Models and mechanisms of energy balance regulation in the young

The proportion of the child and adolescent population that is in appropriate energy balance is declining throughout the developed world, and childhood obesity is a particular problem in the UK relative to other northern European countries. Assessment of the underlying causes of obesity, and the different routes to its development, may assist in the definition of successful intervention strategies. The network of peripheral and central (brain) regulatory systems that underlie energy balance and body weight and composition can, for the most part, only be approached experimentally through the study of appropriate laboratory animal models. This problem is particularly acute when the target is overweight and obesity in the young. Some of the mechanisms underlying the development of energy imbalance and specifically the onset of overweight and obesity in the young, and the metabolic health consequences of obesity, can be addressed by examination of experimental rodent models in which mutation of a single gene causes early-onset extreme obesity, genetic susceptibility to obesity is revealed in an obesogenic environment or early-life nutritional experience programmes susceptibility to obesity or metabolic problems in later life. These studies highlight genes that are essential to normal body-weight regulation in rodents and man, the impact of diet and diet-induced obesity on regulatory systems in the young and the potential sensitivity of developing regulatory systems to nutritional experiences in utero and during early life.     

The autonomic nervous system, adipose tissue plasticity, and energy balance

In most mammals, two types of adipose tissue, white and brown, are present. Both are able to store energy in the form of triacylglycerols and to hydrolyze them into free fatty acids and glycerol. Whereas white adipose tissue can provide lipids as substrates for other tissues according to the needs of the organism, brown adipose tissue will use fatty acids for heat production. Over the long term, white fat mass reflects the net balance between energy expenditure and energy intake. Even though these two parameters are highly variable during the life of an individual, most adult subjects remain relatively constant in body weight throughout their lives. This observation suggests that appetite, energy expenditure, and basal metabolic rate are linked. An important characteristic of the adipose tissue is its enormous plasticity for volume and cell-number variations and an apparent change in phenotype between the brown and white adipose tissues. The present review focuses on the cellular mechanisms participating in the plasticity of adipose tissues and their regulation by the autonomic nervous system. There is compelling evidence with regard to the importance of the nervous system in the regulation of adipose tissue mass, either brown or white, by acting on the metabolic pathways and on the plasticity (proliferation, differentiation, transdifferentiation, apoptosis) of these tissues. A better comprehension of the different mechanisms involved in the feedback loop linking the brain and these two types of adipose tissue will lead to a better understanding of the pathophysiology of various disorders including obesity, cachexia, anorexia, and type II diabetes mellitus.     

Effects of dietary protein and exercise on brown adipose tissue and energy balance in experimental animals

The effects of exercise and of dietary protein level on energy metabolism and brown adipose tissue (BAT) activity were investigated in weaning male mice. Mice were fed diets providing low (7.5%), adequate (12.5%) or high (25%) levels of dietary protein. Half of the animals in each dietary group were given moderate exercise by swimming. The lower the level of dietary protein, the greater the increase in food intake, energy expenditure, body fat and BAT mass; however, total-carcass energy, food efficiency and BAT activity were not affected by the level of dietary protein. In experiment 2, BAT was compared in mice swimming at 33 degrees C and 36 degrees C with non-exercised controls. In a third experiment, energy balance and BAT activity were compared in rats exercised at 36 degrees C and in paired weight gain (PWG) rats whose food intake was restricted to achieve weight gains equal to that of the exercised rats. PWG rats maintained carcass energy content equal to that of the controls and significantly greater than the exercised rats by decreasing energy expenditure. Moderate exercise did not affect food intake, whereas rigorous exercise decreased energy intake. Exercise did not affect BAT mass or thermogenic activity; however, mild cold stress did increase BAT activity. Exercise decreased body fat, carcass energy and food efficiency without affecting BAT.     

Energy balance and body-weight stability: impact of gene-environment interactions

Studies of monozygotic twins in the context of overfeeding and energy deficit experiments have shown that gene-environment interactions affect energy balance. From a clinical standpoint, this implies that some individuals are more susceptible to body-weight gain or loss than others because of genetic differences. This opens new perspectives in predictive medicine. In the future, health professionals should be able to count on early diagnosis of individuals at risk for developing long-term metabolic problems and obesity or for not responding adequately to clinical interventions. However, before predictive medicine is in a position to contribute significantly to prevention or treatment of patients, an enormous amount of work has to be done to identify all genetic and environmental factors of relevance, and their network of interactions.     

Isoproterenol decreases leptin expression in adipose tissue of obese humans.

OBJECTIVE: We investigated the effects of the non-selective beta-adrenergic agonist, isoproterenol (Iso), on leptin expression in human adipose tissue. RESEARCH METHODS AND PROCEDURES: Subcutaneous (SQ) and omental adipose (OM) tissue taken during surgery from 12 morbidly obese subjects (10 women and 2 men) were cultured for up to 24 hours with insulin (7 nM) and/or dexamethasone (25 nM), a synthetic glucocorticoid, in the presence or absence of isoproterenol (10 microM). Adipose tissue was also acutely incubated for 3 hours in media alone with or without isoproterenol. Leptin secretion and leptin mRNA abundance were measured. RESULTS: Iso acutely decreased leptin release by approximately 30% (vs. no hormone controls) in fragments of OM and SQ adipose tissue. In 24-hour culture, addition of Iso (in the presence of insulin) resulted in lower leptin accumulation in the medium (-20-30%) and leptin mRNA levels (-40-50%) from both tissue depots. Culture with insulin and dexamethasone increased leptin expression vs. insulin alone. Addition of Iso with insulin and dexamethasone decreased media leptin (-40-60%) and leptin mRNA levels were lower (-65%) in Iso-treated adipose tissue from both depots after 24 hours. Iso effects were not detectable after 5 hours of culture. DISCUSSION: We conclude that stimulation of beta-adrenergic receptors may modulate leptin expression in human adipose tissue by two mechanisms: an acute effect on leptin release and a longer-term antagonism of stimulatory effects of insulin and dexamethasone on leptin mRNA expression. These mechanisms may contribute to the decline in serum leptin that occurs during fasting.     

Brown adipose tissue: regulation of thermogenesis and implications for obesity

The role of brown adipose tissue in the development and maintenance of obesity has been a recent focus of research efforts. Brown fat serves as a heat-producing tissue, via nonshivering and diet-induced thermogenesis, because of a unique mechanism that uncouples oxidative phosphorylation. The importance of these forms of thermogenesis to energy balance has been characterized in animal models of obesity; increased metabolic efficiency has been attributed to impaired heat production and compositional and functional alterations in brown fat. Although the possibility exists that human obesity may partly result from inadequate thermogenesis, evidence that the defect is related to brown fat is tenuous. Currently, the contribution of brown fat to metabolic rate in human beings has been estimated as minor. However, even if it is found that differences in brown fat cannot explain differences in corpulence, interest in the tissue will likely continue. Because of its ability to waste calories, the potential for manipulating body weight by stimulation of brown fat remains a promising field of investigation.     

Serum leptin and insulin levels in lactating protein-restricted rats: implications for energy balance

The present study analysed the effect of protein restriction on serum insulin and leptin levels and their relationship with energy balance during lactation. Four groups of rats received isocaloric diets containing 170 g protein/kg or 60 g protein/kg from pregnancy until the 14th day of lactation: control non-lactating, control lactating (both fed a control diet), low-protein non-lactating and low-protein lactating. Energy intake, body composition, energy balance, serum insulin and leptin concentrations and the relationship between these hormones and several factors related to obesity were analysed. Low-protein-intake lactating rats exhibited hypoinsulinaemia, hyperleptinaemia, hypophagia and decreased energy expenditure compared with control lactating rats. The protein level in the carcasses was lower in the low-protein lactating group than in the control lactating group, resulting in a higher fat content in the first group compared with the latter. Body fat correlated inversely with serum insulin and positively with serum leptin level. There was a significant negative correlation between serum leptin and energy intake, and a positive relationship between energy intake and serum insulin level in lactating rats and in the combined data from both groups. Energy expenditure was correlated positively with serum insulin and negatively with serum leptin in lactating rats and when data from control non-lactating and lactating rats were pooled. Lactating rats submitted to protein restriction, compared with lactating control rats, showed that maternal reserves were preserved owing to less severe negative energy balance. This metabolic adaptation was obtained, at least in part, by hypoinsulinaemia that resulted in increased insulin sensitivity favouring enhanced fat deposition, hyperleptinaemia and hypophagia.     

Lipolysis induced by leptin in rat adipose tissue from different anatomical locations

Summary. The aim of the present work is to compare the lipolytic response of three fat depots (subcutaneous, epididymal and perirenal) to leptin under in vitro conditions in rats. Moreover an assessment of the potential differences between young and mature rats in terms of the response of these tissues to leptin is made. Adipocytes from 6- and 20-wk-old rats were isolated by collagenase digestion and incubated in vitro both in the absence and the presence of either leptin (10⁻¹²–10⁻⁶ M) or isoproterenol (10⁻⁶ M). Lipolysis was measured by the release of glycerol into the incubation medium over 2 hours of incubation. Adipocytes responded in a dose-dependent manner to leptin concentrations ranging from 10⁻¹² M to 10⁻⁶ M. The lowest leptin concentration inducing a significant lipolytic effect was 10⁻⁹ M in all tissues. No significant differences in the effect of the maximal concentration of leptin (10⁻⁶ M) were observed among tissues for either age. The lipolytic effect of isoproterenol (10⁻⁶ M) was significantly reduced in adipose tissues from mature rats; in contrast no significant differences in the effect of leptin (10⁻⁶ M) were observed between young and mature rats. In summary, no anatomical-specific differences exist in the response of rat adipose tissue to lipid mobilization induced by leptin. Furthermore, this leptin action is not decreased in mature rats compared with young ones. Received: 25 January 2002, Accepted: 16 December 2002 Correspondence to: Dra. María del Puy Portillo     

Influence of topiramate in the regulation of energy balance

Topiramate (TPM) is a novel neurotherapeutic agent currently indicated for the treatment of epilepsy and undergoing development for other central nervous system indications including neuropathic pain, bipolar disorder, and migraine prophylaxis. TPM is synthesized from D-fructose and contains a sulfamate moiety that is essential for its pharmacologic activity. TPM has been observed to significantly reduce body weight in patients treated for seizure, which has prompted the realization of preclinical studies to characterize the effects of TPM in the regulation of energy balance. Studies carried out in various strains of rats have provided good evidence for the ability of TPM to blunt energy deposition. Body composition analyses from rat trials have demonstrated that TPM inhibits fat deposition while reducing the activity of lipoprotein lipase (LPL) in various white adipose tissue depots. High doses of TPM (likely above the therapeutic dose range) have also been observed to reduce protein gain without catabolic effects. Although TPM cannot be described as a potent anorectic agent, it seems to have the ability to reduce food intake; significant reductions in food intake have been observed in female obese (fa/fa) Zucker rats and in female Wistar rats. TPM can also reduce energy deposition in the absence of alterations in food intake. This effect has been clearly emphasized in female lean (Fa/?) Zucker rats. In female Sprague-Dawley rats, TPM also increased energy expenditure and it has been observed to increase LPL activity in brown adipose tissue, which could indicate that TPM has the ability to enhance regulatory thermogenesis. In addition, TPM stimulates LPL activity in skeletal muscles, further emphasizing its potential to promote substrate oxidation. The mechanisms whereby TPM affects the regulation of energy balance have yet to be understood. TPM represents an antiepileptic drug (AED) with complex biochemical/pharmacologic actions. Its negative effects on energy deposition cannot be readily predicted from these actions, as AEDs are generally expected to stimulate body weight gain. Recent data, obtained from investigations aimed at assessing the effects of TPM on neuropeptidergic systems involved in the regulation of energy balance, have failed to demonstrate any significant effects of TPM on the neuropeptide Y and proopiomelanocortin systems. In conclusion, it is clear that TPM can reduce fat deposition by either reducing food intake or stimulating energy expenditure. The mechanisms whereby an AED such as TPM controls food intake and energy expenditure remains to be delineated. Copyright1999 ASCRS and ESCRS     

Energy balance, thermogenesis and brown adipose tissue activity in tube-fed rats

Young adult male rats were given a portion (42%) of their normal daily food intake by stomach tube (tube-fed), but they were also allowed free access to the same powdered diet. Total metabolizable energy intake was identical to that of controls, but tube-fed rats gained 25% weight and 50% more body energy than controls over 15 days. Total energy expenditure and resting oxygen consumption, measured during the latter part of the day, were reduced in tube-fed rats. Intubated animals showed a lower thermogenic response to noradrenaline and depressed activity of the mitochondrial proton conductance pathway in brown adipose tissue (assessed from GDP-binding), but brown fat mass, protein content, the density of beta-adrenoreceptors in brown fat cell membranes and plasma triiodothyronine (T3) levels did not differ between groups. These data indicate that the enhanced energetic efficiency and fat deposition of tube-fed rats is due to a lower energy expenditure, resulting, at least in part, from lower levels of thermogenesis in brown adipose tissue.     

Serum leptin in elderly people: associations with sex hormones, insulin, and adipose tissue volumes

OBJECTIVE: There are few data for associations of serum leptin with body fat, fat distribution, sex hormones, or fasting insulin in elderly adults. We hypothesized that the sex difference in serum leptin concentrations would disappear after adjustment for subcutaneous, but not visceral body fat. Serum leptin would not be associated with sex hormone concentrations or serum fasting insulin after adjusting for body fat and fat distribution. RESEARCH METHODS AND PROCEDURES: Subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes were measured using magnetic resonance imaging in a cross-sectional sample of 56 nondiabetic, elderly men and women aged 64 years to 94 years. Serum leptin, sex hormones (testosterone and estrone), sex hormone-binding globulin, and fasting insulin were also measured. Nine women were taking hormone replacement, and five men were clinically hypogonadal. RESULTS: Leptin was significantly associated with both SAT and VAT in each sex. Adjustment for SAT reduced the sex difference in leptin by 56%, but adjustment for VAT increased the difference by 25%. Leptin was not associated with serum estrone or hormone replacement therapy in the women, but had a significant, negative association with testosterone in the men that was independent of SAT, but not VAT. Leptin was significantly associated with fasting insulin in both sexes independent of age, sex hormones, sex hormone-binding globulin, VAT and SAT. DISCUSSION: Sex difference in serum leptin is partly explained by different amounts of SAT. Studies including both men and women should adjust for SAT rather than total body fat that includes VAT. The sex difference in serum leptin is not due to estrogen, but may be partly explained by testosterone. Testosterone is negatively associated with leptin in men, but the association is confounded with VAT. Leptin is associated with fasting insulin in nondiabetic elderly men and women independent of body fat, fat distribution, or sex hormones.