The rapidly rising prevalence of obesity, worldwide, has prompted re-evaluations of the definitions and diagnostic criteria, and of the extent of the burden it contributes to health care services. Although categorized arbitrarily for epidemiological purposes according to BMI > 25 kg/m2 (‘overweight’) and BMI > 30 kg/m2 (‘obese’), the disease itself (ICD code E.66) is the process of excess fat accumulation. It leads to multiple organ-specific pathological consequences, particularly if there is a tendency to intra-abdominal fat accumulation. The simplest field method to identify obesity and risk of medical problems is the waist circumference, and this method has found a special role in health promotion. Risks begin with waist > 80 cm (women) or > 94 cm (men). As a broad generalization, obesity produces few symptoms below the age of 40 years, but then several symptoms often develop; tiredness, breathlessness, back pain, arthritis, sweatiness, poor sleeping, depression and menstrual disorders all being common. The symptoms are often attributed to diseases in other body systems. Metabolic diseases like diabetes, hyperlipidaemia and, hypertension develop later, but the mean BMI at diagnosis of diabetes is 28 kg/m2. Ultimately, obesity increases the likelihood of myocardial infarction, stroke and several major cancers, but its biggest impact on health, especially in the elderly, is probably the multiplicity of effects on other body systems. The greatest challenge for public health is to develop effective preventive measures, recognizing that BMI > 25 kg/m2 before the age of 20 years is a very strong predictor of obesity and ill health in adulthood.

The aetiology and treatment of obesity have been fraught with disappointment for researchers, because the mechanisms that control fuel homeostasis and adiposity are incompletely understood. It is assumed that regulatory processes match the dietary fuel supply with energy requirements in order to maintain a stable body mass and adiposity. In this context several theories have been proposed to explain the laws of thermodynamics describing the conservation and transformation of energy in living organisms. In the light of new evidence it can now be hypothesized that the control of body weight and composition depends on an axis with three interrelated and self-controlled components: (1) food intake; (2) nutrient turnover and thermogenesis; (3) body fat stores. Complex feedback mechanisms underlie all these components. The major factors involved in obesity seem to be dietary and physical activity habits. These factors are affected by susceptibility genes that in turn may influence energy expenditure, fuel metabolism, muscle fibre function and appetite or food preferences. However, the increasing rates of obesity cannot be explained exclusively by changes in the gene pool, although genetic variants that were previously ‘silent’ are now being triggered by the high availability of energy- and fat-dense foods, and by the increasingly sedentary lifestyle of modern societies. The study of factors such as genetics and lifestyle implicated in weight gain and obesity is crucial for predictions about the future impact of the global epidemic of obesity, and provides a unique opportunity for the implementation of preventive action.

Despite widespread interest in body-weight control, the prevalence of obesity continues to rise worldwide. Current public health advice for obesity prevention is clearly failing. The present paper examines the appropriateness of current public health advice for body-weight control, i.e. to reduce consumption of fatty foods, to reduce consumption of sugar and to avoid snacking between meals. An increase in carbohydrate : fat ratio should improve body-weight control, as high-carbohydrate low-fat diets are less likely to lead to overeating, and if overeating does occur, less of the excess energy is likely to be stored as fat. However, it is suggested that for the long-term prevention of weight gain, advice to increase consumption of carbohydrate-rich foods may be more effective than advice which focuses on reducing consumption of fatty food. Moreover, in view of the inverse relationship between fat and sugar intakes, sugar may have a positive role to play in body-weight control in facilitating an increase in carbohydrate : fat ratio. Snacking for most individuals appears not to adversely affect body-weight control, and for some it may improve control. This situation may exist because frequent eating helps appetite control, thus preventing overeating at meals, and as snacks overall tend to be higher in carbohydrate and lower in fat than meals, frequent eating may be a strategy for increasing carbohydrate : fat ratio. It is also suggested that eating ‘little and often’ may be a more compatible pattern of eating for a physically-active lifestyle than eating large meals. Perhaps the most appropriate advice on food intake that would work synergistically with concurrent advice to increase physical activity is to eat more carbohydrate, and to eat frequently.

Adipose tissue performs complex metabolic and endocrine functions. Among the endocrine products produced by adipose tissue are tumour necrosis factor α, interleukin 6, acylation-stimulating protein and leptin. The present review will focus primarily on mechanisms regulating leptin production and leptin action, and the implications of this regulation in the control of energy balance. Leptin acts in the central nervous system where it interacts with a number of hypothalamic neuropeptide systems to regulate feeding behaviour and energy expenditure. The presence of extreme obesity in animals and human subjects with mutations of the leptin gene or the leptin receptor demonstrates that normal leptin production and action are critical for maintaining energy balance. Insulin is the major regulator of leptin production by adipose tissue. Insulin infusions increase circulating leptin concentrations in human subjects. Plasma leptin levels are markedly decreased in insulin-deficient diabetic rodents, and the low leptin levels contribute to diabetic hyperphagia. Based on in vitro studies, the effect of insulin to stimulate leptin production appears to involve increased glucose metabolism. Blockade of glucose transport or glycolysis inhibits leptin expression and secretion in isolated adipocytes. Evidence suggests that anaerobic metabolism of glucose to lactate does not stimulate leptin production. Alterations in insulin-mediated glucose metabolism in adipose tissue are likely to mediate the effects of energy restriction to decrease, and refeeding to increase, circulating leptin levels. Changes in glucose metabolism may also explain the observation that high-fat meals lower 24 h circulating leptin levels relative to high-carbohydrate meals in human subjects, suggesting a mechanism that may contribute to the effects that high-fat diets have in promoting increased energy intake, weight gain and obesity. The decreased circulating leptin observed during energy restriction is related to increased sensations of hunger in human subjects. Thus, decreases in leptin during energy-restricted weight-loss regimens may contribute to the strong propensity for weight regain. A better understanding of the precise mechanisms regulating leptin production and leptin action may lead to new approaches for managing obesity.

Food intake is a regulated system. Afferent signals provide information to the central nervous system, which is the centre for the control of satiety or food seeking. Such signals can begin even before food is ingested through visual, auditory and olfactory stimuli. One of the recent interesting findings is the demonstration that there are selective fatty acid taste receptors on the tongue of rodents. The suppression of food intake by essential fatty acids infused into the stomach and the suppression of electrical signals in taste buds reflect activation of a K rectifier channel (K 1.5). In animals that become fat eating a high-fat diet the suppression of this current by linoleic acid is less than that in animals that are resistant to obesity induced by dietary fat. Inhibition of fatty acid oxidation with either mercaptoacetate (which blocks acetyl-CoA dehydrogenase) or methyl­palmoxirate will increase food intake. When animals have a choice of food, mercaptoacetate stimulates the intake of protein and carbohydrate, but not fat. Afferent gut signals also signal satiety. The first of these gut signals to be identified was cholecystokinin (CCK). When CCK acts on CCK-A receptors in the gastrointestinal tract, food intake is suppressed. These signals are transmitted by the vagus nerve to the nucleus tractus solitarius and thence to higher centres including the lateral parabrachial nucleus, amygdala, and other sites. Rats that lack the CCK-A receptor become obese, but transgenic mice lacking CCK-A receptors do not become obese. CCK inhibits food intake in human subjects. Enterostatin, the pentapeptide produced when pancreatic colipase is cleaved in the gut, has been shown to reduce food intake. This peptide differs in its action from CCK by selectively reducing fat intake. Enterostatin reduces hunger ratings in human subjects. Bombesin and its human analogue, gastrin inhibitory peptide (also gastrin-insulin peptide), reduce food intake in obese and lean subjects. Animals lacking bombesin-3 receptor become obese, suggesting that this peptide may also be important. Circulating glucose concentrations show a dip before the onset of most meals in human subjects and rodents. When the glucose dip is prevented, the next meal is delayed. The dip in glucose is preceded by a rise in insulin, and stimulating insulin release will decrease circulating glucose and lead to food intake. Pyruvate and lactate inhibit food intake differently in animals that become obese compared with lean animals. Leptin released from fat cells is an important peripheral signal from fat stores which modulates food intake. Leptin deficiency or leptin receptor defects produce massive obesity. This peptide signals a variety of central mechanisms by acting on receptors in the arcuate nucleus and hypothalamus. Pancreatic hormones including glucagon, amylin and pancreatic polypeptide reduce food intake. Four pituitary peptides also modify food intake. Vasopressin decreases feeding. In contrast, injections of desacetyl melanocyte-stimulating hormone, growth hormone and prolactin are associated with increased food intake. Finally, there are a group of miscellaneous peptides that modulate feeding. β-Casomorphin, a heptapeptide produced during the hydrolysis of casein, stimulates food intake in experimental animals. In contrast, the other peptides in this group, including calcitonin, apolipoprotein A-IV, the cyclized form of histidyl-proline, several cytokines and thyrotropin-releasing hormone, all decrease food intake. Many of these peptides act on gastrointestinal or hepatic receptors that relay messages to the brain via the afferent vagus nerve. As a group they provide a number of leads for potential drug development.

The hypothalamus is the focus of many peripheral signals and neural pathways that control energy homeostasis and body weight. Emphasis has moved away from anatomical concepts of ‘feeding’ and ‘satiety’ centres to the specific neurotransmitters that modulate feeding behaviour and energy expenditure. We have chosen three examples to illustrate the physiological roles of hypothalamic neurotransmitters and their potential as targets for the development of new drugs to treat obesity and other nutritional disorders. Neuropeptide Y (NPY) is expressed by neurones of the hypothalamic arcuate nucleus (ARC) that project to important appetite-regulating nuclei, including the paraventricular nucleus (PVN). NPY injected into the PVN is the most potent central appetite stimulant known, and also inhibits thermogenesis; repeated administration rapidly induces obesity. The ARC NPY neurones are stimulated by starvation, probably mediated by falls in circulating leptin and insulin (which both inhibit these neurones), and contribute to the increased hunger in this and other conditions of energy deficit. They therefore act homeostatically to correct negative energy balance. ARC NPY neurones also mediate hyperphagia and obesity in the ob/ob and db/db mice and fa/fa rat, in which leptin inhibition is lost through mutations affecting leptin or its receptor. Antagonists of the Y5 receptor (currently thought to be the NPY ‘feeding’ receptor) have anti-obesity effects. Melanocortin-4 receptors (MC4-R) are expressed in various hypothalamic regions, including the ventromedial nucleus and ARC. Activation of MC4-R by agonists such as α-melanocyte-stimulating hormone (a cleavage product of pro-opiomelanocortin which is expressed in ARC neurones) inhibits feeding and causes weight loss. Conversely, MC4-R antagonists such as ‘agouti’ protein and agouti gene-related peptide (AGRP) stimulate feeding and cause obesity. Ectopic expression of agouti in the hypothalamus leads to obesity in the AVY mouse, while AGRP is co-expressed by NPY neurones in the ARC. Synthetic MC4-R agonists may ultimately find use as anti-obesity drugs in human subjects Orexins-A and -B, derived from prepro-orexin, are expressed in specific neurones of the lateral hypothalamic area (LHA). Orexin-A injected centrally stimulates eating and prepro-orexin mRNA is up regulated by fasting and hypoglycaemia. The LHA is important in receiving sensory signals from the gut and liver, and in sensing glucose, and orexin neurones may be involved in stimulating feeding in response to falls in plasma glucose.

Whilst a number of neuroendocrine afferent signals are implicated in body-weight homeostasis, the major efferent pathway is the sympathetic nervous system (SNS), which affects both energy expenditure and substrate utilization. Thyroid hormones and their interactions with the SNS may also have a role to play. Some of the variability in resting energy expenditure can be explained by differences in SNS activity, and β-blockade can reduce energy expenditure and diet-induced thermogenesis in Caucasians. Excess energy intake leads to SNS activation and increased diet-induced thermogenesis. A relationship has also been demonstrated between spontaneous physical activity and SNS activity. In many animal models the SNS activates brown adipose tissue thermogenesis, hence increasing diet-induced thermogenesis and dissipating excess energy as heat. This effect is mediated via β3-adrenoceptors and activation of an uncoupling protein unique to brown adipose tissue. Homologous proteins have been identified in human tissues and may play a role in human energy expenditure. How the SNS is implicated in this process is unclear at present. β3-Adrenoceptor polymorphism has been associated both with lower resting energy expenditure in some populations and with reduced autonomic nervous system activity. SNS effects on substrate cycling may also play a role. In the development of obesity the effects of the SNS in promoting lipolysis and fat oxidation are likely to be at least as important as its effects on thermogenesis. β-Blockade has relatively small effects on energy expenditure, but more pronounced effects on reducing lipid oxidation, so tending to favour fat storage and weight gain. Low lipid oxidation is a risk factor for weight gain, and there is some evidence that low basal sympathetic nerve activity in muscle is associated with this process. Overall, the relationship between SNS activity and obesity is complex, with evidence of low SNS activity occurring in some, but not all, studies.

Obesity, which is becoming one of the major health hazards in developed and developing societies, results from a long-term positive energy balance. Body-weight regulation and stability depend on an axis with three interrelated components: food intake, energy expenditure and adipogenesis, although there are still many unknown features concerning fuel homeostasis and energy balance. Biochemical processes are interconnected, and a separate consideration of each component is often useful for methodological purposes and to achieve a better understanding of the whole system. Thus, many different experimental approaches can be applied by using laboratory animals, cell culture or human subjects to unravel the molecular mechanisms which participate in body-weight regulation. Thus, both in vitro (cellular and subcellular models) and in vivo methods have dramatically increased our knowledge of weight control. Several strategies in obesity research are reported here, exploiting the opportunities of the molecular era as well as novel whole-body approaches, which will impact on the development of new targets for obesity management and prevention.

Adipose tissue is a major source of metabolic fuel. This metabolic fuel is stored in the form of triacylglycerol. Lipolysis of triacylglycerol yields non-esterified fatty acids and glycerol. In human subjects in vivo studies of the regulation of lipid metabolism in adipose tissue have been difficult because of the heterogeneous nature of the tissue and lack of a vascular pedicle. In the last decade the methodology of study of adipose tissue has improved with the advent of the anterior abdominal wall adipose tissue preparation technique and microdialysis. These techniques have demonstrated that lipid metabolism in adipose tissue is finely coordinated during feeding and fasting cycles, in order to provide metabolic fuel when required. Lipolysis takes place both in extracellular and intracellular space. The extracellular lipolysis is regulated by lipoprotein lipase and the intracellular lipolysis is regulated by hormone-sensitive lipase. In pathophysiological conditions such as trauma, sepsis and starvation profound changes are induced in the regulation of lipid metabolism. The increased mobilization of lipid fuel is brought about by the differential actions of various counter-regulatory hormones on adipose tissue blood flow and adipose tissue lipolysis through lipoprotein lipase and hormone-sensitive lipase, resulting in increased availability of non-esterified fatty acids as a source of fuel. In recent years, it has been demonstrated that adipose tissue produces various cytokines and these cytokines can have paracrine and endocrine effects. It would appear that adipose tissue has the ability to regulate lipid metabolism locally as well as at distant sites such as liver, muscle and brain. In future, it is likely that the mechanisms that lead to the secondary effects of lipid metabolism on atheroma, immunity and carcinogenesis will be demonstrated.