Josée Lalonde

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

Mechanisms of the Depot Specificity of Peroxisome Proliferator–Activated Receptor γ Action on Adipose Tissue Metabolism

In this study, we aimed to establish the mechanisms whereby peroxisome proliferator–activated receptor γ (PPARγ) agonism brings about redistribution of fat toward subcutaneous depots and away from visceral fat. In rats treated with the full PPARγ agonist COOH (30 mg · kg−1 · day−1) for 3 weeks, subcutaneous fat mass was doubled and that of visceral fat was reduced by 30% relative to untreated rats. Uptake of triglyceride-derived nonesterified fatty acids was greatly increased in subcutaneous fat (14-fold) and less so in visceral fat (4-fold), with a concomitant increase, restricted to subcutaneous fat only, in mRNA levels of the uptake-, retention-, and esterification-promoting enzymes lipoprotein lipase, aP2, and diacylglycerol acyltransferase 1. Basal lipolysis and fatty acid recycling were stimulated by COOH in both subcutaneous fat and visceral fat, with no frank quantitative depot specificity. The agonist increased mRNA levels of enzymes of fatty acid oxidation and thermogenesis much more strongly in visceral fat than in subcutaneous fat, concomitantly with a stronger elevation in O2 consumption in the former than in the latter. Mitochondrial biogenesis was stimulated equally in both depots. These findings demonstrate that PPARγ agonism redistributes fat by stimulating the lipid uptake and esterification potential in subcutaneous fat, which more than compensates for increased O2 consumption; conversely, lipid uptake is minimally altered and energy expenditure is greatly increased in visceral fat, with consequent reduction in fat accumulation.

Comparative effects of the antipsychotics sulpiride or risperidone in rats: I: Bodyweight, food intake, body composition, hormones and glucose tolerance

Obesity and related metabolic disorders are important side effects of some antipsychotic drugs (APs). The currently available animal model of AP-induced bodyweight gain (BWG) in rats is based on administration of sulpiride (SUL). However, this model has important limitations. For example, SUL is a pure dopamine antagonist, whereas most APs in current clinical use interact with multiple neurotransmitter receptors involved in food intake (FI) and metabolism regulation. Therefore, we evaluated the effects of risperidone (RIS, 0.125, 0.25 or 0.5 mg/kg during 16 days) on BWG and FI in male and female rats. Comparison between RIS (0.5 mg/kg), SUL (20 mg/kg) and vehicle (VEH) during 12 days was also conducted in females. In male rats, RIS did not significantly affect BWG, FI, glucose tolerance or leptin levels, even though prolactin and corticosterone were significantly elevated. In females, both APs significantly increased BWG and FI, but the effect was stronger with SUL. The BWG was significantly associated with an increase in body fat. Serum leptin levels were increased only in SUL-treated rats. The area under the curve for glucose (AUGC) was significantly lower in the SUL group, but it was similar for insulin in all treatment groups. The area under the curve for insulin (AUIC) and BWG positively correlated only in the RIS group. Prolactin and corticosterone were significantly increased by both APs. Serum estradiol levels were significantly increased by RIS but not by SUL, but progesterone levels were similar in both groups. The observed positive correlation between BWG and the AUIC during RIS administration suggests that this agent may represent a better model of AP administration in humans. The animal model of RIS-induced obesity in rats might be improved by testing other doses, route of administration and type of diet.

Awakening Cortisol Response in Lean, Obese, and Reduced Obese Individuals: Effect of Gender and Fat Distribution

Objective: Our goal was to assess the awakening cortisol response (ACR) in obese and reduced obese men and women.

Effects of Rimonabant (SR141716) on Fasting-Induced Hypothalamic-Pituitary-Adrenal Axis and Neuronal Activation in Lean and Obese Zucker Rats

The effects of the cannabinoid-1 receptor (CB1) antagonist rimonabant on energy metabolism and fasting-induced hypothalamic-pituitary-adrenal (HPA) axis and neuronal activation were investigated. Lean and obese Zucker rats were treated orally with a daily dose of 10 mg/kg rimonabant for 14 days. A comprehensive energy balance profile based on whole-carcass analyses further demonstrated the potential of CB1 antagonists for decreasing energy gain through reducing food intake and potentially increasing brown adipose tissue thermogenesis. Rimonabant also reduced plasma glucose, insulin, and homeostasis model assessment of insulin resistance, which further confirms the ability of CB1 antagonists to improve insulin sensitivity. To test the hypothesis that rimonabant attenuates the effect of fasting on HPA axis activation in the obese Zucker model, rats were either ad libitum–fed or food-deprived for 8 h. Contrary to expectation, rimonabant increased basal circulating corticosterone levels and enhanced the HPA axis response to food deprivation in obese rats. Rimonabant also exacerbated the neuronal activation seen in the arcuate nucleus (ARC) after short-term deprivation. In conclusion, the present study demonstrates that CB1 blockade does not prevent the hypersensitivity to food deprivation occurring at the level of HPA axis and ARC activation in the obese Zucker rats. This, however, does not prevent CB1 antagonism from exerting beneficial effects on energy and glucose metabolism.

Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats

OBJECTIVE: The estrogen antagonist EM-652.HCl behaves as a highly potent and pure antiestrogen in human breast and uterine cancer cells. Because of its pure antiestrogenic activity in these cells, and because its prodrug, EM-800, reduces bone loss and decreases serum cholesterol and triglycerides in the rat, EM-652.HCl can be classified as a pure selective estrogen receptor modulator (SERM). This study was conducted to assess the ability of EM-652.HCl to prevent obesity and abnormalities of lipid metabolism induced by ovariectomy in a rat model.DESIGN: Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E2), or EM-652.HCl for 20 days. At the end of the treatment period, parameters of energy balance and determinants of lipid metabolism were assessed.RESULTS: As expected, OVX increased energy intake, which in turn was accompanied by an increased energy, fat and protein gain and higher food efficiency. OVX also increased the triglyceride content of the liver and produced hypercholesterolemia and hyperinsulinemia. The weight of representative white adipose depots was higher in OVX than in intact rats. Lipoprotein lipase activity was higher in white adipose tissues of OVX rats than in those of intact animals, whereas its activity was lower in oxidative tissues (brown adipose and soleus muscle). Replacement therapy with a physiological dose of E2 prevented most of the abnormalities in energy and lipid metabolism brought about by OVX, although its orexigenic effect was only partially corrected. In contrast, treatment of OVX rats with EM-652.HCl completely abolished OVX-induced obesity and its related abnormalities in lipid metabolism and glucose/insulin homeostasis.CONCLUSION: These findings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVX-induced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with obesity such as hyperlipidemia and insulin resistance.

The effects of topiramate and sex hormones on energy balance of male and female rats

OBJECTIVE: The effects of topiramate (TPM) on components of energy balance were tested in male and female rats that were (i) left intact, (ii) castrated or (iii) castrated with replacement therapies consisting of testosterone administration in orchidectomized (OCX) rats and of estradiol or progesterone treatments in ovariectomized (OVX) rats.METHODS: TPM was mixed into the diet and administered at a dose of 60 mg per kg of body weight. Male and female rats were treated for 28 and 35 days, respectively. At the end of the treatment period, variables of energy balance and determinants of lipid and glucose metabolism were assessed.RESULTS: TPM reduced energy and fat gains in both male and female rats either in the absence or in the presence of hormone replacement therapies. In male rats, it also decreased food intake, protein gain and energetic efficiency. In female animals, TPM reduced energetic efficiency while it stimulated lipoprotein lipase activity in brown adipose tissue. TPM also reduced plasma glucose and plasma leptin levels in female rats as well as plasma insulin and liver triglycerides in male animals. As expected, castration and sex hormones also strongly influenced energy balance. In male rats, OCX led to a decrease in energy and protein gains that was blocked by treatment with testosterone. In female rats, OVX caused increases in energy, fat and protein gains that were prevented by treatment with estradiol.CONCLUSION: In female rats, the effects of TPM on fat and energy gains were clearly not influenced by the sex hormone status of the rats. In male animals, there was also no interaction of TPM and the status of sex hormones on energy balance, suggesting that OCX and testosterone minimally interfere with the action of TPM on energy balance. The effects of TPM on energy balance were accounted for by a decrease in energetic efficiency, resulting from an effect exerted by the drug on both energy intake and thermogenesis. The present results also suggest that TPM can enhance insulin sensitivity.

Comparative effects of the antipsychotics sulpiride and risperidone in female rats on energy balance, body composition, fat morphology and macronutrient selection

Previous studies showed that the antipsychotic drugs (APDs) sulpiride (SUL) and risperidone (RIS) induced body weight gain (BWG), hyperphagia, and increased serum levels of leptin, prolactin and corticosterone in female rats. Neither SUL nor RIS increased BWG or food intake (FI) in male rats. To further develop the animal model of APD-induced obesity, SUL (20 mg/kg/sc), RIS (0.5 mg/kg/sc) or vehicle (1 cm(3)/kg/sc) were administered to female Wistar rats for 10 or 12 days. Body composition, fat tissue morphology, energy expenditure and food efficiency were assessed in animals fed a high-fat diet. In another experiment, macronutrient selection was evaluated in animals fed with pure diets. SUL and RIS significantly increased BWG and FI, with a stronger effect of SUL. Both drugs increased fat gain and food efficiency, and did not modify energy expenditure. Obesity was due to adipocyte hyperplasia. SUL-treated rats significantly decreased fat intake (p = 0.039), showed a tendency to increase protein intake and did not modify carbohydrate consumption. No differences were observed between the RIS and the vehicle group. The macronutrient selection pattern differs from that observed in obese people undergoing APD treatment and in most animal models of obesity. Those findings suggest that SUL administration does not properly model APD treatment in humans. Results on macronutient selection in RIS-treated rats must be considered as preliminary, since in this experiment the animals did not gain weight significantly. Other diet protocols and lower APD doses must be tested to further characterize the RIS model.

Additive effects of leptin and topiramate in reducing fat deposition in lean and obese ob/ob mice.

The objective of the present study was to investigate the effects of the antiepileptic drug topiramate (TPM) on components of energy balance in lean and obese (ob/ob) mice in the presence or absence of leptin. Lean and ob/ob mice infused with either leptin or phosphate-buffered saline were treated with TPM for 7 days. TPM was mixed into the diet and administered at a dose of 60 mg/kg/day, whereas leptin was infused at the rate of 100 microg/kg/day using osmotic minipumps, which were subcutaneously implanted in the interscapular region. Food intake and body weight were monitored throughout the study. Body composition was measured prior to and following treatment with TPM and leptin, using dual-energy X-ray absorptiometry (DEXA). Glucose (glucose oxidase method) and insulin (radioimmunoassay) were also determined. TPM and leptin significantly reduced body weight gain, food intake and body fat gain in obese mice. The effects of TPM and leptin on fat gain were also statistically significant in lean animals. There was no interaction of TPM and leptin on the energy balance variables, the effects of the two substances being additive instead. Leptin abrogated hyperinsulinemia in obese mutants whereas TPM did not alter insulin levels in either lean or obese mice. The combination of leptin and TPM led to the normalization of glucose levels in obese mice. Our study demonstrates an effect of TPM in leptin-deficient animals, which suggests that TPM does not require the presence of leptin to exert its effect. They also show that the effects of leptin and TPM can be additive. The treatment with leptin in ob/ob mice neither accentuated nor blunted the effect of TPM on energy balance.

Cortisol response to the Trier Social Stress Test in obese and reduced obese individuals

Impact of body weight loss, body fat distribution and the nutritional status on the cortisol response to the Trier Social Stress Test (TSST) was investigated in this study. Fifty-one men (17 non-obese, 20 abdominally obese and 14 reduced obese) and 28 women (12 non-obese, 10 peripherally obese and 6 reduced obese) were subjected to the TSST in fed and fasted states. The TSST response was determined using salivary cortisol measurements. The nutritional status (being fed or fasted) had no effect on the cortisol levels during and following the TSST. Reduced obese men exhibited lower cortisol levels than non-obese men. Cortisol levels in obese men were not different from those of non-obese and reduced obese subjects. In women, there was no significant difference between groups. These finding suggest that weight status in men influences cortisol reactivity to a psychological stress and the different responses seen among genders could be linked to the different fat distributions that characterize men and women.