ is there as yet unequivocal evidence of a link between adipose tissue secretion and adverse metabolic events in other tissues. The bestdocumented of these adipokines in relation to insulin resistance is adiponectin. Here, unusually, adiponectin confers insulin sensitivity, and its secretion is down regulated in obesity. It could be again that adipose tissue has down regulated its function in an attempt to compensate for itsincreased mass, although certainly that down-regulation is too extreme. On balance, it is clear that adipose tissue is a link in the chain of events leading to metabolic disease, but in many respects it is an innocent intermediary trying to deal with the consequences of positive energy balance, the real culprit.

Atherosclerotic CVD is the most common cause of death in the West. Yet, its pathogenesis and early development are only partially understood. Central to the early atherosclerotic process is impairment of vascular endothelial function. Endothelial dysfunction can be measured non-invasively and is evident in children before clinical manifestations of atherosclerosis in adulthood. Factors in early life, such as conventional cardiovascular risk factors, or programming by perinatal growth and nutrition strongly affect endothelial function and hence the development of atherosclerosis and CVD. For instance, low birth weight and faster growth early in infancy have a detrimental effect on vascular structure and function. Childhood obesity, a key independent risk factor for CVD, also adversely affects early vascular health. Obesity is associated with endothelial dysfunction and greater arterial stiffness from as early as the first decade of life, while weight loss is beneficial. This effect on vascular function is probably mediated in part by low-grade inflammation and insulin resistance associated with obesity or by the production by adipose tissue of cytokine-like molecules, collectively termed adipokines. A high leptin concentration, in particular, is found in obese individuals and is strongly associated with vascular changes related to early atherosclerosis. The present review focuses on the early origins of endothelial dysfunction, emphasising the role of obesity. It also considers the mechanisms by which obesity impairs endothelial function, understanding of which will be important to further scientific knowledge and to improve public health.

The metabolic syndrome is a very common condition, characterised by insulin resistance, dyslipidaemia, abdominal obesity and hypertension, that is associated with a high risk of type 2 diabetes mellitus (T2DM) and CVD. Obesity is a key aetiological factor in the development of the metabolic syndrome. In light of the increasing prevalence of obesity, there is a high requirement to reduce the impact of the adverse health effects associated with the metabolic syndrome. The aetiological role of nutrient-derived metabolic stressors, in particular fatty acids, in the development of obesity and the metabolic syndrome is explored. Also, the evidence that pro-inflammatory stressors may predispose to obesity-induced insulin resistance is reviewed. The present paper explores the concept that reducing the impact of metabolic and inflammatory stressors may reduce the adverse health effects of obesity and slow the progression towards the metabolic syndrome and T2DM. Evidence from human dietary intervention studies that have investigated the potential therapeutic effects of dietary fatty acid modification is explored. The present review highlights the requirement to take account of genetic background, within the context of nutrient regulation of gene expression and individual responsiveness to dietary therapy. This approach will further the understanding of the interaction between fatty acids in the pathogenesis and progression of the metabolic syndrome.

Obesity is a multidisciplinary area, the ‘biology’ of which encompasses: (1) the fundamental mechanisms of energy balance and its regulation; (2) the biological basis for the development of obesity; (3) adipose tissue function; (4) the biological description of the obese state; (5) the pathological consequences of obesity; (6) the physiological basis for treatment strategies. At a mechanistic level, important developments in recent years include the identification of novel neuroendocrine factors in the control of appetite (such as cocaine- and amphetamine-regulated transcript, the orexins, the endocannabinoids) and the discovery of new peripheral signals (such as leptin, ghrelin). Despite the identification of additional uncoupling proteins (UCP2, UCP3), mitochondrial uncoupling in brown adipose tissue through UCP1 remains the only major mechanism for adaptive thermogenesis. White adipose tissue (WAT) has now moved centre stage in energy balance and obesity research, and there are three main reasons: (1) it is the organ which defines obesity; (2) it is the source of a critical endocrine signal in the control of body weight; (3) it secretes a range of diverse protein factors, termed adipokines, some of which are directly implicated in the pathologies associated with obesity. WAT is now recognised as a key endocrine organ, communicating both with the brain and peripheral tissues through the adipokines. Obesity is characterised by mild inflammation, and WAT may be the main locus of the inflammatory state, producing cytokines, chemokines, acute-phase proteins and angiogenic factors. It has been suggested that inflammation in obesity is principally an adaptive response to hypoxia in clusters of adipocytes within the expanding adipose mass.

The regulation of energy balance is complex and, in man, imprecise. Nevertheless, in many individuals intake and expenditure are balanced with <1% error with little or no conscious effect. Essential components of such a regulatory system are signals, leptin and insulin, that reflect the size of lipid stores. Leptin receptors signal via phosphatidylinositol 3-kinase (as do insulin receptors) and via the transcription factor signal transducer and activator of transcription-3 to activate various types of neurone. Obese rodents, and possibly man, are resistant to leptin; in some cases because of genetic or perinatal programming (primary resistance), but commonly in response to high leptin levels (secondary resistance). Secondary leptin resistance may be a result of reduced transport of leptin to the brain or down-regulation of leptin signalling. Signals that reflect lipid stores form the tonic homeostatic regulatory system. They interact with episodic homeostatic signals carried by neurones, hormones and metabolites to regulate meal size and frequency. They also interact with signals related to the palatability of food, biorhythms and learning. Many neurotransmitters and hormones mediate responses to more than one input (e.g. gastric and adipocyte leptin), but are nevertheless most involved with particular inputs (e.g. leptin with adipocyte fat stores). Feeding can be divided into appetitive (preparation for feeding) and consummatory phases, which can both be further subdivided. Different sets of neurotransmitters and hormones are involved at each stage. In the long term it may be possible to customise obesity therapies according to those inputs and outputs that are most disturbed and most amenable to intervention in individual subjects.

While investigating the reversible seasonal obesity of Siberian hamsters, direct sympathetic nervous system (SNS) postganglionic innervation of white adipose tissue (WAT) has been demonstrated using anterograde and retrograde tract tracers. The primary function of this innervation is lipid mobilization. The brain SNS outflow to WAT has been defined using the pseudorabies virus (PRV), a retrograde transneuronal tract tracer. These PRV-labelled SNS outflow neurons are extensively co-localized with melanocortin-4 receptor mRNA, which, combined with functional data, suggests their involvement in lipolysis. The SNS innervation of WAT also regulates fat cell number, as noradrenaline inhibits and WAT denervation stimulates fat cell proliferation in vitro and in vivo respectively. The sensory innervation of WAT has been demonstrated by retrograde tract tracing, electrophysiological recording and labelling of the sensory-associated neuropeptide calcitonin gene-related peptide in WAT. Local injections of the sensory nerve neurotoxin capsaicin into WAT selectively destroy this innervation. Just as surgical removal of WAT pads triggers compensatory increases in lipid accretion by non-excised WAT depots, capsaicin-induced sensory denervation triggers increases in lipid accretion of non-capsaicin-injected WAT depots, suggesting that these nerves convey information about body fat levels to the brain. Finally, parasympathetic nervous system innervation of WAT has been suggested, but the recent finding of no WAT immunoreactivity for the possible parasympathetic marker vesicular acetylcholine transporter (VAChT) argues against this claim. Collectively, these data suggest several roles for efferent and afferent neural innervation of WAT in body fat regulation.

Obesity treatment remains a ‘Cinderella’ of all clinical management programmes, but generally without a happy ending. The great expectation for new therapeutic agents has not been fulfilled in clinical practice, whilst the restriction of eating through surgical division of the upper bowel seems strange in an age of advanced and sophisticated technology. The better understanding of the neuro-regulation of appetite, and its application as part of evidence-based clinical interventions, could lead to a more coherent approach to obesity treatment. Nevertheless, investigation of potential neuroendocrine targets for appetite suppression suggests redundancy in the systems, which make development of effective agents against single receptors impractical. Importantly, the progressive rise in the prevalence of obesity will inevitably mean that only a small proportion of afflicted patients will actually be treated by long-term drugs and surgery. Drugs and surgery are not currently the answer for the majority of obese individuals. What is required is a better way of identifying patients who may particularly benefit from such approaches. However, the major emphasis must be the development of effective population-wide interventions that halt the increase in fatness and ensure that future generations maintain and enjoy a healthy body weight.

Childhood obesity poses one of the greatest challenges to paediatric health in the 21st century. Developing effective strategies for treatment and prevention is therefore a priority for clinical medicine and public health. This process is taking place at a time of unprecedented change in the understanding of the role of genetic factors in human health and disease, and genetic research into obesity has challenged assumptions about causal processes. In the spirit of the conference theme, the present paper will discuss the implications of the understanding of genetic and environmental influences on obesity for the development of effective behavioural treatments.

Currently, in many European countries more than half the adult population is overweight; it hass become ‘abnormal’ to be of ‘normal weight’. The risk of type 2 diabetes, CVD, hypertension and certain forms of cancer increase with increasing weight. Biological evolution has produced body-fat-regulating mechanisms that are more powerful in protecting against weight loss than against weight gain. The current environment offers constant availability of affordable palatable energy-rich foods, with no need to consume the energy through physical activity. The ‘obesogenic’ environment is to some extent a political issue, but it has been shown that the healthcare system can also have a role in preventing obesity-related morbidity. The Finnish Diabetes Prevention Study was the first controlled randomised study to show that individualised lifestyle counselling of individuals with high risk of developing type 2 diabetes can influence diet, physical activity and body weight, and that type 2 diabetes can be prevented, or at least postponed. Most importantly, lifestyle changes do not have to be extreme. If the population would adopt a lifestyle in line with the official nutrition recommendations, the obesity and diabetes trend could at least be stabilised.

Obesity is a serious and increasing health issue. Approximately two-thirds of adults in the UK are now overweight or obese. Recent public health reports firmly reinforce the importance of engaging individuals to look after their health, including their weight. They also spell out the need for individuals to be supported more actively, on many levels, to enable this ‘engagement’. Meanwhile, national surveys indicate that approximately two-thirds of adults are concerned about weight control, with one-third actively trying to lose weight. This finding is hardly surprising considering current weight statistics, plus the plethora of popular diets on offer. Weight-loss methods include diet clubs, diet books, exercise, meal replacements, advice from healthcare professionals and following a self-styled diet. Obesity is a multi-factorial problem, and losing weight and, in particular, maintaining weight loss is difficult and often elusive. It is argued that the modern obesogenic or ‘toxic’ environment has essentially taken body-weight control from an instinctive ‘survival’ process to one that needs sustained cognitive and skill-based control. The evidence suggests that health professionals can help individuals achieve longer-term weight control by supporting them in making sustainable lifestyle changes using a range of behavioural techniques. These techniques include: assessing readiness to change; self-monitoring; realistic goal setting; dietary change; increased physical activity; stimulus control; cognitive restructuring; relapse management; establishing ongoing support. Consistently working in a client-centred way is also being increasingly advocated and incorporated into practice to help motivate and encourage, rather than hinder, the individual's progress.

Obesity is often difficult to tackle in primary care. Pressure of time in the consultation, a lack of appropriately-trained primary care staff, a shortage of community dietitians or nutritionists, the potentially enormous caseload, language or cultural barriers and the sheer intractability of patients' eating habits, exercise behaviour and their clinical condition, all conspire to make general practitioners, other team members and often the patients themselves lose heart and stop even trying. However, there are ways of overcoming these difficulties. Examples of changes that evidence suggests are able to support and enhance basic one-to-one interventions in general practice include: improved clinical guidelines; better training of primary care staff; at-risk patient registers; smarter database search tools; new quality incentives; closer working with dietitians, counsellors and pharmacists; more hospital outreach clinics; designated general practitioner specialists and practice clustering; expanded exercise referral schemes and links with leisure providers; subsidised referral to commercial slimming groups; better use of patient groups and voluntary and community workers. The present paper describes a proposed ‘triple-tier’ pathway for weight management incorporating most of the elements mentioned earlier. With a more joined-up and creative approach to the development and organisation of primary care, more comprehensive training and workforce planning, and better integration with social care, voluntary groups and the commercial sector, weight management in general practice has the potential to be much more effective.

The present review considers the background to terminology that relates foods, glycaemia and health, including ‘available carbohydrate’, ‘glycaemic index’ (GI), 'glycaemic glucose equivalent', 'glycaemic response index' and 'net carbohydrate', and concludes that central to each of these terms is 'glycaemic load' (GL). GL represents the acute increase in exposure of tissue to glucose determined by foods; it is expressed in ingested glucose equivalents (per 100 g fresh weight or per serving), and is regarded as independent of the state of glucose metabolism from normal to type 2 diabetes mellitus (T2DM). Ad libitum studies in overweight or obese adults and children show that low-GL diets are associated with marked weight benefits, loss of adiposity and reduced food intake. Weight benefits appear on low-glycaemic v. high-glycaemic available carbohydrates, unavailable v. available carbohydrates and protein v. available carbohydrate. Energy intake immediately after lowering of meal GL via carbohydrate exchanges is apparent only after a threshold cumulative intake of >2000 MJ. Various epidemiological and interventional studies are discussed. A relationship between GL and the development of T2DM and CHD is evident. Studies that at first seem conflicting are actually consistent when data are overlaid, such that diets with a GL of >120 glucose equivalents/d would appear to be inadvisable. Whereas certain studies might place GI as being slightly stronger than GL in relationto T2DM risk, this situation appears to be associated with observations in a lower range of GL or when the range of GI is too narrow for accuracy; nevertheless, authors emphasise the importance of GL. Among the studies reviewed, GL offers a better or stronger explanation than GI in various observations including body weight, T2DM in nurses, CHD, plasma triacylglycerols, HDL-cholesterol, high-sensitivity C-reactive protein and protein glycation. Where information is available, the associations between risk factors and GL are either similar or stronger in the overweight or obese, as judged by BMI, and apply to both body weight and blood risk factors. The implications tend to favour a long-term benefit of reducing GL, for which further study is necessary to eliminate any possibility of publication bias and to establish results in clinical trials with overweight and obese patients.

The glycaemic index (GI) was introduced to guide food exchanges within equicarbohydrate food categories, and it expresses the glycaemic potency of the available carbohydrate component in a food relative to that of glucose. As GI is a relative value based on ‘available carbohydrate’ it cannot guide food choice for glycaemic control unless the foods are equal in available carbohydrate. Furthermore, GI cannot respond to food intake or to effects on food glycaemic potency of replacing glycaemic ingredients with non-glycaemic ingredients. The glycaemic glucose equivalent (GGE) overcomes these limitations of GI. The GGE content of an amount of food is the weight of glucose (g) that would induce a glycaemic response equal to that induced by the food. Few studies have compared GI and GGE as guides to food choice for glycaemic control, but in a direct test of the predictive validity of GGE in a group of foods of differing carbohydrate and GI, GGE predicted glycaemic potency well, whereas GI was unrelated to glycaemic effect. Furthermore, an information-processing model of the use of food information in food choice shows that GI has fundamental flaws when used outside the restriction of equicarbohydrate food exchange categories. As a general guide to food choices for the control of glycaemia GI does not satisfy the criteria predictive validity, accuracy, safety, ease of use, flexibility, sufficiency and compatability, whereas GGE does. GGE is also a scientifically precise and meaningful term with which to express glycaemic potency than is ‘glycaemic load’.

Plant secondary metabolites (PSM) have many ecological functions, but have long been considered as defences against pathogens or herbivores (vertebrate or invertebrate), reducing the likelihood and extent of attack. However, mammalian herbivores ingest many foods containing PSM and use both behavioural methods and physiological strategies to limit their negative effects. Most physiological counter-adaptations are inducible in response to ingested PSM, providing efficient protection against toxic effects. Possible positive effects of PSM include antioxidant and anthelminthic properties and complex formation between protein and condensed tannins that protects dietary protein from degradation by the symbiotic microflora of foregut fermenters, increasing its utilisation by the animal. This protein effect is probably only beneficial to animals under a narrow range of nutrient-rich conditions found mainly in agricultural systems. There are many examples of PSM causing food avoidance or reducing food intake, but there is as yet relatively little evidence for positive selection of them by herbivores. Although the feedback mechanisms relating the post-ingestive consequences of PSM to subsequent foraging behaviour are beginning to be understood, knowledge of the integration of behavioural and physiological strategies for regulating the effects of PSM is relatively poor. The opportunities for learned avoidance of PSM may be restricted in animals with complex diets that cannot associate a particular feedback signal with a given food type. A greater emphasis on the study of subclinical effects of PSM rather than acute effects, on pharmaco-kinetic studies in relation to behavioural studies and on the use of realistic experimental models is advocated.