Efficacy and safety of semaglutide in patients with heart failure with preserved ejection fraction and obesity.

BACKGROUND: Semaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, has shown promise in weight management and cardiovascular outcomes in other populations. This study aimed to evaluate the efficacy of semaglutide in heart failure with preserved ejection fraction (HFpEF) patients with obesity. METHODS: A retrospective study analyzed 318 patients with HFpEF, of which 104 received semaglutide and 214 received placebo. Primary endpoints included evaluating changes in exercise capacity and weight management. RESULTS: Semaglutide treatment led to significant improvements in the primary endpoints. Patients in the semaglutide group demonstrated substantial enhancements in exercise capacity, as measured by the 6-min walk distance, compared to the placebo group (mean difference 15.1 meters, 95% CI 5.8 to 24.4, p = 0.002). Additionally, semaglutide resulted in substantial weight loss compared to placebo (mean difference -2.9%, 95% CI -4.1--1.7, p = 0.001). Several secondary endpoints, including reductions in C-reactive protein levels and improvements in other clinical parameters, further supported the efficacy of semaglutide. Adverse events were generally well-tolerated, with no unexpected safety concerns. CONCLUSION: Semaglutide demonstrated significant clinical benefits in HFpEF patients with obesity, as evidenced by improved symptoms, physical function, and weight reduction.

Intranasal Oxytocin for Obesity.

BACKGROUND: Accumulating preclinical and preliminary translational evidence shows that the hypothalamic peptide oxytocin reduces food intake, increases energy expenditure, and promotes weight loss. It is currently unknown whether oxytocin administration is effective in treating human obesity. METHODS: In this randomized, double-blind, placebo-controlled trial, we randomly assigned adults with obesity 1:1 (stratified by sex and obesity class) to receive intranasal oxytocin (24 IU) or placebo four times daily for 8 weeks. The primary end point was change in body weight (kg) from baseline to week 8. Key secondary end points included change in body composition (total fat mass [g], abdominal visceral adipose tissue [cm2], and liver fat fraction [proportion; range, 0 to 1; higher values indicate a higher proportion of fat]), and resting energy expenditure (kcal/day; adjusted for lean mass) from baseline to week 8 and caloric intake (kcal) at an experimental test meal from baseline to week 6. RESULTS: Sixty-one participants (54% women; mean age ± standard deviation, 33.6 ± 6.2 years; body-mass index [the weight in kilograms divided by the square of the height in meters], 36.9 ± 4.9) were randomly assigned. There was no difference in body weight change from baseline to week 8 between oxytocin and placebo groups (0.20 vs. 0.26 kg; P=0.934). Oxytocin (vs. placebo) was not associated with beneficial effects on body composition or resting energy expenditure from baseline to week 8 (total fat: difference [95% confidence interval], 196.0 g [-1036 to 1428]; visceral fat: 3.1 cm2 [-11.0 to 17.2]; liver fat: -0.01 [-0.03 to 0.01]; resting energy expenditure: -64.0 kcal/day [-129.3 to 1.4]). Oxytocin compared with placebo was associated with reduced caloric intake at the test meal (-31.4 vs. 120.6 kcal; difference [95% confidence interval], -152.0 kcal [-302.3 to -1.7]). There were no serious adverse events. Incidence and severity of adverse events did not differ between groups. CONCLUSIONS: In this randomized, placebo-controlled trial in adults with obesity, intranasal oxytocin administered four times daily for 8 weeks did not reduce body weight. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov number, NCT03043053.).

Assessment of the potential effects of l-carnitine and cinnamon supplementation on weight loss and body composition.

OBJECTIVE: Aim: To assess efficacy of L-carnitine and cinnamon alone and in combination on body composition parameters in addition to compare between them. PATIENTS AND METHODS: Materials and Methods: Sample of 28 obese and overweight adults in Babylon city, sample collection includes patients in places, or by internet, where interview take place according to specialize questionnaire height, weight, and body mass index were measured. RESULTS: Results: A significant differences P<0.05 among gender distribution between male and female. A significant difference between (150-160 cm, 160-170 cm) as compared with (170-180 cm, 180-190 cm). A significant difference between 170-180 cm as compared with 180-190 cm but non-significant differences between 150-160 cm as compared with 160-170 cm. A significant difference between 26-35 as compared with 36-45, 46-55, but non-significant differences between 36-45 as compared with 46-55. A significant difference between body weight, body fat, water content, skeletal muscle, and body mass index after treatment, but non-significant differences between protein, and inorganic salt after treatment and at baseline. A significant difference between body weight, water content, skeletal muscle, and body mass index in group treated with cinnamon as compared with negative control group, but non-significant differences between body fat, protein, and inorganic salt as compared with negative control group. CONCLUSION: Conclusions: The prevalence of overweight and obesity within accepted range of that reported in Iraq, important relationship was reported between several life style risk factor, as soon as diagnose increase in weight and education health program for behavior of life style were high recommended.

Retrospective study of Cognitive Behavioral Therapy for Obesity modified as FIRE method (CBT-F) in combination with medication for weight loss.

Obesity rates continue to rise globally, posing a significant public health concern. Current treatments often lack long-term effectiveness, necessitating the exploration of new approaches. This study examines the effectiveness of a modified treatment method called Cognitive Behavioral Therapy modified as FIRE method (CBT-F), which combines cognitive behavioral therapy with pharmacotherapy. The study involves 62 women seeking weight loss treatment, divided into a CBT-F group and a control group receiving only pharmacotherapy. Anthropometric measures and blood chemistry data were collected over an average follow-up period of 68.5 days. The results demonstrate that the CBT-F group achieved significantly greater weight loss compared to the control group. No notable differences were observed in blood chemistry data. The combination of CBT-F and pharmacotherapy offers a comprehensive and planned approach to obesity treatment by addressing psychological factors and leveraging the effects of medication. Modules specifically designed to handle medication side effects and changes in eating behavior may contribute to treatment success and sustainability. Although this study focused on women, future research should examine the effectiveness of CBT-F in diverse populations. CBT-F shows promise as an alternative or complementary treatment option for individuals who have undergone CBT for extended periods or struggle with lifestyle changes. Overall, the findings suggest that CBT-F, with its shorter treatment duration and immediate effects of pharmacotherapy, holds potential as an effective and sustainable approach to obesity treatment. Further studies are necessary to validate these findings and expand the evidence base for this novel treatment.

[Severe gastroparesia associated with the use of GLP-1 receptor agonists for weight loss]. / Gastroparesia severa asociada al uso de agonistas del receptor GLP-1 para bajar de peso.

Initially developed as medications for diabetes mellitus, GLP-1 agonists have gained much popularity in the treatment of obesity and weight loss. The present case describes a 69-year-old woman with a history of peptic ulcer and use of NSAIDs, who presented with abdominal pain and oral intolerance refractory to conventional management, for which an upper digestive endoscopy was performed, diagnosing severe gastroparesis. Asking more about the story, revealed surreptitious use of semaglutide. She continued with supportive therapy and the symptoms resolved spontaneously. The present case report aims to warn of the potential risks of the use of GLP-1 analogues in the context of endoscopy with sedation.

Effect of Salvia hispanica (Chia seeds) and Foeniculum vulgare (Fennel seeds) against weight-loss and lipid profile in obese human subjects.

Increased levels of bad cholesterol in the body result in increasing blood pressure and weight gain. The rate of mortality in people, especially who are obese, is increasing due to absence of organic sources of fiber in their diets. Chia and fennel seeds are rich sources of fiber. The objective of this study was to evaluate the combined effect of Salvia hispanica (Chia seeds) and Foeniculum vulgare (Fennel seeds) against weight-loss and lipid profile in obese human subjects. The research was conducted on obese people aged 25 to 40 years at the Jinnah Hospital Lahore. The study design was randomized control trial (RCT). The sample size was calculated and was divided in-to two groups. With the duration of study being 3 months, pre-testing of all the participants was done. Group 1 was control group, given placebo treatment and Group 2 was an intervention group and given chia and fennel seeds. Post-testing was done and data were analyzed. Results showed that chia and fennel seeds have significant effect (p <0.05) on BMI and lipid profile hence, both are beneficial for lowering body weight and improving LDL, HDL, serum triglycerides and total cholesterol levels.

Cost-effectiveness analysis of once-weekly semaglutide vs. once-daily liraglutide administered subcutaneously in patients with overweight and obesity: a decision analysis.

OBJECTIVE: Obesity presents an enduring and multifaceted dilemma that impacts individuals, society, economies, and healthcare systems alike. Glucagon-like peptide-1 (GLP-1) receptor agonists, including liraglutide and semaglutide, have received FDA approval for obesity treatment. This study aims to present a cost-effectiveness analysis to compare the cost and clinical outcomes of semaglutide vs. liraglutide on weight loss in people with overweight and obesity. MATERIALS AND METHODS: A cost-effectiveness analysis was conducted to compare the cost and the clinical outcomes of adding weekly 2.4 mg SC semaglutide vs. daily 3.0 mg SC liraglutide or placebo to physical activity and diet control in overweight and obese patients. A clinical outcome of achieving ≥15% weight loss was chosen. A simple decision analysis model from a third-payer perspective was applied. Drug costs were based on the retail price of the USA market. One-way sensitivity analyses were performed. RESULTS: Results showed that 2.4 mg weekly semaglutide, when added to physical activity and diet control, was the most cost-effective choice in terms of ≥15% weight loss (ICER: $ 7,056/patient/68 weeks). The model was robust against the 50% increase in the unit cost of semaglutide and the 50% decrease in the unit cost of liraglutide, as well as the changes in probabilities by the corresponding 95% confidence intervals across the model. CONCLUSIONS: This cost-effectiveness analysis suggests that employing once-weekly 2.4 mg semaglutide emerges as a remarkably cost-effective option when contrasted with once-daily 3.0 mg liraglutide in patients with overweight and obesity when added to physical activity and diet control.

In HFpEF with obesity, semaglutide improved health status and weight loss at 52 wk, regardless of initial health status.

SOURCE CITATION: Kosiborod MN, Verma S, Borlaug BA, et al; STEP-HFpEF Trial Committees and Investigators. Effects of semaglutide on symptoms, function, and quality of life in patients with heart failure with preserved ejection fraction and obesity: a prespecified analysis of the STEP-HFpEF trial. Circulation. 2024;149:204-216. 37952180.

Hepatic IRE1α-XBP1 signaling promotes GDF15-mediated anorexia and body weight loss in chemotherapy.

Platinum-based chemotherapy drugs can lead to the development of anorexia, a detrimental effect on the overall health of cancer patients. However, managing chemotherapy-induced anorexia and subsequent weight loss remains challenging due to limited effective therapeutic strategies. Growth differentiation factor 15 (GDF15) has recently gained significant attention in the context of chemotherapy-induced anorexia. Here, we report that hepatic GDF15 plays a crucial role in regulating body weight in response to chemo drugs cisplatin and doxorubicin. Cisplatin and doxorubicin treatments induce hepatic Gdf15 expression and elevate circulating GDF15 levels, leading to hunger suppression and subsequent weight loss. Mechanistically, selective activation by chemotherapy of hepatic IRE1α-XBP1 pathway of the unfolded protein response (UPR) upregulates Gdf15 expression. Genetic and pharmacological inactivation of IRE1α is sufficient to ameliorate chemotherapy-induced anorexia and body weight loss. These results identify hepatic IRE1α as a molecular driver of GDF15-mediated anorexia and suggest that blocking IRE1α RNase activity offers a therapeutic strategy to alleviate the adverse anorexia effects in chemotherapy.

A long-acting LEAP2 analog reduces hepatic steatosis and inflammation and causes marked weight loss in mice.

OBJECTIVE: The number of individuals affected by metabolic dysfunction associated fatty liver disease [1] is on the rise, yet hormonal contributors to the condition remain incompletely described and only a single FDA-approved treatment is available. Some studies suggest that the hormones ghrelin and LEAP2, which act as agonist and antagonist/inverse agonist, respectively, for the G protein coupled receptor GHSR, may influence the development of MAFLD. For instance, ghrelin increases hepatic fat whereas synthetic GHSR antagonists do the opposite. Also, hepatic steatosis is less prominent in standard chow-fed ghrelin-KO mice but more prominent in 42% high-fat diet-fed female LEAP2-KO mice. METHODS: Here, we sought to determine the therapeutic potential of a long-acting LEAP2 analog (LA-LEAP2) to treat MAFLD in mice. LEAP2-KO and wild-type littermate mice were fed a Gubra-Amylin-NASH (GAN) diet for 10 or 40 wks, with some randomized to an additional 28 or 10 days of GAN diet, respectively, while treated with LA-LEAP2 vs Vehicle. Various metabolic parameters were followed and biochemical and histological assessments of MAFLD were made. RESULTS: Among the most notable metabolic effects, daily LA-LEAP2 administration to both LEAP2-KO and wild-type littermates during the final 4 wks of a 14 wk-long GAN diet challenge markedly reduced liver weight, hepatic triglycerides, plasma ALT, hepatic microvesicular steatosis, hepatic lobular inflammation, NASH activity scores, and prevalence of higher-grade fibrosis. These changes were accompanied by prominent reductions in body weight, without effects on food intake, and reduced plasma total cholesterol. Daily LA-LEAP2 administration during the final 10 d of a 41.5 wk-long GAN diet challenge also reduced body weight, plasma ALT, and plasma total cholesterol in LEAP2-KO and wild-type littermates and prevalence of higher grade fibrosis in LEAP2-KO mice. CONCLUSIONS: Administration of LA-LEAP2 to mice fed a MAFLD-prone diet markedly improves several facets of MAFLD, including hepatic steatosis, hepatic lobular inflammation, higher-grade hepatic fibrosis, and transaminitis. These changes are accompanied by prominent reductions in body weight and lowered plasma total cholesterol. Taken together, these data suggest that LEAP2 analogs such as LA-LEAP2 hold promise for the treatment of MAFLD and obesity.

Role of lifestyle and glucagon-like peptide-1 receptor agonists for weight loss in obesity, type 2 diabetes and steatotic liver diseases.

BACKGROUND: The current obesity pandemic has given rise to associated comorbidities and complications, including type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). During the last decade, certain glucagon-like peptide 1 receptor agonists (GLP-1RA), originally developed as antihyperglycemic drugs, also demonstrated efficacy for weight loss. AIMS: To review shared pathophysiologic features of common metabolic diseases and compare therapeutic strategies to reduce body weight and related complications. METHODS: We performed an extensive literature research to describe the effects of lifestyle modification, first-generation anti-obesity drugs, and GLP-1RA on weight loss in humans with obesity, type 2 diabetes and MASLD. RESULTS: Until recently, treatment of obesity has been limited to lifestyle modification, which offer moderate degree and sustainability of weight loss. The few approved first-generation anti-obesity drugs are either limited to short term use or to certain forms of obesity. Some GLP-1RA significantly decrease caloric intake and body weight. Liraglutide and semaglutide have therefore been approved for treating people with obesity. They also lead to a reduction of hepatic fat content and inflammation in people with biopsy-confirmed MASLD. Possible limitations comprise adverse effects, treatment adherence and persistence. CONCLUSION: Certain GLP-1RA are superior to lifestyle modification and first-generation anti-obesity drugs in inducing weight loss. They have therefore markedly changed the portfolio of obesity treatment with additional beneficial effects on steatotic liver disease.

Doxorubicin causes cachexia, sarcopenia, and frailty characteristics in mice.

While chemotherapy treatment can be lifesaving, it also has adverse effects that negatively impact the quality of life. To investigate the effects of doxorubicin chemotherapy on body weight loss, strength and muscle mass loss, and physical function impairments, all key markers of cachexia, sarcopenia, and frailty. Seventeen C57/BL/6 mice were allocated into groups. 1) Control (n = 7): mice were exposed to intraperitoneal (i.p.) injections of saline solution. 2) Dox (n = 10): mice were exposed to doxorubicin chemotherapy cycles (total dose of 18 mg/kg divided over 15 days). The body weight loss and decreased food intake were monitored to assess cachexia. To assess sarcopenia, we measured muscle strength loss using a traction method and evaluated muscle atrophy through histology of the gastrocnemius muscle. To evaluate physical function impairments and assess frailty, we employed the open field test to measure exploratory capacity. Doxorubicin administration led to the development of cachexia, as evidenced by a significant body weight loss (13%) and a substantial decrease in food intake (34%) over a 15-day period. Furthermore, 90% of the mice treated with doxorubicin exhibited sarcopenia, characterized by a 20% reduction in traction strength (p<0,05), a 10% decrease in muscle mass, and a 33% reduction in locomotor activity. Importantly, all mice subjected to doxorubicin treatment were considered frail based on the evaluation of their overall condition and functional impairments. The proposed model holds significant characteristics of human chemotherapy treatment and can be useful to understand the intricate relationship between chemotherapy, cachexia, sarcopenia, and frailty.

Semaglutide as a potential treatment for obesity in Smith-Kingsmore syndrome (SKS) patients: A mosaic mutation case report.

We present for the first-time efficacy and tolerability of GLP-1-RA (Semaglutide) in Smith-Kingsmore syndrome (SKS). SKS is a rare genetic disorder characterized by intellectual disability, macrocephaly, seizures and distinctive facial features due to MTOR gene mutation. We present a 22-year-old woman with mosaic SKS and severe obesity (Body Mass Index ≥40 kg/m²), treated with semaglutide. She achieved a 9 kg (7.44%) weight loss over 12 months without adverse effects.This case highlights semaglutide's potential in managing obesity in SKS patients, emphasizing the need for further research in this rare genetic disorder.

The maintenance of long-term weight loss after semaglutide withdrawal in obese women with PCOS treated with metformin: a 2-year observational study.

Background: Withdrawal of semaglutide is frequently followed by weight regain due to compensatory biological changes that prevent the maintenance of long-term weight loss. There are some studies implying that metformin might attenuate weight regain. The weight trajectory after discontinuation of short-term semaglutide treatment in obese women with PCOS who continued metformin treatment has not yet been evaluated. Aims: We explored changes in body weight, cardiometabolic and endocrine parameters in obese women with PCOS who continued treatment with metformin 2 years after discontinuation of short-term intervention with semaglutide. Methods: 25 women with PCOS and obesity, aged 33.7 ± 5.3 years (mean ± SD), were treated with once-weekly subcutaneous semaglutide 1.0 mg as an adjunct to metformin 2000 mg/day and lifestyle intervention for 16 weeks. At week 16, semaglutide was discontinued. Treatment with metformin 2000 mg/day and promotion of lifestyle intervention were continued during the 2-year follow-up period. Weight change, cardiometabolic, and endocrine parameters were assessed 2 years after semaglutide discontinuation. Results: During semaglutide treatment phase, weight decreased from 101 (90-106.8) kg to 92 (83.3-100.8) kg. Two years after semaglutide withdrawal, weight was 95 (77-104) kg. The net weight loss 2 years after discontinuation of semaglutide remained significant when compared to baseline (p=0.003). At the end of the study, 21 out of 25 subjects had lower body weight compared to baseline. Improvements in cardiometabolic parameters including decrease in total and LDL cholesterol, fasting glucose, and glucose after OGTT that had been seen during semaglutide-treatment phase reverted towards baseline two years after semaglutide cessation. Free testosterone levels significantly decreased during semaglutide treatment from 6.16 (4.07-9.71) to 4.12 (2.98-6.93) nmol/l, (p= 0.012) and did not significantly deteriorate after semaglutide discontinuation. Conclusion: Two years after semaglutide withdrawal, women with PCOS who continued with metformin regained about one-third of the semaglutide-induced weight loss. At the end of the follow up, 84% of women had a lower body weight than at baseline.

Liraglutide and not lifestyle intervention reduces soluble CD163 after comparable weight loss in obese participants with prediabetes or type 2 diabetes mellitus.

BACKGROUND: The GLP-1 receptor agonist liraglutide is used to treat hyperglycemia in type 2 diabetes but is also known to induce weight loss, preserve the beta cell and reduce cardiovascular risk. The mechanisms underlying these effects are however still not completely known. Herein we explore the effect of liraglutide on markers of immune cell activity in a population of obese individuals with prediabetes or newly diagnosed type 2 diabetes mellitus. METHOD: Plasma levels of the monocyte/macrophage markers, soluble (s)CD163 and sCD14, the neutrophil markers myeloperoxidase (MPO) and neutrophil gelatinase-associated lipocalin (NGAL),the T-cell markers sCD25 and T-cell immunoglobulin mucin domain-3 (sTIM-3) and the inflammatory marker TNF superfamily (TNFSF) member 14 (LIGHT/TNFSF14) were measured by enzyme-linked immunosorbent assays in obese individuals with prediabetes or diabetes diagnosed within the last 12 months, prior to and after comparable weight loss achieved with lifestyle changes (n = 20) or liraglutide treatment (n = 20), and in healthy subjects (n = 13). RESULTS: At baseline, plasma levels of the macrophage marker sCD163, and the inflammatory marker LIGHT were higher in cases as compared to controls. Plasma levels of sCD14, NGAL, sTIM-3 and sCD25 did not differ at baseline between patients and controls. After weight reduction following lifestyle intervention or liraglutide treatment, sCD163 decreased significantly in the liraglutide group vs. lifestyle (between-group difference p = 0.023, adjusted for visceral adipose tissue and triglycerides basal values). MPO and LIGHT decreased significantly only in the liraglutide group (between group difference not significant). Plasma levels of MPO and in particular sCD163 correlated with markers of metabolic dysfunction and inflammation. After weight loss, only sCD163 showed a trend for decreased levels during OGTT, both in the whole cohort as in those of liraglutide vs lifestyle group. CONCLUSION: Weight loss following treatment with liraglutide was associated with reduced circulating levels of sCD163 when compared to the same extent of weight loss after lifestyle changes. This might contribute to reduced cardiometabolic risk in individuals receiving treatment with liraglutide.

Surgery is associated with better long-term outcomes than pharmacological treatment for obesity: a systematic review and meta-analysis.

Obesity is a highly prevalent disease with numerous complications. Both intensive medical treatment with the use of pharmacological drugs and bariatric surgery are current options. The objective of this meta-analysis was to compare, in the long-term, intensive medical treatment and surgery based on twelve parameters related to weight loss, cardiovascular and endocrine changes. A review of the literature was conducted in accordance with the PRISMA guidelines (PROSPERO: CRD42021265637). The literature screening was done from inception to October 2023 through PubMed, EMBASE and Web of Science databases. We included randomized clinical trials that had separate groups for medical treatment and bariatric surgery as an intervention for obesity. The risk of bias was assessed through RoB2. A meta-analysis was performed with measures of heterogeneity and publication bias. Subgroup analysis for each surgery type was performed. Data is presented as forest-plots. Reviewers independently identified 6719 articles and 6 papers with a total 427 patients were included. All studies were randomized controlled trials, three had a follow up of 5 years and two had a follow up of 10 years. Both groups demonstrated statistical significance for most parameters studied. Surgery was superior for weight loss (- 22.05 kg [- 28.86; - 15.23), total cholesterol (- 0.88 [- 1.59; - 0.17]), triglycerides (- 0.70 [- 0.82; - 0.59]), HDL (0.12 [0.02; 0.23]), systolic pressure (- 4.49 [- 7.65; - 1.33]), diastolic pressure (- 2.28 [- 4.25; - 0.31]), Hb glycated (- 0.97 [- 1.31; - 0.62]), HOMA IR (- 2.94; [- 3.52; - 2.35]) and cardiovascular risk (- 0.08; [- 0.10; - 0.05]). Patient in the surgical treatment group had better long term outcomes when compared to the non-surgical group for most clinical parameters.

Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons.

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here, we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. Using various techniques, we investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induces a greater weight loss in obese rats than lean rats, while differentially modulating the neuronal ensembles and population activity in LH. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensine's food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensine's appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.