GDF15 promotes weight loss by enhancing energy expenditure in muscle.

Caloric restriction that promotes weight loss is an effective strategy for treating non-alcoholic fatty liver disease and improving insulin sensitivity in people with type 2 diabetes1. Despite its effectiveness, in most individuals, weight loss is usually not maintained partly due to physiological adaptations that suppress energy expenditure, a process known as adaptive thermogenesis, the mechanistic underpinnings of which are unclear2,3. Treatment of rodents fed a high-fat diet with recombinant growth differentiating factor 15 (GDF15) reduces obesity and improves glycaemic control through glial-cell-derived neurotrophic factor family receptor α-like (GFRAL)-dependent suppression of food intake4-7. Here we find that, in addition to suppressing appetite, GDF15 counteracts compensatory reductions in energy expenditure, eliciting greater weight loss and reductions in non-alcoholic fatty liver disease (NAFLD) compared to caloric restriction alone. This effect of GDF15 to maintain energy expenditure during calorie restriction requires a GFRAL-ß-adrenergic-dependent signalling axis that increases fatty acid oxidation and calcium futile cycling in the skeletal muscle of mice. These data indicate that therapeutic targeting of the GDF15-GFRAL pathway may be useful for maintaining energy expenditure in skeletal muscle during caloric restriction.

Person-centered choice of anti-obesity pharmacotherapy.

Several novel drugs are being developed for the management of obesity. While this offers newer opportunities for weight management, it also creates challenges for the treating physician to choose the appropriate drug for a given patient in clinical practice. This communication provides a clinically oriented classification of anti-obesity medications, which will help in person-centered choice of therapy. It lists drugs as calorie restrictors (appetite suppressants), calorie restriction mimetics (absorption inhibitors), calorie substitutes (medical nutrition therapy), and calorie utilizers (energy expenditure enhancers). This novel classification will help provide a patient centered pharmacotherapy in the management of obesity.

Regulation of feeding and therapeutic application of bioactive peptides.

Obesity and obesity-related diseases, such as diabetes mellitus and dyslipidemia, are worldwide pandemics; therefore, studies have been conducted energetically to elucidate the mechanism of obesity and develop anti-obesity drugs. Robust progress in the peptide chemistry and molecular biology has identified many peptides that regulate appetite and energy metabolism over the past dozen years. Several drugs, such as analogs or receptor agonists of anorectic peptides, have been developed. Overall, peptide-related drugs have powerful anti-obesity effects with fewer adverse effects than previous anti-obesity drugs. Liraglutide, a glucagon-like peptide-1 receptor agonist, was first used as an antidiabetic drug, and then high-dose liraglutide was used as an anti-obesity drug. Several candidates have been developed to explore their anti-obesity effects. Additionally, hybrid peptides consisting of two or more peptide sequences with strong anorectic effects have been designed. Here, we review peptides that are important for feeding regulation in terms of their mechanisms of action, interactions, and clinical application as anti-obesity drugs.

The use of Caralluma fimbriata as an appetite suppressant and weight loss supplement: a systematic review and meta-analysis of clinical trials.

BACKGROUND: Obesity prevalence has increased during the past few decades, causing a pandemic with an influx in other co-morbidities. Many factors influence weight gain in an obesogenic environment therefore strategies for treating obesity may vary from conventional dietary and physical activity interventions to pharamacotherapy. A shift in unconventional strategies as herbal products for treating obesity have been investigated and one such plant extract is Caralluma fimbriata (C. fimbriata). Further, the studies included were systematically reviewed to gather evidence on potential effects of C. fimbriata as an appetite suppressant and weight loss supplement. METHODS: A systematic review of clinical trials reporting the effects of C. fimbriata as appetite suppression and anti-obesity supplement was reported according to PRISMA guidelines. Data were obtained by searching three databases: PubMed®, Web of Science® and SciVerse Scopus® for studies published until 30th April 2020. RESULTS: A total of 7 articles studying C. fimbriata satisfied the inclusion and exclusion criteria and were sourced from various countries including Australia (3), Cuba (1), India (2) and Spain (1). Almost all studies recruited adults who were overweight or obese with a BMI > 25 kg/m2 (n = 5), with the exception of two studies, one that recruited healthy adults with a BMI average of 26.5 kg/m2 and the second one utilised a population of children and adolescents with Prader-Willis Syndrome (PWS). Parameters assessing obesity, biochemical and appetite factors were analysed by carrying out a meta-analysis. Compared to placebo controlled group, C. fimbriata extract significantly reduced WC by 1.59 cm (95% CI, - 3.07 to - 0.10, p = 0.041) and WHR by 0.06 (95% CI, - 0.12 to - 0.01, p = 0.05) although no significant effects were seen on BW, BMI and HC. Biochemical and appetite parameters outcome on C. fimbriata consumption had no significant changes. Any side effects of individuals who ingested the extract were reported by few studies of which most common effects were constipation, diarrhoea, nausea and rashes. CONCLUSION: Appetite parameters showed no significant changes and metabolic parameters did not improve with C.fimbriata supplementation therefore it is unlikely to recommend C. fimbriata as a weight loss supplement and an appetite suppressant.

Weight-Loss Strategies for Prevention and Treatment of Hypertension: A Scientific Statement From the American Heart Association.

Hypertension is a major risk factor for cardiovascular and renal diseases in the United States and worldwide. Obesity accounts for much of the risk for primary hypertension through several mechanisms, including neurohormonal activation, inflammation, and kidney dysfunction. As the prevalence of obesity continues to increase, hypertension and associated cardiorenal diseases will also increase unless more effective strategies to prevent and treat obesity are developed. Lifestyle modification, including diet, reduced sedentariness, and increased physical activity, is usually recommended for patients with obesity; however, the long-term success of these strategies for reducing adiposity, maintaining weight loss, and reducing blood pressure has been limited. Effective pharmacotherapeutic and procedural strategies, including metabolic surgeries, are additional options to treat obesity and prevent or attenuate obesity hypertension, target organ damage, and subsequent disease. Medications can be useful for short- and long-term obesity treatment; however, prescription of these drugs is limited. Metabolic surgery is effective for producing sustained weight loss and for treating hypertension and metabolic disorders in many patients with severe obesity. Unanswered questions remain related to the mechanisms of obesity-related diseases, long-term efficacy of different treatment and prevention strategies, and timing of these interventions to prevent obesity and hypertension-mediated target organ damage. Further investigation, including randomized controlled trials, is essential to addressing these questions, and emphasis should be placed on the prevention of obesity to reduce the burden of hypertensive cardiovascular and kidney diseases and subsequent mortality.

Function and therapeutic potential of N-acyl amino acids.

N-acyl amino acids (NAAs) are amphiphilic molecules, with different potential fatty acid and head group moieties. NAAs are the largest family of anandamide congener lipids discovered to date. In recent years, several NAAs have been identified as potential ligands, engaging novel binding sites and mechanisms for modulation of membrane proteins such as G-protein coupled receptors (GPRs), nuclear receptors, ion channels, and transporters. NAAs play a key role in a variety of physiological functions as lipid signaling molecules. Understanding the structure, function roles, and pharmacological potential of these NAAs is still in its infancy, and the biochemical roles are also mostly unknown. This review will provide a summary of the literature on NAAs and emphasize their therapeutic potential.

Efficacy and Safety of the New Appetite Suppressant, Liraglutide: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Obesity is a chronic disease associated with metabolic diseases such as diabetes and cardiovascular disease. Since the U.S. Food and Drug Administration approved liraglutide as an anti-obesity drug for nondiabetic patients in 2014, it has been widely used for weight control in overweight and obese people. This study aimed to systematically analyze the effects of liraglutide on body weight and other cardiometabolic parameters. METHODS: We investigated articles from PubMed, EMBASE, and the Cochrane Library to search randomized clinical trials that examined body weight changes with liraglutide treatment. RESULTS: We included 31 studies with 8,060 participants for this meta-analysis. The mean difference (MD) between the liraglutide group and the placebo group was -4.19 kg (95% confidence interval [CI], -4.84 to -3.55), with a -4.16% change from the baseline (95% CI, -4.90 to -3.43). Liraglutide treatment correlated with a significantly reduced body mass index (MD: -1.55; 95% CI, -1.76 to -1.34) and waist circumference (MD: -3.11 cm; 95% CI, -3.59 to -2.62) and significantly decreased blood pressure (systolic blood pressure, MD: -2.85 mm Hg; 95% CI, -3.36 to -2.35; diastolic blood pressure, MD: -0.66 mm Hg; 95% CI, -1.02 to -0.30), glycated hemoglobin (MD: -0.40%; 95% CI, -0.49 to -0.31), and low-density lipoprotein cholesterol (MD: -2.91 mg/dL; 95% CI, -5.28 to -0.53; MD: -0.87% change from baseline; 95% CI, -1.17 to -0.56). CONCLUSION: Liraglutide is effective for weight control and can be a promising drug for cardiovascular protection in overweight and obese people.

Pharmacotherapy of obesity: An update.

Several pharmacological approaches to controlling body weight have been developed over the last decades, albeit with limited success. Currently available agents include centrally acting appetite suppressants and peripherally acting compounds. Efficacy and safety of these agents in the clinical setting require a difficult balance. Further strategies including multiagonists able to simultaneously target multiple actors involved in obesity initiation and expansion such as the glucagon receptor family are under investigation. The results of recent clinical trials are encouraging and highlight emerging compounds as potential game changers. In view of the rising prevalence of obesity and the associated burden of comorbidities worldwide, and compared with other areas of pharmacological intervention, we feel that the field of obesity has been affected by therapeutic inertia. Of note, obesity may also affect the response to concomitant medications such as low-dose aspirin. Lessons from withdrawn agents such as the cannabinoid receptor antagonist rimonabant include developing compounds with a more targeted action profile (i.e., central vs peripheral, or antagonist versus inverse agonist) as well as careful selection of patients based on individual risk factors. We anticipate that the expanding knowledge base and clinical testing will result in improved outcomes for patients with obesity in the near future.

The effect of an orally-dosed Caralluma Fimbriata extract on appetite control and body composition in overweight adults.

To examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. A double-blind, randomised, placebo controlled trial to examine the effect of a Caralluma Fimbriata extract (CFE) on biomarkers of satiety and body composition in overweight adults. Eighty-three men and women aged between 20 and 50 years of age completed 16 weeks of daily supplementation with either CFE or placebo. Plasma cardiometabolic (lipid profile, glucose, insulin) and satiety (ghrelin, leptin, neuropeptideY) biomarkers, body composition, diet history and gastrointenstinal function were assessed at baseline, weeks 4, 8, 12 and 16. Subjects in the CFE and placebo groups were well matched and predominatly female 93% and 87.5%, with a mean age of 40.9 ± 6.7 and 39.5 ± 7.5 years and body mass index (BMI) of 30.0 ± 3.1 and 30.2 ± 2.9 kg/m2 respectively. There was a significant difference in plasma leptin concentration change between groups at week 16 (p = 0.04), with the placebo group increasing concentration (2.27 ± 4.80 ng/mL) while the CFE group (0.05 ± 4.69 ng/mL) remained the same. At week 16, the CFE group had significantly reduced their calorie intake from baseline compared to the placebo group (245 cal vs 15.8 cal respectively p < 0.01). The CFE group also had a significant reduction in waist circumference of 2.7 cm compared to an increase of 0.3 cm in the placebo group (p = 0.02). A weight increase from baseline was seen in the placebo group that was not observed in the CFE group (1.33 kg weight gain vs 0.37 kg weight loss respectively; p = 0.03). The placebo group also had a significant increase in fat mass, android fat mass, BMI and leptin compared to the CFE group (p = 0.04, 0.02, < 0.01 respectively). CFE was effective at maintaining bodyweight during a non-calorie controlled diet compared to a placebo. The mechanism responsible for this action is requiring further research and could be due to an increase in satiety receptor sensitivity.

Pharmacological and non-pharmacological strategies for obese women with subfertility.

BACKGROUND: Clinicians primarily recommend weight loss for obese women seeking pregnancy. The effectiveness of interventions aimed at weight loss in obese women with subfertility is unclear. OBJECTIVES: To assess the effectiveness and safety of pharmacological and non-pharmacological strategies compared with each other, placebo, or no treatment for achieving weight loss in obese women with subfertility. SEARCH METHODS: We searched the CGF Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO, and AMED from inception to 18 August 2020. We also checked reference lists and contacted experts in the field for additional relevant papers. SELECTION CRITERIA: We included published and unpublished randomised controlled trials in which weight loss was the main goal of the intervention. Our primary effectiveness outcomes were live birth or ongoing pregnancy and primary safety outcomes were miscarriage and adverse events. Secondary outcomes included clinical pregnancy, weight change, quality of life, and mental health outcome. DATA COLLECTION AND ANALYSIS: Review authors followed standard Cochrane methodology. MAIN RESULTS: This review includes 10 trials. Evidence was of very low to low quality: the main limitations were due to lack of studies and poor reporting of study methods. The main reasons for downgrading evidence were lack of details by which to judge risk of bias (randomisation and allocation concealment), lack of blinding, and imprecision. Non-pharmacological intervention versus no intervention or placebo Evidence is insufficient to determine whether a diet or lifestyle intervention compared to no intervention affects live birth (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.65 to 1.11; 918 women, 3 studies; I² = 78%; low-quality evidence). This suggests that if the chance of live birth following no intervention is assumed to be 43%, the chance following diet or lifestyle changes would be 33% to 46%. We are uncertain if lifestyle change compared with no intervention affects miscarriage rate (OR 1.54, 95% CI 0.99 to 2.39; 917 women, 3 studies; I² = 0%; very low-quality evidence). Evidence is insufficient to determine whether lifestyle change compared with no intervention affects clinical pregnancy (OR 1.06, 95% CI 0.81 to 1.40; 917 women, 3 studies; I² = 73%; low-quality evidence). Lifestyle intervention resulted in a decrease in body mass index (BMI), but data were not pooled due to heterogeneity in effect (mean difference (MD) -3.70, 95% CI -4.10 to -3.30; 305 women, 1 study; low-quality evidence; and MD -1.80, 95% CI -2.67 to -0.93; 43 women, 1 study; very low-quality evidence). Non-pharmacological versus non-pharmacological intervention We are uncertain whether intensive weight loss interventions compared to standard care nutrition counselling affects live birth (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), clinical pregnancy (OR 11.00, 95% CI 0.43 to 284; 11 women, 1 study; very low-quality evidence), BMI (MD -3.00, 95% CI -5.37 to -0.63; 11 women, 1 study; very low-quality evidence), weight change (MD -9.00, 95% CI -15.50 to -2.50; 11 women, 1 study; very low-quality evidence), quality of life (MD 0.06, 95% CI -0.03 to 0.15; 11 women, 1 study; very low-quality evidence), or mental health (MD -7.00, 95% CI -13.92 to -0.08; 11 women, 1 study; very low-quality evidence). No study reported on adverse events . Pharmacological versus pharmacological intervention For metformin plus liraglutide compared to metformin we are uncertain of an effect on the adverse events nausea (OR 7.22, 95% CI 0.72 to 72.7; 28 women, 1 study; very low-quality evidence), diarrhoea (OR 0.31, 95% CI 0.01 to 8.3; 28 women, 1 study; very low-quality evidence), and headache (OR 5.80, 95% CI 0.25 to 133; 28 women, 1 study; very low-quality evidence). We are uncertain if a combination of metformin plus liraglutide vs metformin affects BMI (MD 2.1, 95% CI -0.42 to 2.62; 28 women, 1 study; very low-quality evidence) and total body fat (MD -0.50, 95% CI -4.65 to 3.65; 28 women, 1 study; very low-quality evidence). For metformin, clomiphene, and L-carnitine versus metformin, clomiphene, and placebo, we are uncertain of an effect on miscarriage (OR 3.58, 95% CI 0.73 to 17.55; 274 women, 1 study; very low-quality evidence), clinical pregnancy (OR 5.56, 95% CI 2.57 to 12.02; 274 women, 1 study; very low-quality evidence) or BMI (MD -0.3, 95% CI 1.17 to 0.57, 274 women, 1 study, very low-quality evidence). We are uncertain if dexfenfluramine versus placebo affects weight loss in kilograms (MD -0.10, 95% CI -2.77 to 2.57; 21 women, 1 study; very low-quality evidence). No study reported on live birth, quality of life, or mental health outcomes. Pharmacological intervention versus no intervention or placebo We are uncertain if metformin compared with placebo affects live birth (OR 1.57, 95% CI 0.44 to 5.57; 65 women, 1 study; very low-quality evidence). This suggests that if the chance of live birth following placebo is assumed to be 15%, the chance following metformin would be 7% to 50%. We are uncertain if metformin compared with placebo affects gastrointestinal adverse events (OR 0.91, 95% CI 0.32 to 2.57; 65 women, 1 study; very low-quality evidence) or miscarriage (OR 0.50, 95% CI 0.04 to 5.80; 65 women, 1 study; very low-quality evidence) or clinical pregnancy (OR 2.67, 95% CI 0.90 to 7.93; 96 women, 2 studies; I² = 48%; very low-quality evidence). We are also uncertain if diet combined with metformin versus diet and placebo affects BMI (MD -0.30, 95% CI -2.16 to 1.56; 143 women, 1 study; very low-quality evidence) or waist-to-hip ratio (WHR) (MD 2.00, 95% CI -2.21 to 6.21; 143 women, 1 study; very low-quality evidence). Pharmacological versus non-pharmacological intervention No study undertook this comparison. AUTHORS' CONCLUSIONS: Evidence is insufficient to support the use of pharmacological and non-pharmacological strategies for obese women with subfertility. No data are available for the comparison of pharmacological versus non-pharmacological strategies. We are uncertain whether pharmacological or non-pharmacological strategies effect live birth, ongoing pregnancy, adverse events, clinical pregnancy, quality of life, or mental heath outcomes. However, for obese women with subfertility, a lifestyle intervention may reduce BMI. Future studies should compare a combination of pharmacological and lifestyle interventions for obese women with subfertility.

Long-term effects of weight-reducing drugs in people with hypertension.

BACKGROUND: This is the third update of this review, first published in July 2009. All major guidelines on treatment of hypertension recommend weight loss; anti-obesity drugs may be able to help in this respect. OBJECTIVES: Primary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on all-cause mortality, cardiovascular morbidity, and adverse events (including total serious adverse events, withdrawal due to adverse events, and total non-serious adverse events).. Secondary objectives: To assess the long-term effects of pharmacologically-induced reduction in body weight in adults with essential hypertension on change from baseline in systolic and diastolic blood pressure, and on body weight reduction. SEARCH METHODS: For this updated review, the Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to March 2020: the Cochrane Hypertension Specialised Register, CENTRAL, MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. The searches had no language restrictions. We contacted authors of relevant papers about further published and unpublished work. SELECTION CRITERIA: Randomised controlled trials of at least 24 weeks' duration in adults with hypertension that compared approved long-term weight-loss medications to placebo.  DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed risks of bias, and extracted data. Where appropriate and in the absence of significant heterogeneity between studies (P > 0.1), we pooled studies using a fixed-effect meta-analysis. When heterogeneity was present, we used the random-effects method and investigated the cause of the heterogeneity. MAIN RESULTS: This third update of the review added one new trial, investigating the combination of naltrexone/bupropion versus placebo. Two medications, which were included in the previous versions of this review (rimonabant and sibutramine) are no longer considered relevant for this update, since their marketing approval was withdrawn in 2010 and 2009, respectively. The number of included studies in this review update is therefore six (12,724 participants in total): four RCTs comparing orlistat to placebo, involving a total of 3132 participants with high blood pressure and a mean age of 46 to 55 years; one trial comparing phentermine/topiramate to placebo, involving 1305 participants with high blood pressure and a mean age of 53 years; and one trial comparing naltrexone/bupropion to placebo, involving 8283 participants with hypertension and a mean age of 62 years. We judged the risks of bias to be unclear for the trials investigating orlistat or naltrexone/bupropion. and low for the trial investigating phentermine/topiramate. Only the study of naltrexone/bupropion included cardiovascular mortality and morbidity as predefined outcomes. There were no differences in the rates of all-cause or cardiovascular mortality, major cardiovascular events, or serious adverse events between naltrexone/bupropion and placebo. The incidence of overall adverse events was significantly higher in participants treated with naltrexone/bupropion. For orlistat, the incidence of gastrointestinal side effects was consistently higher compared to placebo. The most frequent side effects with phentermine/topiramate were dry mouth and paraesthesia. After six to 12 months, orlistat reduced systolic blood pressure compared to placebo by mean difference (MD) -2.6 mm Hg (95% confidence interval (CI) -3.8 to -1.4 mm Hg; 4 trials, 2058 participants) and diastolic blood pressure by MD -2.0 mm Hg (95% CI -2.7 to -1.2 mm Hg; 4 trials, 2058 participants). After 13 months of follow-up, phentermine/topiramate decreased systolic blood pressure compared to placebo by -2.0 to -4.2 mm Hg (1 trial, 1030 participants) (depending on drug dosage), and diastolic blood pressure by -1.3 to -1.9 mm Hg (1 trial, 1030 participants) (depending on drug dosage). There was no difference in the change in systolic or diastolic blood pressure between naltrexone/bupropion and placebo (1 trial, 8283 participants). We identified no relevant studies investigating liraglutide or lorcaserin in people with hypertension. AUTHORS' CONCLUSIONS: In people with elevated blood pressure, orlistat, phentermine/topiramate and naltrexone/bupropion reduced body weight; the magnitude of the effect was greatest with phentermine/topiramate. In the same trials, orlistat and phentermine/topiramate, but not naltrexone/bupropion, reduced blood pressure. One RCT of naltrexone/bupropion versus placebo showed no differences in all-cause mortality or cardiovascular mortality or morbidity after two years. The European Medicines Agency refused marketing authorisation for phentermine/topiramate due to safety concerns, while for lorcaserin the application for European marketing authorisation was withdrawn due to a negative overall benefit/risk balance. In 2020 lorcaserin was also withdrawn from the US market. Two other medications (rimonabant and sibutramine) had already been withdrawn from the market in 2009 and 2010, respectively.

Iodination of CART(61-102) peptide: Preserved binding and anorexigenic activity in mice.

CART (cocaine- and amphetamine-regulated transcript) peptides are involved in food intake regulation, stress, and other physiological functions. Although CART peptides have been known for over 25 years, their receptor(s) have not yet been characterized. In this short review, we will summarize our previous studies, where we reported specific binding of 125 I-CART(61-102) to PC12 rat pheochromocytoma cells. Competitive binding experiments performed with mono- and di-iodinated peptides and their isoforms with oxidized Met67 resulted in nanomolar binding affinity. Moreover, in our previous study, CART(61-102), as well as di-iodinated CART(61-102), have shown a strong anorexigenic effect in fasted lean mice after intracerebroventricular administration. In conclusion, from our previous studies, iodination of CART(61-102) resulted in mono- and di-iodinated analogs with or without oxidized Met67 . All analogs revealed a high affinity to binding sites at PC12 cells and preserved biological activity.

A combined healthy strategy for successful weight loss, weight maintenance and improvement of hepatic lipid metabolism.

Obesity is critically related with the development of metabolic and pathophysiological alterations among which non-alcoholic fatty liver disease (NAFLD) is of especial relevance. Although there are numerous strategies to successfully treat obesity, the prevention of weight regain still remains challenging for individuals who have undergone weight loss programs. In such context, diet and physical activity are considered essential for the regulation of body weight and lipid metabolism. In this study, rats were fed a high-fat diet (HFD) to induce obesity and alterations in hepatic lipid metabolism. Obese rats were then treated with single or combined strategies of caloric restriction, physical exercise, and/or pharmacological treatment with an appetite suppressant, to lose weight, reverse the obesity-related alterations in hepatic morphology and lipid metabolism and maintain the beneficial effects of the interventions used. HFD induced excess body weight, hepatic steatosis, altered fatty acid profile, dysregulated gene expression of lipogenic and lipolytic enzymes, as well as plasma markers of liver damage, and modifications in liver antioxidant enzyme activity. Such alterations were ameliorated by caloric restriction in combination with a mixed training protocol and/or food-intake inhibitor administration during a weight loss intervention period of 3 weeks, and the beneficial effects remained after 6 weeks of weight maintenance, with some interesting interactions observed. In conclusion, weight loss strategies assayed were efficient at correcting the obesogenic action of a HFD and related alterations in hepatic functionality through different molecular mechanisms. The beneficial effects were also evident along the post-intervention maintenance period to avoid body weight regain.

Chemistry, Analysis, Pharmacokinetics and Pharmacodynamics Aspects of Lorcaserin, a Selective Serotonin 5-HT2C Receptor Agonist: An Update.

This review refers to the all-inclusive details of Lorcaserin Hydrochloride on comprehensive information about the synthesis, analytical methods, pharmacodynamics, pharmacokinetics, drug interactions and adverse effects. Lorcaserin Hydrochloride is chemically (R)-8-Chloro-1-methyl-2,3,4,5- tetrahydro-1H-3-benzazepine hydrochloride. Lorcaserin HCl is a novel, synthetic, centrally-acting selective serotonin C (5-HT2c) receptor, l agonist, which results in increased satiety and decreased food consumption in patients. Headache, dizziness and nausea are the most common side effects associated with this drug. Lorcaserin HCl has two major metabolites, one conjugated with glucuronide called N-carbamoyl glucuronide which is excreted in urine and the second Lorcaserin N-sulfamate, which is circulated in the blood. Lorcaserin HCl is synthesized using four different schemes of which a six-step method that resulted in 92.3% yield with 99.8% of purity is employed for scale-up production. It is analyzed quantitatively in the plasma and brain tissue matrix of rats by Ultra Performance Liquid chromatographic (UPLC) method using MS-MS (Mass Spectrometric) detection.

Engineering a Potent, Long-Acting, and Periphery-Restricted Oxytocin Receptor Agonist with Anorexigenic and Body Weight Reducing Effects.

The effects of oxytocin on food intake and body weight reduction have been demonstrated in both animal models and human clinical studies. Despite being efficacious, oxytocin is enzymatically unstable and thus considered to be unsuitable for long-term use in patients with obesity. Herein, a series of oxytocin derivatives were engineered through conjugation with fatty acid moieties that are known to exhibit high binding affinities to serum albumin. One analog (OT-12) in particular was shown to be a potent full agonist at the oxytocin receptor (OTR) in vitro with good selectivity and long half-life (24 h) in mice. Furthermore, OT-12 is peripherally restricted, with very limited brain exposure (1/190 of the plasma level). In a diet-induced obesity mouse model, daily subcutaneous administration of OT-12 exhibited more potent anorexigenic and body weight reducing effects than carbetocin. Thus, our results suggest that the long-acting, peripherally restricted OTR agonist may offer potential therapeutic benefits for obesity.

Meta-analysis and Approach of the Real Impact of Anorexigenic Drugs in the Obesity in Humans: The Last Five Years of the Randomized Studies.

INTRODUCTION: Obesity shows a multifactorial disease and presents a serious public health problem, with an alarming epidemic character. According to NHANES (National Health and Nutrition Examination Survey) from 2015 to 2016, 39.6% of American adults and 18.5% of young people were obese and 7.7% of adults and 5.6% of young people had severe obesity. Brazil ranks fifth in the world ranking, with about 18 million people reaching up to 70 million overweight individuals. Despite shortterm weight loss with diet and exercise, weight regain continues to be a concern. Anti-obesity drugs, such as Sibutramine (SIB), Phentermine (PHEN), Fenproporex (FEN), Mazindol (MAZ), Amfepramone (AMFE) and Orlistat (ORL) may play a role in weight reduction in patients whose condition is refractory to non- and maintenance of weight loss. OBJECTIVE: A systematic review followed by meta-analysis of randomized clinical trials over the past five years to explore the efficacy and safety of anorexigenic drugs for weight reduction and consequent treatment of obesity. METHODS: The search strategy in MEDLINE / Pubmed, Web of Science, ScienceDirect Journals (Elsevier), Scopus (Elsevier), OneFile (Gale) is as follows : - search for mesh terms (Sibutramine, Phentermine, Fenproporex, Mazindol, Amfepramone , Orlistat, Weight loss, Safety), and the use of booleans "and" between mesh terms and "or" among historical findings. RESULTS: It was observed that in the last five years of randomized studies no significant general complications were found, with only 5.7%. The mean overall weight loss was 6.18 (± 2.8) kg in the mean time of 12 months. The overall success rate among these drugs was 80.18%. The p-value values did not present a significant statistical difference, being p <0.05 within each drug group analyzed, for both weight and success rates. CONCLUSION: The scientific findings of randomized studies on the use of anorexigenic drugs to treat obesity have shown safety and efficiency in the last five years, with a reasonable weight loss and no significant complications.

The pharmacotherapeutic management of obstructive sleep apnea.

Introduction: Obstructive sleep apneas are a frequent clinical condition in which there are momentary interruptions or reductions in breathing activity. To date, the gold standard therapy is the use of Continous Positive Airway Pressure (CPAP). But, due to the relatevely high frequency of poor compliant patients, there is the need to research possible pharmacological treatments for obstructive apnea (OSA). Areas covered: A recent study divided OSA into four major phenotypes. With this characterization in hand, the authors have reviewed the pharmacological treatments present to date according to the different phenotypes in which they could be used. Afterwards, they analyzed the efficacy of different medicaments for the therapy of the residual (despite CPAP treatment) excessive day-time sleepiness (EDS) that often afflicts OSA' patients. Expert opinion: Different drug classes have been evaluated, with some positive results. However, there is still the need to better define treatment strategies for every single phenotype. This underlines the importance to avoid considering the pathology like a single entity without any differences between each single form. The authors are concerned about the risk that, treating only EDS, patients could reduce their compliance to CPAP, thus not reducing the cardiovascular risk associated with OSA.

Appetite-Suppressing and Satiety-Increasing Bioactive Phytochemicals: A Systematic Review.

The prevalence of obesity is increasing worldwide. Bioactive phytochemicals in food supplements are a trending approach to facilitate dieting and to improve patients' adherence to reducing food and caloric intake. The aim of this systematic review was to assess efficacy and safety of the most commonly used bioactive phytochemicals with appetite/hunger-suppressing and/or satiety/fullness-increasing properties. To be eligible, studies needed to have included at least 10 patients per group aged 18 years or older with no serious health problems except for overweight or obesity. Of those studies, 32 met the inclusion criteria, in which 27 different plants were tested alone or as a combination, regarding their efficacy in suppressing appetite/hunger and/or increasing satiety/fullness. The plant extracts most tested were derived from Camellia sinensis (green tea), Capsicum annuum, and Coffea species. None of the plant extracts tested in several trials showed a consistent positive treatment effect. Furthermore, only a few adverse events were reported, but none serious. The findings revealed mostly inconclusive evidence that the tested bioactive phytochemicals are effective in suppressing appetite/hunger and/or increasing satiety/fullness. More systematic and high quality clinical studies are necessary to determine the benefits and safety of phytochemical complementary remedies for dampening the feeling of hunger during dieting.

Proanthocyanidins Limit Adipose Accrual Induced by a Cafeteria Diet, Several Weeks after the End of the Treatment.

A dose of proanthocyanidins with satiating properties proved to be able to limit body weight increase several weeks after administration under exposure to a cafeteria diet. Here we describe some of the molecular targets and the duration of the effects. We treated rats with 500 mg grape seed proanthocyanidin extract (GSPE)/kg BW for ten days. Seven or seventeen weeks after the last GSPE dose, while animals were on a cafeteria diet, we used reverse transcriptase-polymerase chain reaction (RT-PCR) to measure the mRNA of the key energy metabolism enzymes from the liver, adipose depots and muscle. We found that a reduction in the expression of adipose Lpl might explain the lower amount of adipose tissue in rats seven weeks after the last GSPE dose. The liver showed increased expression of Cpt1a and Hmgs2 together with a reduction in Fasn and Dgat2. In addition, muscle showed a higher fatty oxidation (Oxct1 and Cpt1b mRNA). However, after seventeen weeks, there was a completely different gene expression pattern. At the conclusion of the study, seven weeks after the last GSPE administration there was a limitation in adipose accrual that might be mediated by an inhibition of the gene expression of the adipose tissue Lpl. Concomitantly there was an increase in fatty acid oxidation in liver and muscle.