The mechanisms underlying the body weight and fat loss after the biliopancreatic diversion with duodenal switch (BPD/DS) remain to be fully delineated. The aim of this study was to examine the contributions of the two main components of BPD/DS, namely sleeve gastrectomy (SG) and duodenal switch (DS), on energy balance changes in rats rendered obese with a high-fat (HF) diet. Three different bariatric procedures (BPD/DS, SG, and DS) and three sham surgeries were performed in male Wistar rats. Sham-operated animals fed HF were either fed ad libitum (Sham HF) or pair weighed (Sham HF PW) by food restriction to the BPD/DS rats. A group of sham-operated rats was kept on standard chow and served as normal diet control (Sham Chow). All three bariatric surgeries resulted in a transient reduction in food intake. SG per se induced a delay in body weight gain. BPD/DS and DS led to a noticeable gut malabsorption and a reduction in body weight and fat gains along with significant elevations in plasma levels of glucagon-like peptide-1(7-36) and peptide YY. BPD/DS and DS elevated energy expenditure above that of Sham HF PW during the dark phase. However, they reduced the volume, oxidative metabolism, and expression of thermogenic genes in interscapular brown adipose tissue. Altogether the results of this study suggest that the DS component of the BPD/DS, which led to a reduction in digestible energy intake while sustaining energy expenditure, plays a key role in the improvement in the metabolic profile led by BPD/DS in rats fed a HF diet.

Background The mechanisms underlying the metabolic benefits of the biliopancreatic diversion with duodenal switch (BPD/DS) have not been clarified. The objective of this study was to investigate the metabolic roles of sleeve gastrectomy (SG) and duodenal switch (DS) as main surgical components of BPD/DS. Methods BPD/DS, SG, and DS surgeries were performed on chow-fed nonobese Wistar rats. Weight and energy intake were recorded during 8 postsurgical weeks. Glucagon-like peptide 1 (GLP-1), peptide tyrosine-tyrosine (PYY), glucose-dependent insulinotropic peptide, and ghrelin were measured pre- and postprandially at weeks 3 and 8, after surgery. Body composition, muscle, liver, and adipose tissue weights were measured. Gut morphometry and the presence and distribution of GLP-1 and PYY (L-cells) in the gut were determined using histochemical techniques. Results Compared with sham, BPD/DS and DS led to significant reductions in weight gain, percentage of fat, and adipose tissue weight. These effects were accompanied by a reduction in digestible energy intake associated with fecal energy loss due to DS. BPD/DS and DS produced intestinal hypertrophy, as well as higher plasma GLP-1 and PYY in both fasted and refed states. It is noteworthy that none of those alterations were observed after SG, which nonetheless led to transient postoperative reduction in gross energy intake and weight. Similar to BPD/DS, SG alone produced a reduced meal size and an enhanced postprandial depression of plasma ghrelin. Conclusion BPD/DS results in metabolic benefits, which appear largely caused by food malabsorption due to DS. The elevation of anorectic GLP-1 and PYY are additional consequences of DS, which, together with malabsorption, could promote the metabolic benefits of BPD/DS.

The present study was designed to investigate the role of the medial preoptic nucleus (MPO) as a site of the thermogenic and metabolic effects of the α-melanocyte-stimulating hormone analog melanotan II (MTII). We also assessed the involvement of the dorsomedial hypothalamic nucleus (DMH) by investigating the effects of the MPO infusion of MTII in rats with DMH lesions produced by kainic acid. Infusion of MTII in the MPO led to increases in interscapular brown adipose tissue (iBAT) temperature and iBAT uptake of 14C-bromopalmitate. Both increases were blocked by DMH lesions. iBAT temperature increase (area under curve) and 14C-bromopalmitate uptake emerged as two correlated variables ( r = 0.63, P < 0.001). DMH lesions also blocked MTII-induced expression of mRNAs coding for proteins involved in 1) thermogenesis [type II iodothyronine deiodinase ( Dio2) and peroxisome proliferator-activated receptor gamma coactivator 1-α ( Pgc1α)], 2) lipolysis [hormone-sensitive lipase ( Hsl)], and 3) lipogenesis [diacylglycerol-O-acyltransferase 2 ( Dgat2), fatty acid synthase ( Fas)], in iBAT of rats killed 1 h after MPO infusion of MTII. MTII also stimulated expression of genes in iWAT but only in rats with DMH lesions. These genes included glucose transporter member 4 ( Glut4), glycerol-3-phosphate acyltransferase 3 ( Gpat3), Dgat1, Dgat2, triglyceride lipase ( Atgl), Hsl, and carnitine palmitoyltransferase 1β ( Cpt1β). Altogether, the present results reveal the MPO as a site of the thermogenic and metabolic actions of MTII. They also contribute to establish the MPO-DMH duet as a significant target for melanocortins to modulate energy homeostasis.

The present study was designed to investigate the involvement of the cannabinoid receptor 1 (CB1) in the stimulating effects of the melanocortin-4 receptor (MC4R) agonism on whole-body and brown adipose tissue (BAT) thermogenesis. In a first series of experiments, whole-body and BAT thermogenesis were investigated in rats infused in the third ventricle of the brain with the MC4R agonist melanotan II (MTII) and the CB1 agonist δ9-tetrahydrocannabinol (δ9-THC) or the CB1 antagonist AM251. Whole-body thermogenesis was measured by indirect calorimetry and BAT thermogenesis assessed from interscapular BAT (iBAT) temperature. δ9-THC blunted the effects of MTII on energy expenditure and iBAT temperature, whereas AM251 tended to potentiate the MTII effects. δ9-THC also blocked the stimulating effect of MTII on 14C-bromopalmitate and 3H-deoxyglucose uptakes in iBAT. Additionally, δ9-THC attenuated the stimulating effect of MTII on the expression of peroxisome proliferator-activated receptor-γ coactivator 1-α (Pgc1α), type II iodothyronine deiodinase (Dio2), carnitine palmitoyltransferase 1B (Cpt1b), and uncoupling protein 1 (Ucp1). In a second series of experiments, we addressed the involvement of the paraventricular hypothalamic nucleus (PVH) in the CB1-mediated effects of MTII on iBAT thermogenesis, which were assessed following the infusion of MTII in the PVH and δ9-THC or AM251 in the fourth ventricle of the brain. We demonstrated the ability of δ9-THC to blunt MTII-induced iBAT temperature elevation. δ9-THC also blocked the PVH effect of MTII on 14C-bromopalmitate uptake as well as on Pgc1α and Dio2 expression in iBAT. Altogether the results of this study demonstrate the involvement of the PVH in the CB1-mediated stimulating effects of the MC4R agonist MTII on whole-body and BAT thermogenesis.

The brain melanin-concentrating hormone (MCH) system represents an anabolic system involved in energy balance regulation through influences exerted on the homeostatic and nonhomeostatic controls of food intake and energy expenditure. The present study was designed to further delineate the effect of the MCH system on energy balance regulation by assessing the actions of the MCH receptor 1 (MCHR1) agonism on both food intake and energy expenditure after intracerebroventricular (third ventricle) and intra-nucleus-accumbens-shell (intraNAcSH) injections of a MCHR1 agonist. Total energy expenditure and substrate oxidation were assessed following injections in male Wistar rats using indirect calorimetry. Food intake was also measured. Pair-fed groups were added to evaluate changes in thermogenesis that would occur regardless of the meal size and its thermogenic response. Using such experimental conditions, we were able to demonstrate that acute MCH agonism in the brain, besides its orexigenic effect, induced a noticeable change in the utilization of the main metabolic fuels. In pair-fed animals, MCH significantly reduced lipid oxidation when it was injected in the third ventricle. Such an effect was not observed following the injection of MCH in the NAcSH, where MCH nonetheless strongly stimulated appetite. The present results further delineate the influence of MCH on energy expenditure and substrate oxidation while confirming the key role of the NAcSH in the effects of the MCH system on food intake.

The corticotropin-releasing factor (CRF) system is involved in numerous physiological and behavioral actions, including the regulation of energy balance. We examined the effects of the CRF1 receptor antagonist, SSR125543, on energy balance and food deprivation-induced neuronal activation in obese rats. Lean (Fa/?) and obese (fa/fa) Zucker rats were treated orally with SSR125543 at a daily dose of 30 mg/kg for 21 days. Rats were killed either fed ad libitum or food deprived for 6 h in order to induce a mild stress response in obese rats. SSR125543 reduced plasma corticosterone levels in lean rats, prevented corticosterone response to fasting in obese rats, and increased CRF mRNA levels in the paraventricular hypothalamic nucleus (PVN) of both lean and obese rats, further confirming that the antagonist partially blocked CRF1 receptors. SSR125543 increased protein gain in obese rats. Whole carcass analyses showed reduced energy and fat gains in lean rats. Consistent with reduced fat gain, circulating triglyceride and leptin levels were reduced in SSR125543-treated lean rats. In obese rats, circulating glucose levels and the homeostasis model assessment of insulin resistance index of insulin resistance were reduced by SSR125543 treatment. CRF1 receptor blockade increased uncoupling protein-1 mRNA levels in interscapular brown adipose tissue of obese rats. The antagonist partly blocked the fasting-induced changes in c-fos mRNA levels in the PVN and arcuate nucleus of obese rats. Overall, these results suggest that although SSR125543 had relatively mild effects on energy balance, CRF1 receptor blockade attenuated several metabolic effects of short-term fasting and improved plasma variables related to the metabolic syndrome and diabetes.

The corticotropin-releasing factor (CRF) system is involved in numerous physiological and behavioral actions, including the regulation of energy balance. We examined the effects of the CRF1 receptor antagonist, SSR125543, on energy balance and food deprivation-induced neuronal activation in obese rats. Lean (Fa/?) and obese ( fa/fa) Zucker rats were treated orally with SSR125543 at a daily dose of 30 mg/kg for 21 days. Rats were killed either fed ad libitum or food deprived for 6 h in order to induce a mild stress response in obese rats. SSR125543 reduced plasma corticosterone levels in lean rats, prevented corticosterone response to fasting in obese rats, and increased CRF mRNA levels in the paraventricular hypothalamic nucleus (PVN) of both lean and obese rats, further confirming that the antagonist partially blocked CRF1 receptors. SSR125543 increased protein gain in obese rats. Whole carcass analyses Journal of Endocrinology (2007) 193, 11–19 0022–0795/07/0193–011 q 2007 Society for Endocrinology Printed in Great showed reduced energyand fat gains in lean rats. Consistentwith reduced fat gain, circulating triglyceride and leptin levels were reduced in SSR125543-treated lean rats. In obese rats, circulating glucose levels and the homeostasis model assessment of insulin resistance index of insulin resistance were reduced by SSR125543 treatment. CRF1 receptor blockade increased uncoupling protein-1 mRNA levels in interscapular brown adipose tissue of obese rats. The antagonist partly blocked the fasting-induced changes in c-fos mRNA levels in the PVN and arcuate nucleus of obese rats. Overall, these results suggest that although SSR125543 had relatively mild effects on energy balance, CRF1 receptor blockade attenuated several metabolic effects of short-term fasting and improved plasma variables related to the metabolic syndrome and diabetes. Journal of Endocrinology (2007) 193, 11–19

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.

OBJECTIVE:This study was carried out to determine the effects of the biliopancreatic diversion (BPD), a bariatric surgery applied to the treatment of morbidly obese humans, on energy balance in rats.METHODS:BPD was performed on a group of male Wistar rats. Body weight and food intake were measured daily throughout the study. Feces were also collected to assess energy losses and the determination of digestible energy. Energy expenditure and body composition were also determined for the 50-day length of the protocol. On the day of killing, the brain, the entire intestinal tract and white and brown adipose tissues were collected and weighed. Expression of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the ARC nucleus were assessed by in situ hybridization.RESULTS:Marked changes in the regulation of energy balance were observed in the BPD-operated rats. A decrease in digestible energy and food intake coupled with an increase in the fecal energy density and protein fecal energy led to an important weight loss in the BPD-operated rats. This weight loss was observed in the loss of fat mass (specifically the white epididymal, inguinal, retroperitoneal and brown adipose tissues). The rats modified their food intake pattern to be able to potentially eat more during the entire day. An increase in the surfaces of all intestinal structures (muscular and mucosal layers) was observed in the BPD-operated rats. The NPY and AgRP expression in the brain were both shown to be greater in the BPD-operated rats than in the control animals. At the beginning of the study, the surgery led to an energy expenditure decrease, which, however, did not persist throughout the study despite the fact that BPD-operated rats exhibited persistent lower fat free masses.CONCLUSION:BPD led to a noticeable reduction in weight and fat gains in rats, which was in large part owing to a decrease in digestible energy intake led to by the gastrectomy, the intestinal malabsorption inherent to the surgery and to potentially a thermogenesis stimulation that occurred in the second end of the study. The reduction in energy gain occurs despite adaptations to thwart the intestinal malabsorption and the hunger signals from the central nervous system.

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)gamma modulates the expression of numerous genes involved in glucose and lipid homeostasis and plays a critical role in adipocyte differentiation. Expression of uncoupling protein (UCP)1, which is necessary for thermogenesis, is strongly stimulated by PPARgamma agonists but without an increase in energy expenditure. This study was designed to assess whether PPARgamma-induced UCP1 has any functional impact and, if so, whether it involves sympathetic activity. In a first phase, obese ob/ob C57BL/6J mice and lean controls were treated for 2 wk with the PPARgamma agonist [2-(2-[4-phenoxy-2-propylphenoxy]ethyl)indole-5-acetic acid] (COOH). COOH induced UCP1 expression in brown and white adipose tissues as well as that of other genes associated with substrate oxidation and thermogenesis. However, UCP1 induction did not increase energy expenditure, as assessed by indirect calorimetry and other energy balance measurements. In a second phase, mice received for an additional 2 wk a combination of COOH and the beta(3)-adrenergic receptor (beta(3)-AR) agonist CL-316243 to stimulate the adrenergic signaling pathway and assess whether COOH-induced UCP1 was physiologically functional. The beta(3)-AR agonist stimulated thermogenesis in lean and ob/ob mice, an effect that was much stronger in COOH-pretreated mice, which exhibited lower respiratory quotient, higher oxygen consumption, and marked weight and fat mass loss, compared with mice not pretreated with COOH. These results demonstrate that PPARgamma agonism increases the thermogenic potential of white and brown adipose depots in lean and obese mice. This enhanced capacity leads to increased thermogenesis under beta-adrenergic stimulation, suggesting that the sympathetic drive is blunted by PPARgamma agonism.

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 μg/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.

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.

INTRODUCTION: An observational trial was conducted to assess the effect of orlistat on body weight and obesity-related co-morbidities in clinical practice in Germany. METHODS: A total of 15549 obese patients (women, nˆ11131; men, nˆ 4418) were observed for a maximum of 9 months of orlistat therapy. Most patients (nˆ15201) were treated by primary health care physicians (nˆ5686); 348 patients were treated by hospital physicians (nˆ60). Recommended therapy was orlistat 120 mg tid combined with a reduced-fat diet for 6 ± 9 months. RESULTS: Mean duration of treatment was 7.1 months. Orlistat was used in conjunction with a reduced-fat diet in 73% of patients and with physical activity in 53% of patients. One-third of patients participated in a speci®c orlistat-based weight management program (XENI-CALculiertes Abnehmen). Mean age of observed patients was 48 years and mean duration of obesity prior to orlistat therapy was 14 years. Most patients had previously attempted to lose weight; however, very few had been able to achieve and maintain weight loss of 5%. Approximately 50% of patients had 1 ± 2 stated comorbidities while 30% of patients had 3 co-morbidities. Incidences of hypertension, dyslipidaemia and diabetes were 41%, 34% and 16%, respectively. Mean weight loss with orlistat after 7.1 months of therapy was 10.7% (p< 0.000l vs baseline). Weight loss of 5% was achieved by 87% of patients while over half (51%) had weight loss of 10%. Waist circumference decreased by 7.7 cm in women and 8.5 cm in men (both p<0.0001). Orlistat was also associated with signi®cant (p<0.0001) improvements in systolic and diastolic BP (710 and 75 mmHg, respectively), blood glucose (77.5%), total cholesterol (711%), LDL-cholesterol (712%), HDL-cholesterol (‡11%) and triglycerides (714%). Improvements were most marked in patients with comorbidities at the start of therapy. In patients with hypertension (nˆ3391), systolic and diastolic BP decreased by 18 and 13 mmHg, respectively; in patients with diabetes (nˆ 2445), blood glucose was reduced by 15% and, in patients with dyslipidaemia (nˆ 5248), total cholesterol, LDL-cholesterol and triglycerides all decreased (714%, 714% and 718%, respectively) while HDL-cholesterol increased (‡13%). In addition, 26% of hypertensive patients, 34% of diabetes patients and 46% of patients with dyslipidaemia had their comorbidity medication reduced or stopped during orlistat therapy. Orlistat was well-tolerated, with adverse events (primarily gastrointestinal) documented in only 1.5% of patients. The ef®cacy of orlistat was considered good=excellent by 86% of physicians while 92% considered orlistat safety to be good=excellent. CONCLUSION: Orlistat therapy effectively promotes weight loss, improves co-morbidities and allows for reduced co-morbidity medications in daily clinical practice.