Modulation of central leptin sensitivity and energy balance in a rat model of diet-induced obesity.

AIM: The aim of this study was to further explore the time-dependent changes in leptin sensitivity using a rat model of dietary fat-induced obesity and to investigate the potential mechanisms governing these changes. METHODS: We used male, adult Sprague-Dawley rats that were fed either a standard laboratory chow diet (3% fat) or a high-saturated fat (HF) diet (60% fat) for 2 or 5 weeks. Energy balance (body weight, energy intake and energy expenditure); sensitivity to central leptin and central alpha-melanin stimulating hormone (alpha-MSH) administration and expression levels of hypothalamic ObRb, signal transducers and activators of transcription factor (STAT)-3 phosphorylation, suppressor of cytokine signalling-3 (SOCS-3), proopiomelanocortin (POMC) processing hormones (prohormone convertase-1 and prohormone convertase-2) and neuropeptide Y (NPY) were measured. RESULTS: After 2 weeks of feeding HF diet, there was an increase in total energy intake (TEI) but a reduction in food intake as measured by the mass of food ingested. Body weight at this time was not significantly different between the two diet groups; however, white adipose tissue (WAT) weight was significantly greater in the HF-fed rats than in the chow-fed rats. In addition, spontaneous physical activity levels were increased, but no changes were observed in resting energy expenditure. Furthermore, chow-fed lean rats responded to central leptin administration by reducing the energy intake by approximately 67 kJ compared with saline treatment (p < 0.05), while the HF-fed diet-induced obese (DIO) rats responded by reducing their energy intake by approximately 197 kJ compared with saline treatment (p < 0.05). After 5 weeks of feeding HF diet, TEI remained significantly higher, body weight was significantly increased by 5% in the HF-fed rats and WAT weight was significantly heavier in HF-fed rats than in the chow-fed lean rats. After leptin treatment, the chow-fed lean rats reduced their energy intake by approximately 97 kJ (p < 0.05); yet, leptin had no significant effect in the HF-fed DIO rats. ObRb protein expression, STAT-3 phosphorylation levels, content and messenger RNA (mRNA) expression of NPY, SOCS-3 mRNA and protein expression and energy intake response to central alpha-MSH administration were not altered after HF diet feeding. CONCLUSION: These results suggest that early in the course of HF diet-induced weight gain, there was a period of central leptin hypersensitivity, and as the obesity progresses, central leptin insensitivity develops. This insensitivity does not appear to be explained by a downregulation of ObRb protein levels, reduced leptin signalling, an increase in either SOCS-3 or NPY expression or reduced function of the melanocortin system. The effect of an HF diet on other actions of leptin such as its effect on the endocannabinoid system should be investigated.

Prevalence of obesity in Australia.

Australia is a large country approximately equal in area to mainland United States. The relatively small population of around 20 million are composed primarily of Caucasians. Extensive immigration from many different countries has made Australia one of the most culturally diverse populations in the world. Indigenous Australians make up only 2.4% of the total population. Australia has a prosperous Western-style capitalist economy, and spends approximately 830 million dollars on the direct health care costs of obesity. For Australians, it is now more common to have a weight problem, with overweight affecting 48% of men and 30% of women and obesity affecting a further 19% of men and 22% of women. This paper reports on recent epidemiological studies documenting the extent of overweight and obesity in adults and children in Australia.

A circulatory model for calculating non-steady-state glucose fluxes. Validation and comparison with compartmental models.

This study presents a circulatory model of glucose kinetics for application to non-steady-state conditions, examines its ability to predict glucose appearance rates from a simulated oral glucose load, and compares its performance with compartmental models. A glucose tracer bolus was injected intravenously in rats to determine parameters of the circulatory and two-compartment models. A simulated oral glucose tolerance test was performed in another group of rats by infusing intravenously labeled glucose at variable rates. A primed continuous intravenous infusion of a second tracer was given to determine glucose clearance. The circulatory model gave the best estimate of glucose appearance, closely followed by the two-compartment model and a modified Steele one-compartment model with a larger total glucose volume. The standard one-compartment model provided the worst estimate. The average relative errors on the rate of glucose appearance were: circulatory, 10%; two-compartment, 13%; modified one-compartment, 11%; standard one-compartment, 16%. Recovery of the infused glucose dose was 93+/-2, 94+/-2, 92+/-2 and 85+/-2%, respectively. These results show that the circulatory model is an appropriate model for assessing glucose turnover during an oral glucose load.

Estrogen deficiency causes central leptin insensitivity and increased hypothalamic neuropeptide Y.

OBJECTIVE: Altered fat distribution is a consequence of menopause, but the mechanisms responsible are unknown. Estrogen insufficiency in humans can be modeled using ovariectomized rats. We have shown that increased adiposity in these rats is due to reduced physical activity and transient hyperphagia, and can be reversed with 17beta-estradiol treatment. The aims of this study were to examine whether this altered energy balance is associated with circulating leptin insufficiency, central leptin insensitivity, decreased hypothalamic leptin receptor (Ob-Rb) expression, and/or increased hypothalamic neuropeptide Y (NPY). METHODS: Plasma leptin levels, adipose tissue ob gene expression, energy balance responses to i.c.v. leptin, hypothalamic Ob-Rb expression and NPY concentration in five separate hypothalamic regions were measured in adult female rats after either ovariectomy or sham operations. RESULTS: Obesity was not associated with hypoleptinemia or decreased ob gene expression in ovariectomized rats; however, it was associated with insensitivity to central leptin administration. Food intake was less suppressed and spontaneous physical activity was less stimulated by leptin. This was not due to decreased hypothalamic Ob-Rb expression. NPY concentration in the paraventricular nucleus of the hypothalamus was elevated in the ovariectomized rats, consistent with leptin insensitivity; however this effect was transient and disappeared as body fat and leptin levels increased further and hyperphagia normalized. CONCLUSION: Impaired central leptin sensitivity and overproduction of NPY may contribute to excess fat accumulation caused by estrogen deficiency.

Increase of fat oxidation and weight loss in obese mice caused by chronic treatment with human growth hormone or a modified C-terminal fragment.

OBJECTIVE: To observe the chronic effects of human growth hormone (hGH) and AOD9604 (a C-terminal fragment of hGH) on body weight, energy balance, and substrate oxidation rates in obese (ob/ob) and lean C57BL/6Jmice. In vitro assays were used to confirm whether the effects of AOD9604 are mediated through the hGH receptor, and if this peptide is capable of cell proliferation via the hGH receptor. METHOD: Obese and lean mice were treated with hGH, AOD or saline for 14 days using mini-osmotic pumps. Body weight, caloric intake, resting energy expenditure, fat oxidation, glucose oxidation, and plasma glucose, insulin and glycerol were measured before and after treatment. BaF-BO3 cells transfected with the hGH receptor were used to measure in vitro 125I-hGH receptor binding and cell proliferation. RESULTS: Both hGH and AOD significantly reduced body weight gain in obese mice. This was associated with increased in vivo fat oxidation and increased plasma glycerol levels (an index of lipolysis). Unlike hGH, however, AOD9604 did not induce hyperglycaemia or reduce insulin secretion. AOD9604 does not compete for the hGH receptor and nor does it induce cell proliferation, unlike hGH. CONCLUSIONS: Both hGH and its C-terminal fragment reduce body weight gain, increase fat oxidation, and stimulate lipolysis in obese mice, yet AOD9604 does not interact with the hGH receptor. Thus, the concept of hGH behaving as a pro-hormone is further confirmed. This data shows that fragments of hGH can act in a manner novel to traditional hGH-stimulated pathways.

Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin.

High-fat feeding has been shown to cause hepatic insulin resistance. The aims of this study were to investigate the biochemical steps responsible for enhanced gluconeogenesis as a result of increased dietary fat intake and the site or sites at which the antihyperglycemic agent metformin acts to inhibit this process. Male Hooded Wistar rats were fed either a standard chow diet (5% fat by weight) or a high-fat diet (60% fat by weight) for 14 days with or without metformin. Total endogenous glucose production and gluconeogenesis were determined using [6-(3)H]glucose and [U-(14)C]alanine, respectively. Gluconeogenic enzyme activity and, where appropriate, protein and mRNA levels were measured in liver tissues. The high-fat diet increased endogenous glucose production (21.9 +/- 4.4 vs. 32.2 +/- 4.8 micromol x kg(-1) x min(-1), P < 0.05) and alanine gluconeogenesis (4.5 +/- 0.9 vs. 9.6 +/- 1.9 micromol x kg(-1) x min(-1), P < 0.05). Metformin reduced both endogenous glucose production (32.2 +/- 4.8 vs. 16.1 +/- 2.1 micromol x kg(-1) x min(-1), P < 0.05) and alanine gluconeogenesis (9.6 +/- 1.9 vs. 4.7 +/- 0.8 micromol x kg(-1) x min(-1), P < 0.05) after high-fat feeding. These changes were reflected in liver fructose-1,6-bisphosphatase protein levels (4.5 +/- 0.9 vs. 9.6 +/- 1.9 arbitrary units, P < 0.05 chow vs. high-fat feeding; 9.5 +/- 1.9 vs. 4.7 +/- 0.8 arbitrary units, P < 0.05 high fat fed in the absence vs. presence of metformin) but not in changes to the activity of other gluconeogenic enzymes. There was a significant positive correlation between alanine gluconeogenesis and fructose-1,6-bisphosphatase protein levels (r = 0.56, P < 0.05). Therefore, excess supply of dietary fat stimulates alanine gluconeogenesis via an increase in fructose-1,6-bisphosphatase protein levels. Metformin predominantly inhibits alanine gluconeogenesis by preventing the fat-induced changes in fructose-1,6-bisphosphatase levels.

The effect of flexible low glycemic index dietary advice versus measured carbohydrate exchange diets on glycemic control in children with type 1 diabetes.

OBJECTIVE: To determine the long-term effect of low glycemic index dietary advice on metabolic control and quality of life in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: Children with type 1 diabetes (n = 104) were recruited to a prospective, stratified, randomized, parallel study to examine the effects of a measured carbohydrate exchange (CHOx) diet versus a more flexible low-glycemic index (GI) dietary regimen on HbA(1c) levels, incidence of hypo- and hyperglycemia, insulin dose, dietary intake, and measures of quality of life over 12 months. RESULTS: At 12 months, children in the low-GI group had significantly better HbA(1c) levels than those in the CHOx group (8.05 +/- 0.95 vs. 8.61 +/- 1.37%, P = 0.05). Rates of excessive hyperglycemia (>15 episodes per month) were significantly lower in the low-GI group (35 vs. 66%, P = 0.006). There were no differences in insulin dose, hypoglycemic episodes, or dietary composition. The low-GI dietary regimen was associated with better quality of life for both children and parents. CONCLUSIONS: Flexible dietary instruction based on the food pyramid with an emphasis of low-GI foods improves HbA(1c) levels without increasing the risk of hypoglycemia and enhances the quality of life in children with diabetes.

The role of low birthweight in the aetiology of type 2 diabetes.

The aetiology of type 2 diabetes is still poorly understood. Although it is clear that obesity is a risk factor for the disease, obesity leads to diabetes only in susceptible individuals. Both genetic and environmental factors determine this susceptibility. This review describes the emerging evidence that low birthweight caused by malnutrition or a genetic predisposition increases the risk of type 2 diabetes.

Aromatase-deficient (ArKO) mice accumulate excess adipose tissue.

Aromatase is the enzyme which catalyses the conversion of C19 steroids into C18 estrogens. We have generated a mouse model wherein the Cyp19 gene, which encodes aromatase, has been disrupted, and hence, the aromatase knockout (ArKO) mouse cannot synthesise endogenous estrogens. We examined the consequences of estrogen deficiency on accumulation of adipose depots in male and female ArKO mice, observing that these animals progressively accrue significantly more intra-abdominal adipose tissue than their wildtype (WT) litter mates, reflected in increased adipocyte volume and number. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared to WT controls, as were elevated insulin levels, although blood glucose was unchanged. Associated with these changes, the livers of ArKO animals were characterised by a striking accumulation of lipid droplets. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.

Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity.

The aromatase-knockout (ArKO) mouse provides a useful model to examine the role that estrogens play in development and homeostasis in mammals. Lacking a functional Cyp19 gene, which encodes aromatase, the ArKO mouse cannot synthesize endogenous estrogens. We examined the adipose depots of male and female ArKO mice, observing that these animals progressively accumulate significantly more intraabdominal adipose tissue than their wild-type (WT) littermates, reflected in increased adipocyte volume at gonadal and infrarenal sites. This increased adiposity was not due to hyperphagia or reduced resting energy expenditure, but was associated with reduced spontaneous physical activity levels, reduced glucose oxidation, and a decrease in lean body mass. Elevated circulating levels of leptin and cholesterol were present in 1-year-old ArKO mice compared with WT controls, as were elevated insulin levels, although blood glucose levels were unchanged. Associated with these changes, a striking accumulation of lipid droplets was observed in the livers of ArKO animals. Our findings demonstrate an important role for estrogen in the maintenance of lipid homeostasis in both males and females.

Novel anti-obesity drugs.

There is increasing evidence that body weight is homeostatically regulated and that in obesity this regulation maintains weight at a high level. Weight loss activates mechanisms that are designed to return individuals to their pre-existing weight. This explains the universally poor results of current strategies to maintain weight loss. On this basis, life-long drug therapy may be justified for those with significant obesity. Currently available drugs include selective serotonin re-uptake inhibitors (e.g., fluoxetine), noradrenergic re-uptake inhibitors (e.g., phentermine), a serotonin and noradrenergic re-uptake inhibitor (sibutramine) and an intestinal lipase inhibitor (orlistat). An active research program is underway to develop new agents based on the rapidly expanding knowledge of the complex mechanisms regulating body weight. Leptin, a hormone produced by adipocytes that inhibits food intake, has undergone clinical trials and analogues are currently being developed. Other agents include amylin, melanocortin-4 receptor agonists, neuropeptide Y antagonists, beta(3) adrenergic agonists and glucagon-like peptide-1 agonists. As some redundancy exists in the central regulatory system controlling body weight, some agents might need to be used in combination to be effective.

Effects of oral administration of a synthetic fragment of human growth hormone on lipid metabolism.

A small synthetic peptide sequence of human growth hormone (hGH), AOD-9401, has lipolytic and antilipogenic activity similar to that of the intact hormone. Here we report its effect on lipid metabolism in rodent models of obesity and in human adipose tissue to assess its potential as a pharmacological agent for the treatment of human obesity. C57BL/6J (ob/ob) mice were orally treated with either saline (n = 8) or AOD-9401 (n = 10) for 30 days. From day 16 onward, body weight gain in AOD-9401-treated animals was significantly lower than that of saline-treated controls. Food consumption did not differ between the two groups. Analyses of adipose tissue ex vivo revealed that AOD-9401 significantly reduced lipogenic activity and increased lipolytic activity in this tissue. Increased catabolism was also reflected in an acute increase in energy expenditure and glucose and fat oxidation in ob/ob mice treated with AOD-9401. In addition, AOD-9401 increased in vitro lipolytic activity and decreased lipogenic activity in isolated adipose tissue from obese rodents and humans. Together, these findings indicate that oral administration of AOD-9401 alters lipid metabolism in adipose tissue, resulting in a reduction of weight gain in obese animals. The marked lipolytic and antilipogenic actions of AOD-9401 in human adipose tissues suggest that this small synthetic hGH peptide has potential in the treatment of human obesity.

Differential and genetically separable associations of leptin with obesity-related traits.

OBJECTIVE: The extent to which leptin protects against obesity is unknown. By intercrossing New Zealand obese mice with lean C57BL/6J mice, we have separated the genes controlling leptin and other weight-related phenotypes. This has allowed us to determine whether hyperleptinaemia is associated with reduced food intake and increased physical activity in mice spanning a large range in body weight. METHODS: Plasma leptin, glucose and insulin, body weight, food intake, running wheel activity, and four adipose depots were measured in 587 adult F2 and backcross mice RESULTS: When mice were categorized by adiposity, a plot of food intake vs leptin illustrated a U-shaped curve. Food intake decreased as leptin levels rose to approximately 15 ng/ml, beyond which the relationship reversed. A negative relationship was observed between activity and leptin with a maximal decrease in activity once leptin reached approximately 15 ng/ml. CONCLUSION: Leptin has differential responses to food intake and activity, suggesting that it has limited potential to defend against obesity. A genetic defect in leptin sensitivity is unlikely to be the primary cause of obesity in these mice, since hyperleptinaemia was not coinherited with both hyperphagia and inactivity as body weight increased.

Short-term, high-fat diets lower circulating leptin concentrations in rats.

BACKGROUND: Leptin is produced in proportion to body fat mass and can act on the brain to induce satiety and regulate adipose tissue mass; factors other than adipose tissue mass may influence circulating leptin concentrations. OBJECTIVE: We explored the possibility that short-term, moderately high-fat diets induce weight gain by producing inappropriately low circulating leptin concentrations. DESIGN: Female Hooded Wistar rats were fed either a moderately high-fat diet or control diet. Body weight, energy intake, body composition, and fasting plasma leptin were compared after 4 and 14 wk of dietary treatment. RESULTS: After 4 wk, abdominal fat mass was 38% greater in rats fed the high-fat diet than in those fed the control diet (P < 0.01). However, plasma leptin concentrations were 24% lower in animals fed the high-fat diet (P < 0.05), resulting in significantly lower plasma leptin concentrations per unit abdominal fat mass than in control animals (P < 0.005). From 4 to 14 wk, animals fed the high-fat diet gained twice as much weight and consumed 32 kJ/d more than controls (both P < 0.05). At 14 wk, plasma leptin concentrations per unit abdominal fat mass were 27% lower in rats fed the high-fat diet (P = 0.058) and there was a significant negative association between leptin concentrations per unit abdominal fat mass and body weight (r = 0.44, P < 0.05). CONCLUSIONS: In the short term, a moderately high-fat diet is associated with lower than expected circulating leptin concentrations, which correlate with a higher body weight. A high-fat diet may therefore contribute to weight gain by reducing leptin secretion in adipose tissue.

Biological determinants of spontaneous physical activity.

A decline in daily physical activity levels is clearly a major factor contributing to the current obesity epidemic affecting both developed and developing countries in the world. This escalating problem is associated with increased morbidity and mortality and reduced psychosocial health. Thus, increasing physical activity has become the strategy of choice in public health strategies to prevent obesity. Efforts to improve levels of physical activity in the population rely upon an accurate understanding of the determinants of physical activity. Most research has focused on environmental and social influences, while the potential for physical activity to be controlled by intrinsic biological processes has been largely overlooked. This review presents some of the compelling and diverse evidence that has emerged recently showing that physical activity energy expenditure is a critical factor in both the successful regulation of energy balance in normal individuals, as well as the abnormal regulation of energy balance that characterizes obesity. Although the metabolic and genetic factors involved in these regulatory processes remain mostly unidentified, some novel discoveries have been made in this area recently and these are described within this review.

Leptin in the pathophysiology of human obesity and the clinical potential of leptin-based therapy.

Leptin is a circulating hormone that is secreted in proportion to fat mass. It can reduce bodyweight by activating signalling molecules in the brain. Leptin appears to affect bodyweight primarily by decreasing food intake; there is no direct evidence that it significantly influences energy expenditure in humans. Its discovery in 1994 raised the possibility that it may be a useful, satiety-inducing, anti-obesity drug. However, treating obese patients with leptin alone does not induce substantial bodyweight loss because most obese patients are insensitive to leptin and are not leptin deficient. In combination with diet therapy, however, leptin treatment has the potential to eliminate the dramatic fall in circulating leptin levels (and the subsequent increase in hunger) caused by calorie restriction. Used in this manner, leptin may play a very useful role in the maintenance of bodyweight loss. In the future, leptin analogues and the development of compounds that increase leptin sensitivity may also prove to be valuable therapeutic approaches for obesity.

Features of syndrome X develop in transgenic rats expressing a non-insulin responsive phosphoenolpyruvate carboxykinase gene.

AIMS/HYPOTHESIS: Obesity, glucose intolerance, dyslipidaemia and hypertension are a cluster of disorders (syndrome X) affecting many people. It has been hypothesised that these abnormalities are caused by insulin resistance, but definitive proof is lacking. We have developed transgenic rats in which the rate-limiting gluconeogenic enzyme, phosphoenolpyruvate carboxykinase, is non-insulin responsive. The aim of our study was to investigate whether syndrome X develops in these animals and if a high-fat diet interacts with this genetic defect. METHODS: Chow-fed transgenic and control rats aged 1, 3, 6 and 17 months and a subgroup of transgenic and control rats fed chow plus cafeteria foods for 6 months were examined for features of syndrome X. RESULTS: At 3 months, transgenic rats had fasting and postprandial hyperinsulinaemia, mild obesity (in abdominal and, to a lesser extent, peripheral regions) and fasting hypercholesterolaemia. Hypertriglyceridaemia was evident after 6 months while hyperglycaemia was apparent at 17 months. Hypertension had not developed by 17 months. The effect of a high-fat diet on insulin, glucose, body weight and body fat was more dramatic than the effect of the transgene alone while the effect of a high-fat diet on cholesterol and triglyceride was similar to the transgene. This illustrates that a high-fat diet is a potent catalyst for many abnormalities associated with syndrome X. There was no evidence of an additive effect of the high-fat diet plus transgene. CONCLUSION/INTERPRETATION: Therefore rats genetically-engineered with a non-insulin responsive gluconeogenic enzyme develop several aspects of syndrome X, supporting the hypothesis that insulin resistance initiates this cluster of disorders.

Peripheral tissue glucose uptake is not reduced after an oral glucose load in Southern Italian subjects at risk of developing non-insulin-dependent diabetes mellitus.

Studies searching for the inherited defects that cause non-insulin-dependent diabetes mellitus (NIDDM) have been performed mostly in Northern European subjects using the hyperinsulinemic clamp technique. The conclusion drawn from most of these studies is that peripheral insulin resistance is likely a primary inherited defect. Our aim was to examine early defects in glucose metabolism using a more physiological technique in a different ethnic group. For this, a double-label oral glucose tolerance test (OGTT) was performed in young diabetes-prone Southern Italian subjects who had both parents with NIDDM (relatives) and in subjects with no family history of NIDDM (matched for age, weight, and ethnicity). Fasting plasma glucose and insulin in the relatives were normal; however, they had impaired glucose tolerance during the OGTT. This was due to reduced hepatic glucose uptake (17.9+/-2.8 v. 28.1+/-2.3 g, P<.02). No defects were found in the metabolic clearance rate (MCR) of glucose or endogenous glucose production. During an intravenous glucose tolerance test (IVGTT), insulin sensitivity was again found to be normal (3.04+/-0.65 in relatives v. 2.33+/-0.38 min(-1) per micromol x L(-1) x min in controls), with a marked reduction in first-phase insulin secretion in the relatives (110+/-12 v. 211+/-18 pmol x L(-1) x min per mmol x L(-1), P<.001). A strong correlation was found between hepatic glucose uptake and insulin secretion (r = .81, P<.001), which may suggest that the same abnormality operates in both the liver and pancreas. Therefore, the metabolic defect that causes hyperglycemia in diabetes-prone subjects is not always a reduced peripheral insulin sensitivity. The genetic basis of NIDDM may differ between different ethnic groups.

Neuropeptides, the hypothalamus and obesity: insights into the central control of body weight.

Body weight tends to remain relatively stable for long periods over an adult's lifespan. Dieting can reduce weight by 5-10%, but in most individuals attempts to lose larger amounts of weight are counteracted by a reduction in energy expenditure and an increase in hunger. The fact that body weight appears to be actively defended in this manner suggests that it is homeostatically regulated at a certain "set-point". Such a mechanism is likely to be centrally controlled by the brain since the hypothalamus can sense the amount of adipose tissue stored in the body and can alter both energy intake and expenditure. Over the past four years a number of major advances have reinforced the critical role the brain may play in controlling body weight, and these have greatly enhanced our understanding of this area. Advances have included the identification of several genetic mutations that cause obesity in animal models, examination of the metabolic consequences of such mutations and the development of mice with genetically engineered altered neuropeptide levels. This review summarises what has been recently discovered about the regulation of body weight by the brain and how this may be disrupted in obesity.

Animal models of obesity--theories of aetiology.

The multiplicity of proposed mechanisms for obesity is confusing and many questions remain to be answered. A review of all the proposed mechanisms for obesity suggests that they can be placed in two groups (Table 3). The first centres on the role of the hypothalamus in the regulation of body weight. With further knowledge it may be possible to find unifying mechanisms originating in the brain for the set-point theory, the autonomic nervous system imbalance hypothesis, the thermogenesis, hyperphagia and the hyperinsulinaemia hypotheses and the gestational undernutrition hypothesis. This group of mechanisms suggests that obesity is due to altered function of central regulatory mechanisms and that the various related hypotheses are merely looking at different aspects of the same problem. The second centres on abnormalities intrinsic to the adipocyte and could link the fat cell and perinatal overnutrition theories. This group of theories suggests that an abnormality at the fat cell level, either genetic or acquired, can result in the excessive accumulation of fat. The two groups are not contradictory. The ability to develop obesity as a result of a fat cell abnormality does not negate the existence of regulatory central mechanisms since there is a finite capacity for these mechanisms to operate.