GLP-1R-positive neurons in the lateral septum mediate the anorectic and weight-lowering effects of liraglutide in mice.

Liraglutide, a glucagon-like peptide-1 (GLP-1) analog, is approved for obesity treatment, but the specific neuronal sites that contribute to its therapeutic effects remain elusive. Here, we show that GLP-1 receptor-positive (GLP-1R-positive) neurons in the lateral septum (LSGLP-1R) play a critical role in mediating the anorectic and weight-loss effects of liraglutide. LSGLP-1R neurons were robustly activated by liraglutide, and chemogenetic activation of these neurons dramatically suppressed feeding. Targeted knockdown of GLP-1 receptors within the LS, but not in the hypothalamus, substantially attenuated liraglutide's ability to inhibit feeding and lower body weight. The activity of LSGLP-1R neurons rapidly decreased during naturalistic feeding episodes, while synaptic inactivation of LSGLP-1R neurons diminished the anorexic effects triggered by liraglutide. Together, these findings offer critical insights into the functional role of LSGLP-1R neurons in the physiological regulation of energy homeostasis and delineate their instrumental role in mediating the pharmacological efficacy of liraglutide.

Subthreshold activation of the melanocortin system causes generalized sensitization to anorectic agents in mice.

The melanocortin-3 receptor (MC3R) regulates GABA release from agouti-related protein (AgRP) nerve terminals and thus tonically suppresses multiple circuits involved in feeding behavior and energy homeostasis. Here, we examined the role of the MC3R and the melanocortin system in regulating the response to various anorexigenic agents. The genetic deletion or pharmacological inhibition of the MC3R, or subthreshold doses of an MC4R agonist, improved the dose responsiveness to glucagon-like peptide 1 (GLP1) agonists, as assayed by inhibition of food intake and weight loss. An enhanced anorectic response to the acute satiety factors peptide YY (PYY3-36) and cholecystokinin (CCK) and the long-term adipostatic factor leptin demonstrated that increased sensitivity to anorectic agents was a generalized result of MC3R antagonism. We observed enhanced neuronal activation in multiple hypothalamic nuclei using Fos IHC following low-dose liraglutide in MC3R-KO mice (Mc3r-/-), supporting the hypothesis that the MC3R is a negative regulator of circuits that control multiple aspects of feeding behavior. The enhanced anorectic response in Mc3r-/- mice after administration of GLP1 analogs was also independent of the incretin effects and malaise induced by GLP1 receptor (GLP1R) analogs, suggesting that MC3R antagonists or MC4R agonists may have value in enhancing the dose-response range of obesity therapeutics.

Analysis of Prescription Trends for Narcotic Appetite Suppressants: Utilizing the Narcotics Information Management System.

PURPOSE: The aim of this study was to systematically analyze the prescription trends of medical narcotic appetite suppressants in South Korea. MATERIALS AND METHODS: Data was extracted from the Narcotics Information Management System dataset from 2020, which encompasses nationwide information concerning the use of medical narcotics. The selected variables for this study included the types of prescribed medical narcotic appetite suppressants, gender, age, region, and the category of medical institution. Regional prescription trends were compared by utilizing the defined daily doses for statistical purposes (S-DDD). RESULTS: The prescription of medical narcotic appetite suppressants was predominantly for females (94%), with the highest prescription rates identified in the 30-40 age group. The majority of these prescriptions were dispensed by clinics. Within the category of narcotic appetite suppressants, phentermine and phendimetrazine were found to have higher prescription rates. Notably, the region of Daegu recorded the highest S-DDD value (12.66) in phentermine consumption. CONCLUSION: Our findings underscore the need for governmental policy and guidance to address the risks linked to the long-term use of medical narcotic appetite suppressants. This is crucial to ensure their safe and efficacious prescription and administration.

Novel Pharmaceuticals in Appetite Regulation: Exploring emerging gut peptides and their pharmacological prospects.

Obesity, a global health challenge, necessitates innovative approaches for effective management. Targeting gut peptides in the development of anti-obesity pharmaceuticals has already demonstrated significant efficacy. Ghrelin, peptide YY (PYY), cholecystokinin (CCK), and amylin are crucial in appetite regulation offering promising targets for pharmacological interventions in obesity treatment using both peptide-based and small molecule-based pharmaceuticals. Ghrelin, a sole orexigenic gut peptide, has a potential for anti-obesity therapies through various approaches, including endogenous ghrelin neutralization, ghrelin receptor antagonists, ghrelin O-acyltransferase, and functional inhibitors. Anorexigenic gut peptides, peptide YY, cholecystokinin, and amylin, have exhibited appetite-reducing effects in animal models and humans. Overcoming substantial obstacles is imperative for translating these findings into clinically effective pharmaceuticals. Peptide YY and cholecystokinin analogues, characterized by prolonged half-life and resistance to proteolytic enzymes, present viable options. Positive allosteric modulators emerge as a novel approach for modulating the cholecystokinin pathway. Amylin is currently the most promising, with both amylin analogues and dual amylin and calcitonin receptor agonists (DACRAs) progressing to advanced stages of clinical trials. Despite persistent challenges, innovative pharmaceutical strategies provide a glimpse into the future of anti-obesity therapies.

Lipidized analogues of the anorexigenic CART (cocaine- and amphetamine-regulated transcript) neuropeptide show anorexigenic and neuroprotective potential in mouse model of monosodium-glutamate induced obesity.

AIMS: This study investigates the neuroprotective effects of lipidized analogues of 2-SS-CART(61-102) derived from anorexigenic neuropeptide cocaine- and amphetamine-regulated transcript peptide (CARTp) in light of the link between obesity, its comorbidities, and the development of Alzheimer's disease. METHODS: We introduce novel lipidized analogues derived from 2-SS-CART(61-102), a specific analogue of natural CART(61-102), with two disulfide bridges. Using hypothermic PC12 cells, we tested the effect of the most potent analogues on Tau phosphorylation. We further described the anorexigenic and neuroprotective potential of subcutaneously (SC) injected lipidized CARTp analogue in a mouse model with prediabetes and obesity induced by neonatal monosodium glutamate (MSG) administration. RESULTS: Compared to the non-lipidized 2-SS-CART(61-102), all lipidized analogues exhibited a potent binding affinity to PC12 cells and enhanced in vitro stability in rat plasma. Two most potent lipidized analogues attenuated hypothermia-induced Tau hyperphosphorylation at multiple epitopes. Subsequently, chronic SC treatment with palm-2-SS-CART(61-102) significantly decreased body weight and food intake, improved metabolic parameters, decreased level of pTau and increased neurogenesis in hippocampi of obese MSG mice. CONCLUSION: Our unique CARTp analogue palm-2-SS-CART(61-102) shows promise as a potent anti-obesity and neuroprotective agent.

Enzyme-linked immunoassay for simultaneous detection of methyl parathion and sibutramine in apple cider vinegar.

Methyl parathion, a highly toxic, efficient, and persistent organophosphorus pesticide, is widely used in China. Sibutramine, a non-amphetamine central nervous system depressant, helps lose weight by disrupting hormone regulation, stimulating sympathetic nerves, and suppressing appetite. However, some unethical businesses fail to properly handle raw materials in foods like apple cider vinegar, leading to residual methyl parathion in apples or illegal excessive addition of sibutramine. Therefore, it is imperative to develop an immunoassay for the rapid detection of methyl parathion and sibutramine. The corresponding two haptens were prepared and coupled with the carrier proteins according to methyl parathion-sulfur-bovine serum protein (BSA)/chicken ovalbumin (OVA)-sibutramine (20 : 1 : excess, 15 : 1 : excess, 10 : 1 : excess, and 5 : 1 : excess), and sibutramine-BSA/OVA-methyl parathion (20 : 1 : excess, 10 : 1 : excess: 5 : 1 : excess, and 0 : 1 : excess). The result shows that the inhibition rate of the antibody obtained by methyl parathion-BSA/OVA-sibutramine (20 : 1 : excess) was higher than that of sibutramine-BSA/OVA-methyl parathion, which was 67.93%, and the concentration of methyl parathion was 8.65 ng mL-1 at this inhibition rate. Thus, methyl parathion-BSA/OVA-sibutramine (8.65 : 1 : excess) and the corresponding antibodies were selected for subsequent method establishment. By changing the concentration of the coating and antibody, the inhibition rate was found when the coating was 0.125 ng mL-1 and the antibody was diluted 4000 times. The antibody was used to develop a standard curve for the detection of sibutramine at the half-maximum inhibitory concentration (IC50) is 4.59 ng mL-1, the limit of detection (IC10) is 2.21 ng mL-1, the detection range is 2.89 to 7.28 ng mL-1, methyl p-phosphorus at the half-maximum inhibitory concentration (IC50) is 15.34 ng mL-1, the limit of detection (IC10) is 0.42 ng mL-1, the detection range is ng mL-1. Under these conditions, the recovery rate was between 88% and 102%, within reasonable limits, indicating the successful establishment of a rapid enzyme-linked ELISA assay.

Sibutramine-induced pheochromocytoma crisis: A rare and lethal occurrence.

Pheochromocytoma is a neuroendocrine tumor that secretes catecholamines; excessive catecholamine secretion can lead to pheochromocytoma crisis (PCC), a rare and life-threatening condition. Sibutramine, a serotonin and norepinephrine reuptake inhibitor, was previously used for obesity treatment but is now banned due to its cardiovascular side effects. Although fatalities related to PCC and adverse events associated with sibutramine have been frequently reported individually, there is no documented literature addressing PCC-induced by sibutramine. Here we report a rare case of fatal sibutramine-induced PCC in a previously asymptomatic young female with undiagnosed pheochromocytoma. The 25-year-old patient took a weight-loss pill containing sibutramine for the first time and subsequently experienced nausea, vomiting, chest tightness, and other symptoms. She went to hospital about 6 hours after taking the pill but died approximately 4 hours later despite the resuscitation efforts. An autopsy revealed a pheochromocytoma in the right adrenal gland. The cause of death was attributed to sibutramine-induced PCC. To our knowledge, this is the first report to document the occurrence of sibutramine-induced PCC.

A polyphenol fraction from Rosa multiflora var. platyphylala reduces body fat in overweight humans through appetite suppression - a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Rosa species are rich sources of polyphenols with physiological functions. In this study a polyphenol-rich Rosa multiflora (var. platyphylala) petal extract (RoseFit™) was investigated for weight loss in humans. METHODS: In a randomized, placebo-controlled, parallel-group, double-blind clinical trial seventy overweight male and female subjects (20-50 years) with body mass index (BMI) 25-30 kg/m2 were randomly allocated to the active treatment group (RoseFit) and placebo group in a 1:1 ratio. The subjects received 300 mg capsules twice daily for 12 weeks. The primary efficacy outcome measures included body weight, BMI, and body composition, as determined using Dual-energy X-ray absorptiometry (DEXA). Secondary measures consisted of serum lipid profile and appetite marker (leptin and ghrelin) analyses. Safety analyses included biochemical and hematological assessments. RESULTS: At the end of the study, a marked reduction in body weight (-1.20 ± 2.62 kg, p < 0.05) and BMI from baseline was observed in the RoseFit group. In addition, the body fat % (RoseFit = -1.69 ± 2.59%, placebo = 0.96 ± 3.21%; p < 0.001) and fat mass (RoseFit = -1.75 ± 1.80 kg, placebo = 1.61 ± 3.82 kg; p < 0.001) were significantly abated in RoseFit group. Importantly, the lean mass was maintained during the intervention. RoseFit ingestion significantly increased the serum leptin levels compared to the placebo (4.85%; p < 0.05). Further, RoseFit group showed reduction in the hunger hormone ghrelin level (2.27%; p < 0.001) from baseline to the end of study, compared to the placebo. The subjective evaluation of appetite using visual analog scale (VAS) questionnaires further confirmed the appetite-suppression effects of RoseFit. The lipid profile significantly improved in RoseFit-treated subjects. No serious adverse events were observed during the study, indicating the tolerability of RoseFit. CONCLUSIONS: Supplementation with RoseFit significantly impacts body weight management and can thus be a potential nutraceutical ingredient for sustainable weight loss. TRIAL REGISTRATION: CTRI/2019/10/021584 dated 09/10/2019.

Development and validation of a high-performance thin-layer chromatography method for detection of sibutramine in dietary supplements.

INTRODUCTION: In the period between 1997 and 2010, sibutramine-containing drugs were widely prescribed for obesity and over-weight management. Due to safety concerns, in 2010 all medicines containing sibutramine were urgently withdrawn from the USA and European pharmaceutical market. Although sibutramine is no longer available in pharmaceutical products, there have been numerous reports of mislabeled weight-loss dietary supplements containing sibutramine.

Physiopathology and Treatment of Obesity and Overweight: A Proposal for a New Anorectic.

The "new epidemic," as WHO calls obesity, is caused by overeating, which, having exceeded the body's actual needs, accumulates in the form of health-damaging fat deposits. Moving more and eating less is the main remedy, but eating belongs to vital instincts, which are beyond the control of reason. In this sense, eating is different from drinking and breathing because without food it is possible to survive for a few weeks, without water for a few days, without oxygen for a few minutes. The first part of this article provides an overview of obesity and its treatment, focusing on the new anorectic anticipated in the title. The second part focuses on compulsive obesity, typically represented by constitutional obesity and food addiction. The article concludes with a discussion of the pharmacological treatment of compulsive diseases, to which some forms of obesity belong.

Khat consumption and undernutrition among adult population in Ethiopia: A systematic review and meta-analysis.

BACKGROUND: In Ethiopia, malnutrition is a public health threat causing a significant burden of morbidity, mortality, and economic crisis. Simultaneously, khat consumption is alarmingly increasing among adults, yet it might contribute to the existing burden of malnutrition, where the current evidence is inconclusive. Hence, this review was to estimate the association between khat consumption and undernutrition among adults in Ethiopia. METHODS: A comprehensive search for Google, Google Scholar, and PubMed, coupled with a thorough manual search of the literature, was done up to date, October 18, 2023, using relevant search terms: "impact," "effects," "khat chewing," "khat consumption," "Ethiopia," "nutritional status," and "undernutrition." An updated PRISMA guideline was used to select relevant literature. The extracted data was summarized in narrative summaries, descriptions, and meta-analyses. The risk of bias was assessed. The results are presented in forest plots and funnel plots to assess publication bias. A pooled effect size (odds ratio) with a 95% certainty level was reported. RESULTS: While a total of 17 articles (n = 45,679) were included in the narrative review, only 15 articles were included in the quantitative meta-analysis. The majority of studies had a low and moderate risk of bias (based on risk of bias assessment tool), mainly due to unclear exposure assessment and high study heterogeneity. A total of 11 studies were cross-sectional studies (71%), three were comparative studies (17.4%), and three were case control studies (17.4%). There is a higher risk of publication bias as evidenced by the funnel plot. Overall, five studies were from the Oromia region, and three studies were conducted at the national level. Overall, chewing had been shown to significantly increase the risk of undernutrition by 53% (pooled OR = 1.53; 95% CI: 1.09-2.16) under a random effect model. Under the fixed effect model, higher weight was given to national-level studies with higher samples, where chewing contributed to a 12% increased risk of undernutrition (AOR = 1.12; 95% CI: 1.01-2.23). Hence, khat chewing could raise the odds of undernutrition by 12-53%. CONCLUSION: There is evidence of an association between khat chewing and an increased risk of undernutrition among adults in Ethiopia, which highlights the need for public health interventions to address the potential adverse effects of khat chewing on nutritional status.

Metformin and feeding increase levels of the appetite-suppressing metabolite Lac-Phe in humans.

Metformin, a widely used first-line treatment for type 2 diabetes (T2D), is known to reduce blood glucose levels and suppress appetite. Here we report a significant elevation of the appetite-suppressing metabolite N-lactoyl phenylalanine (Lac-Phe) in the blood of individuals treated with metformin across seven observational and interventional studies. Furthermore, Lac-Phe levels were found to rise in response to acute metformin administration and post-prandially in patients with T2D or in metabolically healthy volunteers.

Natural Chalcones for the Management of Obesity Disease.

In the last decade, the incidence of obesity has increased dramatically worldwide, reaching a dangerous pandemic spread. This condition has serious public health implications as it significantly increases the risk of chronic diseases such as type 2 diabetes, fatty liver, hypertension, heart attack, and stroke. The treatment of obesity is therefore the greatest health challenge of our time. Conventional therapeutic treatment of obesity is based on the use of various synthetic molecules belonging to the class of appetite suppressants, lipase inhibitors, hormones, metabolic regulators, and inhibitors of intestinal peptide receptors. The long-term use of these molecules is generally limited by various side effects and tolerance. For this reason, the search for natural alternatives to treat obesity is a current research goal. This review therefore examined the anti-obesity potential of natural chalcones based on available evidence from in vitro and animal studies. In particular, the results of the main in vitro studies describing the principal molecular therapeutic targets and the mechanism of action of the different chalcones investigated were described. In addition, the results of the most relevant animal studies were reported. Undoubtedly, future clinical studies are urgently needed to confirm and validate the potential of natural chalcones in the clinical prophylaxis of obesity.

The locus coeruleus contributes to the anorectic, nausea, and autonomic physiological effects of glucagon-like peptide-1.

Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat obesity require complete characterization of the central mechanisms that mediate both the food intake-suppressive and illness-like effects of GLP-1R signaling. Our studies, in the rat, demonstrate that GLP-1Rs in the locus coeruleus (LC) are pharmacologically and physiologically relevant for food intake control. Furthermore, agonism of LC GLP-1Rs induces illness-like behaviors, and antagonism of LC GLP-1Rs can attenuate GLP-1R-mediated nausea. Electrophysiological and behavioral pharmacology data support a role for LC GLP-1Rs expressed on presynaptic glutamatergic terminals in the control of feeding and malaise. Collectively, our work establishes the LC as a site of action for GLP-1 signaling and extends our understanding of the GLP-1 signaling mechanism necessary for the development of improved obesity pharmacotherapies.

Anorectic effect of COR659 in a rat model of overeating.

COR659 is a new compound, the action of which is exerted via a dual mechanism: positive allosteric modulation of the GABAB receptor; antagonism or inverse agonism at the cannabinoid CB1 receptor. Recent lines of experimental evidence have indicated that COR659 potently and effectively reduced operant self-administration of and reinstatement of seeking behaviour for a chocolate-flavoured beverage. The present study was designed to assess whether the ability of COR659 to diminish these addictive-like, food-motivated behaviours extended to a rat model of overeating palatable food. To this end, rats were habituated to feed on a standard rat chow for 3 h/day; every 4 days, the 3-hour chow-feeding session was followed by a 1-hour feeding session with highly palatable, calorie-rich Danish butter cookies. Even though satiated, rats overconsumed cookies. COR659 (0, 2.5, 5, and 10 mg/kg, i.p.) was administered before the start of the cookie-feeding session. Treatment with all 3 doses of COR659 produced a substantial decrease in intake of cookies and calories from cookies. These results extend the anorectic profile of COR659 to overconsumption of a highly palatable food and intake of large amounts of unnecessary calories.

A review of anorexia induced by T-2 toxin.

The presence of anorexia in animals is the most well-known clinical symptom of T-2 toxin poisoning. T-2 toxin is the most characteristic type A toxin in the trichothecene mycotoxins. The consumption of T-2 toxin can cause anorexic response in mice, rats, rabbits, and other animals. In this review, the basic information of T-2 toxin, appetite regulation mechanism and the molecular mechanism of T-2 toxin-induced anorectic response in animals are presented and discussed. The objective of this overview is to describe the research progress of anorexia in animals produced by T-2 toxin. T-2 toxin mainly causes antifeedant reaction through four pathways: vagus nerve, gastrointestinal hormone, neurotransmitter and cytokine. This review aims to give an academic basis and useable reference for the prevention and treatment of clinical symptoms of anorexia in animals resulting from T-2 toxin.

The Alkylamine Stimulant 1,3-Dimethylamylamine Exhibits Substrate-Like Regulation of Dopamine Transporter Function and Localization.

The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used nonmedically as an appetite suppressant and exercise performance enhancer despite adverse cardiovascular effects that have limited its legal status. There is scant research describing the mechanism of action of DMAA, making it difficult to gauge risks or therapeutic potential. An important molecular target of structurally related phenethylamines, such as amphetamine, for regulating mood, cognition, movement, and the development of substance use disorder is the dopamine transporter, which limits the range and magnitude of dopamine signaling via reuptake from the extracellular space. The present studies were therefore initiated to characterize the effects of DMAA on dopamine transporter function. Specifically, we tested the hypothesis that DMAA exhibits substrate-like effects on dopamine transporter function and trafficking. In transport assays in human embryonic kidney cells, DMAA inhibited dopamine uptake by the human dopamine transporter in a competitive manner. Docking analysis and molecular dynamics simulations supported these findings, revealing that DMAA binds to the S1 substrate binding site and induces a conformational change from outward-facing open to outward-facing closed states, similar to the known substrates. Further supporting substrate-like effects of DMAA, the drug stimulated dopamine transporter endocytosis in a heterologous expression system via cocaine- and protein kinase A-sensitive mechanisms, mirroring findings with amphetamine. Together, these data indicate that DMAA elicits neurologic effects by binding to and regulating function of the dopamine transporter. Furthermore, pharmacologic distinctions from amphetamine reveal structural determinants for regulating transporter conformation and add mechanistic insight for the regulation of dopamine transporter endocytosis. SIGNIFICANCE STATEMENT: The alkylamine stimulant 1,3-dimethylamylamine (DMAA) is used as an appetite suppressant and athletic performance enhancer and is structurally similar to amphetamine, but there is scant research describing its mechanism of action. Characterizing the effects of DMAA on dopamine transporter function supports evaluation of potential risks and therapeutic potential while also revealing mechanistic details of dynamic transporter-substrate interactions.