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Miller J, Berry S, Ismail E. Pharmacological Aspects in the Management of Children and Adolescents with Prader-Willi Syndrome. Paediatr Drugs 2025; 27:273-281. [PMID: 39873961 DOI: 10.1007/s40272-025-00681-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/05/2025] [Indexed: 01/30/2025]
Abstract
Prader-Willi syndrome is a rare neurodevelopmental disorder that impacts the musculoskeletal, endocrine, pulmonary, neurologic, ocular, and gastrointestinal systems. In addition, individuals with Prader-Willi syndrome have issues with cognitive development, characteristic behavioral problems, and perhaps most profoundly, appetite control. Currently, the only US Food and Drug Administration-approved therapy for Prader-Willi syndrome is growth hormone, which has been Food and Drug Administration approved for > 20 years for the treatment of growth failure in Prader-Willi syndrome. Growth hormone has shown to improve many aspects of this syndrome, including final height, body composition, developmental milestones, and cognition, but it does not affect hyperphagia, which is the hallmark symptom of this condition. Over the past 15 years, there have been several medication trials for the treatment of hyperphagia in Prader-Willi syndrome, but thus far, all have failed to achieve Food and Drug Administration approval for a variety of reasons. However, hyperphagia is the most life-limiting symptom of Prader-Willi syndrome, thus new pharmacologic therapies are desperately needed. We review ongoing and recently completed clinical trials for hyperphagia. Other issues in Prader-Willi syndrome that significantly impact quality of life include excessive daytime sleepiness and severe behavioral problems. We examine the medication trials to address these issues.
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Affiliation(s)
- Jennifer Miller
- Division of Endocrinology, Department of Pediatrics, University of Florida, PO Box 100296, Gainesville, FL, 32610, USA.
| | - Shivani Berry
- Division of Endocrinology, Department of Pediatrics, University of Florida, PO Box 100296, Gainesville, FL, 32610, USA
| | - Esraa Ismail
- Division of Endocrinology, Department of Pediatrics, University of Florida, PO Box 100296, Gainesville, FL, 32610, USA
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Benedictus B, Pratama VK, Purnomo CW, Tan K, Febrinasari RP. Efficacy of Oral Medication in Weight Loss Management: A Systematic Review and Network Meta-Analysis. Clin Ther 2025; 47:316-329. [PMID: 39843265 DOI: 10.1016/j.clinthera.2024.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Revised: 11/28/2024] [Accepted: 12/25/2024] [Indexed: 01/24/2025]
Abstract
PURPOSE This systematic review was conducted to determine which type of oral medication for obesity provides the best weight loss effect. METHODS This study adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 2020 guideline. For this systematic review, we used 3 databases for journal searches: PubMed, ScienceDirect, and Scopus. This study only included randomized controlled trials or open-label clinical trials. There was no year limit used in the journal search for this systematic review. FINDINGS Eighteen randomized controlled trials, with a total population of 12,259 patients, were included. Of 18 studies, 15 were used for network meta-analysis. Based on the results of the network meta-analysis, weight loss was found in phentermine/topiramate (mean difference [MD], -3.28; 95% CI, -4.47 to -2.09), semaglutide (MD, -2.92; 95% CI, -4.38 to -1.46), phentermine (MD, -2.31; 95% CI, -3.82 to -0.81), naltrexone/bupropion (MD, -1.68; 95% CI, -2.87 to -0.49), topiramate (MD, -1.67; 95% CI, -2.86 to -0.48), and orlistat (MD, -1.44; 95% CI, -2.32 to -0.55). There were no significant differences among the groups. However, compared with placebo, all oral obesity therapies provide better benefits in weight loss (MD, -2.12; 95% CI, -2.64 to -1.59; P ≤ 0.00001). IMPLICATIONS Oral antiobesity drugs provide better weight loss than placebo. However, some side effects can be incurred by utilizing the drug for weight loss, especially related to the gastrointestinal system. Nonetheless, in clinical settings, consideration should be given to particular patients to reduce risk of side effects.
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Affiliation(s)
| | | | | | - Kenneth Tan
- Faculty of Medicine, Universitas Sebelas Maret, Surakarta, Indonesia
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Xiang AS, Sumithran P. Medical management of obesity: unlocking the potential. Climacteric 2025:1-5. [PMID: 39918221 DOI: 10.1080/13697137.2025.2455177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 12/09/2024] [Accepted: 01/02/2025] [Indexed: 02/25/2025]
Abstract
After a long and challenging history, there have finally been major breakthroughs in the development of effective obesity medications. Agents that act at receptors of one or more gut hormones are achieving unprecedented weight reductions and improvements in cardiovascular risk factors, comparable to some bariatric surgical procedures. Importantly, there is evidence of beneficial effects on a growing range of conditions, including type 2 diabetes, fatty liver, chronic kidney disease, obstructive sleep apnea and cardiovascular disease. Barriers to access need to be overcome to allow the standard of care for obesity to match that of other chronic diseases.
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Affiliation(s)
- Angie S Xiang
- Department of Endocrinology and Diabetes, Alfred Health, Melbourne, VIC, Australia
| | - Priya Sumithran
- Department of Endocrinology and Diabetes, Alfred Health, Melbourne, VIC, Australia
- Department of Surgery, School of Translational Medicine, Monash University, Melbourne, Australia
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Hankir MK, Lutz TA. Novel neural pathways targeted by GLP-1R agonists and bariatric surgery. Pflugers Arch 2025; 477:171-185. [PMID: 39644359 PMCID: PMC11761532 DOI: 10.1007/s00424-024-03047-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/18/2024] [Accepted: 11/19/2024] [Indexed: 12/09/2024]
Abstract
The glucagon-like peptide 1 receptor (GLP-1R) agonist semaglutide has revolutionized the treatment of obesity, with other gut hormone-based drugs lined up that show even greater weight-lowering ability in obese patients. Nevertheless, bariatric surgery remains the mainstay treatment for severe obesity and achieves unparalleled weight loss that generally stands the test of time. While their underlying mechanisms of action remain incompletely understood, it is clear that the common denominator between GLP-1R agonists and bariatric surgery is that they suppress food intake by targeting the brain. In this Review, we highlight recent preclinical studies using contemporary neuroscientific techniques that provide novel concepts in the neural control of food intake and body weight with reference to endogenous GLP-1, GLP-1R agonists, and bariatric surgery. We start in the periphery with vagal, intestinofugal, and spinal sensory nerves and then progress through the brainstem up to the hypothalamus and finish at non-canonical brain feeding centers such as the zona incerta and lateral septum. Further defining the commonalities and differences between GLP-1R agonists and bariatric surgery in terms of how they target the brain may not only help bridge the gap between pharmacological and surgical interventions for weight loss but also provide a neural basis for their combined use when each individually fails.
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Affiliation(s)
- Mohammed K Hankir
- Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland
- School of Biochemistry and Immunology, Trinity College Dublin, Dublin, Ireland
| | - Thomas A Lutz
- Institute of Veterinary Physiology, University of Zurich, Zurich, Switzerland.
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5
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Jürgenson M, Chithanathan K, Orav A, Jaako K, Viil J, Guha M, Kask K, Zharkovsky A. Elocalcitol, a fluorinated vitamin D derivative, prevents high-fat diet-induced obesity via SCAP downregulation and miR-146a-associated mechanisms. Front Pharmacol 2025; 15:1505729. [PMID: 39898321 PMCID: PMC11783094 DOI: 10.3389/fphar.2024.1505729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Accepted: 12/27/2024] [Indexed: 02/04/2025] Open
Abstract
Background Obesity is an emerging health problem worldwide as it is associated with increased risk of cardiovascular, metabolic, mental disorders, and cancer. Therapeutic weight management remains one of the options for the treatment of excess weight and associated comorbidities. In this study, the therapeutic potential of elocalcitol, a fluorinated derivative of vitamin D, was studied on the model of high-fat diet (HFD)-induced obesity in mice. Results It was demonstrated that co-administration of elocalcitol in the doses 15 ug/kg (i.p.) twice a week for 16 weeks prevented body weight gain by approximately 15%. The significant retardation in the body weight gain was observed already on the second week of elocalcitol treatment. Administration of elocalcitol also reduced visceral and epididymal fat accumulation by 55% and 35%, respectively, metabolic syndrome development, and lipid droplets accumulation in the liver of mice exposed to HFD. In contrast, the administration of cholecalciferol (vitamin D)-a precursor to calcitriol, the biologically active form of vitamin D, did not affect significantly the signs of obesity and metabolic syndrome, suggesting that the anti-obese effects of elocalcitol are not related to the canonical vitamin D receptor (VDR). Further studies have demonstrated that the preventive effect of elocalcitol is associated with the decreased levels of sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) and upregulation insulin-inducing gene-1 (Insig1) mRNA expression suggesting that the anti-obese effect of elocalcitol is mediated via inhibition of SREBP-mediated lipogenesis. We also demonstrated that elocalcitol prevents an increase in the expression of proinflammatory cytokines such as interleukin-1 beta (Il1b), tumor necrosis factor-alpha (Tnf), and interleukin-18 (Il18), and this effect was associated with upregulation of microRNA-146a (miR-146a). Deletion of the miR-146a gene reduced the anti-obese effects of elocalcitol and prevented its actions on the SCAP levels. The data indicate that elocalcitol's reduction of SCAP is at least partly mediated by miR-146a modulation. Conclusion The study demonstrates that elocalcitol prevents HFD-induced obesity and metabolic syndrome in mice, likely by inhibiting SREBP-mediated lipogenesis and upregulating miR-146a. These findings provide valuable insights into the anti-obesity mechanisms of fluorinated D-vitamin analogs and suggest potential therapeutic strategies for obesity prevention.
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Affiliation(s)
- Monika Jürgenson
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Keerthana Chithanathan
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Aivar Orav
- Tartu University Hospital Joint Laboratory, Tartu University Hospital, Tartu, Estonia
| | - Külli Jaako
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Janeli Viil
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Mithu Guha
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Kalev Kask
- Adge Pharmaceuticals Inc., Mountain View, CA, United States
| | - Alexander Zharkovsky
- Department of Pharmacology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
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Sridhar GR, Gumpeny L. Melanocortin 4 receptor mutation in obesity. World J Exp Med 2024; 14:99239. [PMID: 39713072 PMCID: PMC11551707 DOI: 10.5493/wjem.v14.i4.99239] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/22/2024] [Accepted: 08/27/2024] [Indexed: 10/31/2024] Open
Abstract
Obesity is increasingly prevalent worldwide, with genetic factors contributing to its development. The hypothalamic leptin-melanocortin pathway is central to the regulation of appetite and weight; leptin activates the proopiomelanocortin neurons, leading to the production of melanocortin peptides; these in turn act on melanocortin 4 receptors (MC4R) which suppress appetite and increase energy expenditure. MC4R mutations are responsible for syndromic and non-syndromic obesity. These mutations are classified based on their impact on the receptor's life cycle: i.e. null mutations, intracellular retention, binding defects, signaling defects, and variants of unknown function. Clinical manifestations of MC4R mutations include early-onset obesity, hyperphagia, and metabolic abnormalities such as hyperinsulinemia and dyslipidemia. Management strategies for obesity due to MC4R mutations have evolved with the development of targeted therapies such as Setmelanotide, an MC4R agonist which can reduce weight and manage symptoms without adverse cardiovascular effects. Future research directions must include expansion of population studies to better understand the epidemiology of MC4R mutations, exploration of the molecular mechanisms underlying MC4R signaling, and development of new therapeutic agents. Understanding the interaction between MC4R and other genetic and environmental factors will be key to advancing both the prevention and treatment of obesity.
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Affiliation(s)
- Gumpeny R Sridhar
- Department of Endocrinology and Diabetes, Endocrine and Diabetes Centre, Visakhapatnam 530002, Andhra Pradesh, India
| | - Lakshmi Gumpeny
- Department of Internal Medicine, Gayatri Vidya Parishad Institute of Healthcare and Medical Technology, Visakhapatnam 530048, Andhra Pradesh, India
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Rasouli MA, Dumesic DA, Singhal V. Male infertility and obesity. Curr Opin Endocrinol Diabetes Obes 2024; 31:203-209. [PMID: 39253759 DOI: 10.1097/med.0000000000000883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/11/2024]
Abstract
PURPOSE OF REVIEW The increasing rate of obesity is having an adverse impact on male reproduction. RECENT FINDINGS The negative effect of reactive oxygen species on male reproductive tissues and the age of onset of obesity are new areas of research on male infertility. SUMMARY This review highlights how obesity impairs male reproduction through complex mechanisms, including metabolic syndrome, lipotoxicity, sexual dysfunction, hormonal and adipokine alterations as well as epigenetic changes, and how new management strategies may improve the reproductive health of men throughout life.
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Affiliation(s)
| | | | - Vibha Singhal
- Division of Endocrinology, Department of Pediatrics, University of California, Los Angeles, Los Angeles, California, USA
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Ueda P, Söderling J, Wintzell V, Svanström H, Pazzagli L, Eliasson B, Melbye M, Hviid A, Pasternak B. GLP-1 Receptor Agonist Use and Risk of Suicide Death. JAMA Intern Med 2024; 184:1301-1312. [PMID: 39226030 PMCID: PMC11372654 DOI: 10.1001/jamainternmed.2024.4369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Accepted: 07/03/2024] [Indexed: 09/04/2024]
Abstract
Importance Concerns have been raised regarding a link between use of glucagon-like peptide-1 (GLP-1) receptor agonists and increased risk of suicidality and self-harm. Objective To assess the association between use of GLP-1 receptor agonists and the risk of suicide death in routine clinical practice. Design, Setting, and Participants This active-comparator new-user cohort study used nationwide register data from Sweden and Denmark from 2013 to 2021. Adults 18 to 84 years old who initiated treatment with GLP-1 receptor agonists or the comparator sodium-glucose cotransporter-2 (SGLT2) inhibitors were included. Data were analyzed from March to June 2024. Exposure Initiation of treatment with a GLP-1 receptor agonist or SGLT2 inhibitor. Main Outcomes and Measures The primary outcome was suicide death recorded in the cause of death registers. Secondary outcomes were the composite of suicide death and nonfatal self-harm and the composite of incident depression and anxiety-related disorders. Using propensity score weighting, hazard ratios (HRs) with 95% CIs were calculated separately in the 2 countries and pooled in a meta-analysis. Results In total, 124 517 adults initiated a GLP-1 receptor agonist and 174 036 initiated an SGLT2 inhibitor; among GLP-1 receptor agonist users, the mean (SD) age was 60 (13) years, and 45% were women. During a mean (SD) follow-up of 2.5 (1.7) years, 77 suicide deaths occurred among users of GLP-1 receptor agonists and 71 suicide deaths occurred among users of SGLT2 inhibitors: weighted incidences were 0.23 vs 0.18 events per 1000 person-years (HR, 1.25; 95% CI, 0.83-1.88), with an absolute difference of 0.05 (95% CI, -0.03 to 0.16) events per 1000 person-years. The HR was 0.83 (95% CI, 0.70-0.97) for suicide death and nonfatal self-harm, and the HR was 1.01 (95% CI, 0.97-1.06) for incident depression and anxiety-related disorders. Conclusions and Relevance This cohort study, including mostly patients with type 2 diabetes, does not show an association between use of GLP-1 receptor agonists and an increased risk of suicide death, self-harm, or incident depression and anxiety-related disorders. Suicide death among GLP-1 receptor agonist users was rare, and the upper limit of the confidence interval was compatible with an absolute risk increase of no more than 0.16 events per 1000 person-years.
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Affiliation(s)
- Peter Ueda
- Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Jonas Söderling
- Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Viktor Wintzell
- Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Henrik Svanström
- Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
| | - Laura Pazzagli
- Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
| | - Björn Eliasson
- The Swedish National Diabetes Register, Västra Götalandsregionen, Gothenburg, Sweden
- Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mads Melbye
- HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Faculty of Medicine and Health Science, Norwegian University of Science and Technology, Trondheim, Norway
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California
- Danish Cancer Institute, Copenhagen, Denmark
| | - Anders Hviid
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
- Pharmacovigilance Research Center, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Björn Pasternak
- Division of Clinical Epidemiology, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden
- Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark
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Islam KN, Islam RK, Tong VT, Shami MZ, Allen KE, Brodtmann JR, Book JA. Obesity Medications and Their Impact on Cardiovascular Health: A Narrative Review. Cureus 2024; 16:e71875. [PMID: 39559664 PMCID: PMC11573306 DOI: 10.7759/cureus.71875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2024] [Indexed: 11/20/2024] Open
Abstract
Obesity is a major global issue linked to cardiovascular diseases (CVDs). While lifestyle changes are the primary treatment, medications are often required for long-term weight management and reducing risk in patients with obesity. The cardiovascular effects of many obesity medications are still being studied. This review examines the cardiovascular impact of commonly prescribed obesity medications, focusing on their mechanisms, effectiveness, and safety. A review of the literature was conducted to evaluate the cardiovascular effects of these drugs, including their impact on major cardiovascular outcomes, cholesterol, blood pressure, and other heart-related factors. Some medications, like glucagon-like peptide-1 receptor agonists (GLP-1 RAs), show cardiovascular benefits, while others like orlistat have a lesser effect. Medications such as naltrexone-bupropion and phentermine-topiramate offer weight loss but still require further review for their cardiovascular safety. Data on setmelanotide's long-term effects are limited. Obesity medications differ in their effects on cardiovascular health, with some offering more consistent benefits. More studies are needed to fully understand their long-term risks and benefits, but combining medication with lifestyle changes remains key to improving both weight and heart health.
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Affiliation(s)
- Kazi N Islam
- Agricultural Research Development Program, Central State University, Wilberforce, USA
| | - Rahib K Islam
- School of Medicine, Louisiana State University (LSU) Health Sciences Center New Orleans, New Orleans, USA
| | - Victoria T Tong
- School of Medicine, Louisiana State University (LSU) Health Sciences Center New Orleans, New Orleans, USA
| | - M Zaid Shami
- Internal Medicine, Aventura Hospital and Medical Center, Miami, USA
| | - Kaitlyn E Allen
- School of Medicine, Louisiana State University (LSU) Health Sciences Center New Orleans, New Orleans, USA
| | - Jared R Brodtmann
- School of Medicine, Louisiana State University (LSU) Health Sciences Center New Orleans, New Orleans, USA
| | - Jordan A Book
- School of Medicine, Louisiana State University (LSU) Health Sciences Center New Orleans, New Orleans, USA
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Li W, Liu C, Zhang Z, Cai Z, Lv T, Zhang R, Zuo Y, Chen S. Exploring the top 30 drugs associated with drug-induced constipation based on the FDA adverse event reporting system. Front Pharmacol 2024; 15:1443555. [PMID: 39286628 PMCID: PMC11402663 DOI: 10.3389/fphar.2024.1443555] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2024] [Accepted: 08/20/2024] [Indexed: 09/19/2024] Open
Abstract
Objective This project aims to identify the top 30 drugs most commonly associated with constipation and their signal values within the FDA Adverse Event Reporting System database. Methods We extracted adverse drug events (ADEs) related to constipation from the FAERS database spanning from January 1, 2004, to September 30, 2023. We compiled the 30 most frequently reported drugs based on the frequency of constipation events. We employed signal detection methodologies to ascertain whether these drugs elicited significant signals, including reporting odds ratio, proportional reporting ratio, multi-item gamma Poisson shrinker, and information component given by the Bayesian confidence propagation neural network. Furthermore, we conducted a time-to-onset (TTO) analysis for drugs generating significant signals using the medians, quartiles, and the Weibull shape parameter test. Results We extracted a total of 50, 659, 288 ADEs, among which 169,897 (0.34%) were related to constipation. We selected and ranked the top 30 drugs. The drug with the highest ranking was lenalidomide (7,730 cases, 4.55%), with the most prevalent drug class being antineoplastic and immunomodulating agents. Signal detection was performed for the 30 drugs, with constipation risk signals identified for 26 of them. Among the 26 drugs, 22 exhibited constipation signals consistent with those listed on the FDA-approved drug labels. However, four drugs (orlistat, nintedanib, palbociclib, and dimethyl fumarate) presented an unexpected risk of constipation. Ranked by signal values, sevelamer carbonate emerged as the drug with the strongest risk signal [reporting odds ratio (95% CI): 115.51 (110.14, 121.15); PRR (χ2): 83.78 (191,709.73); EBGM (EB05): 82.63 (79.4); IC (IC025): 6.37 (4.70)]. A TTO analysis was conducted for the 26 drugs that generated risk signals, revealing that all drugs exhibited an early failure type. The median TTO for orlistat was 3 days, the shortest of all the drugs, while the median TTO for clozapine was 1,065 days, the longest of all the drugs. Conclusion Our study provides a list of drugs potentially associated with drug-induced constipation (DIC). This could potentially inform clinicians about some alternative medications to consider when managing secondary causes of constipation or caring for patients prone to DIC, thereby reducing the incidence and mortality associated with DIC.
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Affiliation(s)
- Wenwen Li
- Second School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Cuncheng Liu
- Department of Neonatology, Weifang Traditional Chinese Hospital, Weifang, China
| | - Zhongyi Zhang
- Second School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Zhikai Cai
- Second School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Tailong Lv
- Second School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Ruiyuan Zhang
- Second School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yaoyao Zuo
- Second School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Shouqiang Chen
- Second School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China
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Baraghithy S, Gammal A, Permyakova A, Hamad S, Kočvarová R, Calles Y, Tam J. 5-Methoxy-2-aminoindane Reverses Diet-Induced Obesity and Improves Metabolic Parameters in Mice: A Potential New Class of Antiobesity Therapeutics. ACS Pharmacol Transl Sci 2024; 7:2527-2543. [PMID: 39144560 PMCID: PMC11320730 DOI: 10.1021/acsptsci.4c00353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2024] [Revised: 07/07/2024] [Accepted: 07/15/2024] [Indexed: 08/16/2024]
Abstract
The escalating prevalence of obesity and its related disorders represents a daunting global health challenge. Unfortunately, current pharmacological interventions for obesity remain limited and are often associated with debilitating side effects. Against this backdrop, the psychoactive aminoindane derivative 5-methoxy-2-aminoindane (MEAI) has gained considerable attention for its ability to induce a pleasurable, alcohol-like sensation while curbing alcohol consumption. Given the potential impact of MEAI on food addiction and energy homeostasis, we examined its metabolic efficacy on appetite regulation, obesity, and related comorbidities under acute and chronic settings, utilizing a mouse model of diet-induced obesity (DIO). Our results demonstrated that MEAI treatment significantly reduced DIO-induced overweight and adiposity by preserving lean mass and decreasing fat mass. Additionally, MEAI treatment exhibited positive effects on glycemic control by attenuating DIO-induced hyperglycemia, glucose intolerance, and hyperinsulinemia. Furthermore, MEAI reduced DIO-induced hepatic steatosis by decreasing hepatic lipid accumulation and lowering liver triglyceride and cholesterol levels, primarily by inhibiting de novo lipid synthesis. Metabolic phenotyping revealed that MEAI increased energy expenditure and fat utilization while maintaining food consumption similar to that of the vehicle-treated group. Lastly, MEAI normalized voluntary locomotion actions without any overstimulatory effects. These findings provide compelling evidence for the antiobesity effects of MEAI treatment and call for further preclinical testing. In conclusion, our study highlights the potential of MEAI as a novel therapeutic approach for treating obesity and its associated metabolic disorders, offering hope for the development of new treatment options for this global health challenge.
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Affiliation(s)
- Saja Baraghithy
- Obesity and Metabolism Laboratory,
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Asaad Gammal
- Obesity and Metabolism Laboratory,
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Anna Permyakova
- Obesity and Metabolism Laboratory,
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Sharleen Hamad
- Obesity and Metabolism Laboratory,
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Radka Kočvarová
- Obesity and Metabolism Laboratory,
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Yael Calles
- Obesity and Metabolism Laboratory,
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
| | - Joseph Tam
- Obesity and Metabolism Laboratory,
The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel
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Dorogan M, Namballa HK, Harding WW. Natural Product-Inspired Dopamine Receptor Ligands. J Med Chem 2024; 67:12463-12484. [PMID: 39038276 PMCID: PMC11320586 DOI: 10.1021/acs.jmedchem.4c00537] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 06/30/2024] [Accepted: 07/11/2024] [Indexed: 07/24/2024]
Abstract
Due to their evolutionary bias as ligands for biologically relevant drug targets, natural products offer a unique opportunity as lead compounds in drug discovery. Given the involvement of dopamine receptors in various physiological and behavioral functions, they are linked to numerous diseases and disorders such as Parkinson's disease, schizophrenia, and substance use disorders. Consequently, ligands targeting dopamine receptors hold considerable therapeutic and investigative promise. As this perspective will highlight, dopamine receptor targeting natural products play a pivotal role as scaffolds with unique and beneficial pharmacological properties, allowing for natural product-inspired drug design and lead optimization. As such, dopamine receptor targeting natural products still have untapped potential to aid in the treatment of disorders and diseases related to central nervous system (CNS) and peripheral nervous system (PNS) dysfunction.
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Affiliation(s)
- Michael Dorogan
- Department
of Chemistry, Hunter College, City University
of New York, 695 Park
Avenue, New York, New York 10065, United States
| | - Hari K. Namballa
- Department
of Chemistry, Hunter College, City University
of New York, 695 Park
Avenue, New York, New York 10065, United States
| | - Wayne W. Harding
- Department
of Chemistry, Hunter College, City University
of New York, 695 Park
Avenue, New York, New York 10065, United States
- Program
in Biochemistry, CUNY Graduate Center, 365 Fifth Avenue, New York, New York 10016, United States
- Program
in Chemistry, CUNY Graduate Center, 365 Fifth Avenue, New York, New York 10016, United
States
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13
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Sudeep HV, Prithviraj P, Jestin TV, Shyamprasad K. A polyphenol fraction from Rosa multiflora var. platyphylala reduces body fat in overweight humans through appetite suppression - a randomized, double-blind, placebo-controlled trial. BMC Complement Med Ther 2024; 24:197. [PMID: 38773474 PMCID: PMC11110278 DOI: 10.1186/s12906-024-04487-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Accepted: 04/30/2024] [Indexed: 05/23/2024] Open
Abstract
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.
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Affiliation(s)
- Heggar Venkataramana Sudeep
- Department of Biomedicinal Research, R&D Center for Excellence, Vidya Herbs Pvt Ltd, No. 14/A, KIADB, Jigani Industrial Area, Anekal Taluk, Bangalore, Karnataka, 560105, India.
| | - Puwar Prithviraj
- Anand Multispeciality Hospital, Gorwa, Vadodara, Gujarat, 390016, India
| | - Thomas V Jestin
- Leads Clinical Research and Bioservices Pvt Ltd, Bangalore, India
| | - Kodimule Shyamprasad
- Department of Biomedicinal Research, R&D Center for Excellence, Vidya Herbs Pvt Ltd, No. 14/A, KIADB, Jigani Industrial Area, Anekal Taluk, Bangalore, Karnataka, 560105, India
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14
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Yi F, Wang W, Yi Y, Wu Z, Li R, Song Y, Chen H, Zhou L, Tao Y. Research on the mechanism of regulating spleen-deficient obesity in rats by bawei guben huashi jiangzhi decoction based on multi-omics analysis. JOURNAL OF ETHNOPHARMACOLOGY 2024; 325:117826. [PMID: 38296174 DOI: 10.1016/j.jep.2024.117826] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/16/2024] [Accepted: 01/23/2024] [Indexed: 02/13/2024]
Abstract
ETHNOPHARMACOLOGY RELEVANCE Bawei Guben Huashi Jiangzhi Decoction (BGHJ), a traditional Chinese compound formula, comprises eight Chinese medicinal herbs: Codonopsis Radix, Atractylodis Macrocephalae Rhizoma, Cassiae Semen, Lysimachiae Herba, Edgeworthiae Gardner Flos, Oryzae Semen cum Monasco, Nelumbinis Folium, and Alismatis Rhizoma. It has the therapeutic effects of improving digestive and absorptive functions of the gastrointestinal tract, reducing cholesterol levels, and helping to lose weight. Therefore, BGHJ is mainly used to treat spleen-deficient obesity (SDO) clinically. AIM OF THE STUDY This study aims to examine the efficacy and mechanism of BGHJ in a model of SDO in rats, as well as the potentially involved constituents entering the blood and differential metabolites. METHODS The SDO rat model was replicated utilizing a high-fat and high-sugar diet in conjunction with exhaustive swimming. Subsequently, the rats were subjected to a six-week intervention comprising varying dosages of BGHJ and a positive control, orlistat. To evaluate the efficacy of BGHJ on SDO model rats, we first measured the rats' body weight, body surface temperature, spleen index, as well as biochemical indicators in the serum and colon, and then assessed the pathological state of the colon and liver. Afterward, we analyzed the 16S rDNA gut microbiota, non-targeted serum metabolomics, and serum pharmacology to study the main active components of BGHJ and its action mechanism against SDO model rats. In addition, we constructed a network diagram for overall visualization and analysis, and experimentally verified the predicted results. Finally, we used quantitative polymerase chain reaction (qPCR) to detect the gene expression of proopiomelanocortin (POMC) and neuropeptide Y (NPY) indicators in rat hypothalamic neurons. We quantitatively targeted the detection of neurotransmitters dopamine (DA), acetylcholine (Ach), 5-hydroxytryptamine (5-HT), and noradrenaline (NA) in rat hypothalamus. RESULTS The results demonstrated that all dosage regimens of BGHJ exhibited the capacity to moderately modulate parameters including body weight, surface temperature, spleen index, total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), 5-HT, interleukin 6 (IL-6) and interleukin 17 (IL-17), while concurrently reducing hepatic lipid droplet deposition and restoring intestinal integrity. Subsequent experimental results showed that we successfully identified 27 blood components of BGHJ and identified 52 differential metabolites in SDO model rats. At the same time, the experiment proved that BGHJ could effectively inhibit the metabolic pathway of arachidonic acid. In addition, BGHJ can also restore the intestinal microbiota composition of SDO model rats. Finally, we also found that BGHJ could regulate the expression of hypothalamic neurons and neurotransmitters. CONCLUSIONS The research revealed the main active ingredients of BGHJ and its mechanism against SDO model rats through gut microbiota, non-target serum metabolomics, and serum drug chemistry.
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Affiliation(s)
- Fei Yi
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Wanchun Wang
- The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, 330006, China
| | - Yuliu Yi
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Zhenhui Wu
- The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, 330006, China
| | - Rui Li
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Yonggui Song
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China; Key Research Office for Evaluation of Chinese Medicine Efficacy (Prevention and Treatment of Mental Disorders and Brain Diseases) of Jiangxi Administration of Chinese Medicine, Jiangxi University of Chinese Medicine, Nanchang, 330004, China
| | - Hao Chen
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China; The Affiliated Hospital of Jiangxi University of Chinese Medicine, Nanchang, 330006, China.
| | - Li Zhou
- School of Computer, Jiangxi University of Chinese Medicine, Nanchang, 330004, China.
| | - Yingzhou Tao
- School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, 330004, China; Cancer Research Center& Jiangxi Engineering Research Center for Translational Cancer Technology, Jiangxi University of Chinese Medicine, Nanchang, 330004, China.
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15
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Lee J, Song Y, Kim YA, Kim I, Cha J, Lee SW, Ko Y, Kim CS, Kim S, Lee S. Characterization of a new selective glucocorticoid receptor modulator with anorexigenic activity. Sci Rep 2024; 14:7844. [PMID: 38570726 PMCID: PMC10991430 DOI: 10.1038/s41598-024-58546-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2023] [Accepted: 04/01/2024] [Indexed: 04/05/2024] Open
Abstract
Obesity, a worldwide epidemic, leads to various metabolic disorders threatening human health. In response to stress or fasting, glucocorticoid (GC) levels are elevated to promote food intake. This involves GC-induced expression of the orexigenic neuropeptides in agouti-related protein (AgRP) neurons of the hypothalamic arcuate nucleus (ARC) via the GC receptor (GR). Here, we report a selective GR modulator (SGRM) that suppresses GR-induced transcription of genes with non-classical glucocorticoid response elements (GREs) such as Agrp-GRE, but not with classical GREs, and via this way may serve as a novel anti-obesity agent. We have identified a novel SGRM, 2-O-trans-p-coumaroylalphitolic acid (Zj7), a triterpenoid extracted from the Ziziphus jujube plant, that selectively suppresses GR transcriptional activity in Agrp-GRE without affecting classical GREs. Zj7 reduces the expression of orexigenic genes in the ARC and exerts a significant anorexigenic effect with weight loss in both high fat diet-induced obese and genetically obese db/db mouse models. Transcriptome analysis showed that Zj7 represses the expression of a group of orexigenic genes including Agrp and Npy induced by the synthetic GR ligand dexamethasone (Dex) in the hypothalamus. Taken together, Zj7, as a selective GR modulator, showed beneficial metabolic activities, in part by suppressing GR activity in non-classical GREs in orexigenic genes. This study demonstrates that a potential anorexigenic molecule may allow GRE-specific inhibition of GR transcriptional activity, which is a promising approach for the treatment of metabolic disorders.
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Affiliation(s)
- Junekyoung Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Yeonghun Song
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Young A Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Intae Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Jooseon Cha
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Su Won Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Yoonae Ko
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea
| | - Chong-Su Kim
- Department of Food and Nutrition, College of Natural Information Sciences, Dongduk Women's University, Seoul, 02748, Korea
| | - Sanghee Kim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.
| | - Seunghee Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Korea.
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16
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Darapaneni H, Lakhanpal S, Chhayani H, Parikh K, Patel M, Gupta V, Anamika F, Munjal R, Jain R. Shedding light on weight loss: A narrative review of medications for treating obesity. ROMANIAN JOURNAL OF INTERNAL MEDICINE = REVUE ROUMAINE DE MEDECINE INTERNE 2024; 62:3-11. [PMID: 37752761 DOI: 10.2478/rjim-2023-0023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2023] [Indexed: 09/28/2023]
Abstract
Obesity and overweight are the major risk factors for numerous chronic diseases, including cardiovascular diseases such as heart disease and stroke, which are the leading causes of death worldwide. The prevalence of obesity has dramatically risen in both developed and developing countries, making it a significant public health concern and a global crisis. Despite lifestyle modifications being the first-line treatment, the high risk of relapse has led to a growing interest in non-invasive pharmacotherapeutic interventions to achieve and maintain weight loss and reverse the growth of the obesity epidemic. Cardiovascular diseases and cancer account for the highest mortality rates among other comorbidities associated with obesity and overweight. Excess and abnormally deposited adipose tissue secretes various inflammatory mediators, leading to cardiovascular diseases and cancers. Weight loss of 5-10% significantly reduces cardiometabolic risk. Medications currently approved in the USA for long-term management of obesity are orlistat, naltrexone, bupropion, phentermine/topiramate, and Glucagon Like Peptide-1 (GLP-1) agonists such as liraglutide and semaglutide. The benefit-to-risk of medications, comorbidities, and individual responses should guide the treatment decisions. The article provides a comprehensive overview and discussion of several weight loss medications used previously and currently, including their efficacy, mechanisms of action, and side effects.
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Affiliation(s)
| | | | | | - Kinna Parikh
- G.M.E.R.S. Medical College, Gandhinagar, Gujarat, India
| | - Meet Patel
- Tianjin Medical University, Tianjin, China
| | - Vasu Gupta
- Dayanand Medical College and Hospital, Ludhiana, India
| | - Fnu Anamika
- University College of Medical Sciences, New Delhi, India
| | | | - Rohit Jain
- Penn state Milton S. Hershey Medical Center, Hershey, USA
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17
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Kamiński M, Miętkiewska-Dolecka M, Kręgielska-Narożna M, Bogdański P. Popularity of Surgical and Pharmacological Obesity Treatment Methods Searched by Google Users: the Retrospective Analysis of Google Trends Statistics in 2004-2022. Obes Surg 2024; 34:882-891. [PMID: 38103152 PMCID: PMC10899289 DOI: 10.1007/s11695-023-06971-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2023] [Revised: 11/17/2023] [Accepted: 11/26/2023] [Indexed: 12/17/2023]
Abstract
PURPOSE Many individuals search for obesity treatment options on the Internet. We aimed to analyze the popularity of pharmacological and surgical obesity treatment methods searched by Google users. MATERIAL AND METHODS We used Google Trends to identify topics representing the following: recommended surgical methods (n = 9), recommended pharmacological methods (n = 10), and not recommended pharmacological methods (n = 34). The data was generated for 2004-2022 and 2020-2022. Relative search volume (RSV) was adjusted using "Gastric bypass surgery" as a benchmark. We analyzed the geographical and temporal trends of the topics. RESULTS In 2004-2022, the topics representing recommended surgical methods numerically gained the most popularity among Google users, but in 2020-2022 the recommended drugs exceeded other obesity treatment methods. The most popular individual topics since 2004 were "flaxseed," "Spirulina," "Carnitine," "Bariatric surgery," and "Orlistat." The most dynamic increases of searches since 2004 were observed for "Sleeve gastrectomy," "Curcumin," "Psyllium," and "Bupropion/Naltrexon." Since 2018, topics representing GLP-1 analogs such as "Semaglutide" and "Saxenda" revealed exponential increases in RSV, causing that "Semaglutide" to become the fourth most popular topic in 2020-2022. CONCLUSIONS Google users across the world were the most interested in topics representing bariatric surgery, but recently recommended drugs for the treatment of obesity gained the most attention. The most popular individual topics were dietary supplements with uncertain effects on weight loss.
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Affiliation(s)
- Mikołaj Kamiński
- Department of the Treatment of Obesity and Metabolic Disorders, and of Clinical Dietetics, Poznań University of Medical Sciences, Szamarzewskiego 84, 60-569, Poznań, Poland
| | - Maja Miętkiewska-Dolecka
- Student Scientific Club of Clinical Dietetics, Department of the Treatment of Obesity and Metabolic Disorders, and of Clinical Dietetics, Poznań University of Medical Sciences, Szamarzewskiego 84, 60-569, Poznań, Poland.
| | - Matylda Kręgielska-Narożna
- Department of the Treatment of Obesity and Metabolic Disorders, and of Clinical Dietetics, Poznań University of Medical Sciences, Szamarzewskiego 84, 60-569, Poznań, Poland
| | - Paweł Bogdański
- Department of the Treatment of Obesity and Metabolic Disorders, and of Clinical Dietetics, Poznań University of Medical Sciences, Szamarzewskiego 84, 60-569, Poznań, Poland
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18
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Dedic N, Wang L, Hajos-Korcsok E, Hecksher-Sørensen J, Roostalu U, Vickers SP, Wu S, Anacker C, Synan C, Jones PG, Milanovic S, Hopkins SC, Bristow LJ, Koblan KS. TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding. Mol Metab 2024; 80:101883. [PMID: 38237896 PMCID: PMC10839149 DOI: 10.1016/j.molmet.2024.101883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 01/10/2024] [Accepted: 01/11/2024] [Indexed: 01/24/2024] Open
Abstract
OBJECTIVE Metabolic Syndrome, which can be induced or exacerbated by current antipsychotic drugs (APDs), is highly prevalent in schizophrenia patients. Recent preclinical and clinical evidence suggest that agonists at trace amine-associated receptor 1 (TAAR1) have potential as a new treatment option for schizophrenia. Intriguingly, preclinical tudies have also identified TAAR1 as a novel regulator of metabolic control. Here we evaluated the effects of three TAAR1 agonists, including the clinical development candidate ulotaront, on body weight, metabolic parameters and modulation of neurocircuits implicated in homeostatic and hedonic feeding. METHODS Effects of TAAR1 agonists (ulotaront, RO5166017 and/or RO5263397) on body weight, food intake and/or metabolic parameters were investigated in rats fed a high-fat diet (HFD) and in a mouse model of diet-induced obesity (DIO). Body weight effects were also determined in a rat and mouse model of olanzapine-, and corticosterone-induced body weight gain, respectively. Glucose tolerance was assessed in lean and diabetic db/db mice and fasting plasma glucose and insulin examined in DIO mice. Effects on gastric emptying were evaluated in lean mice and rats. Drug-induced neurocircuit modulation was evaluated in mice using whole-brain imaging of c-fos protein expression. RESULTS TAAR1 agonists improved oral glucose tolerance by inhibiting gastric emptying. Sub-chronic administration of ulotaront in rats fed a HFD produced a dose-dependent reduction in body weight, food intake and liver triglycerides compared to vehicle controls. In addition, a more rapid reversal of olanzapine-induced weight gain and food intake was observed in HFD rats switched to ulotaront or RO5263397 treatment compared to those switched to vehicle. Chronic ulotaront administration also reduced body weight and improved glycemic control in DIO mice, and normalized corticosterone-induced body weight gain in mice. TAAR1 activation increased neuronal activity in discrete homeostatic and hedonic feeding centers located in the dorsal vagal complex and hypothalamus with concurrent activation of several limbic structures. CONCLUSION The current data demonstrate that TAAR1 agonists, as a class, not only lack APD-induced metabolic liabilities but can reduce body weight and improve glycemic control in rodent models. The underlying mechanisms likely include TAAR1-mediated peripheral effects on glucose homeostasis and gastric emptying as well as central regulation of energy balance and food intake.
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Affiliation(s)
- Nina Dedic
- Sumitomo Pharma America, Inc., Marlborough, MA, USA.
| | - Lien Wang
- Sumitomo Pharma America, Inc., Marlborough, MA, USA
| | | | | | | | | | - Serena Wu
- Department of Psychiatry, New York State Psychiatric Institute (NYSPI), Columbia University, NY, New York City, USA
| | - Christoph Anacker
- Department of Psychiatry, New York State Psychiatric Institute (NYSPI), Columbia University, NY, New York City, USA
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19
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Kim HN, Lee YA, Song SW. Sunflower seed extract supplementation reduces body fat in adults with obesity: A double-blind, randomized, placebo-controlled trial. Nutr Res 2024; 122:113-122. [PMID: 38217909 DOI: 10.1016/j.nutres.2023.12.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 12/14/2023] [Accepted: 12/14/2023] [Indexed: 01/15/2024]
Abstract
Obesity is an important public health problem and socioeconomic burden. We hypothesized that an intake of sunflower seed extract (SUN-CA) would decrease body fat and then investigated the effects and safety of SUN-CA intake on body fat in adults with obesity as an option for obesity treatment. In this double-blind, randomized, placebo-controlled study, 100 adults with body mass indices of 25 to 31.9 kg/m2 were assigned to groups that received SUN-CA (n = 50) or a placebo (n = 50) and received 1 tablet/day containing 500 mg of SUN-CA or the placebo over a 12-week period. The primary endpoint was the change in mass and percentage of body fat. The group that received SUN-CA daily showed decreases in body fat mass greater than those in the placebo group (-0.9 ± 1.8 kg vs. -0.1 ± 1.4 kg, P = .043). In addition, body weight, body mass index, and hip circumference improved after the intake of SUN-CA relative to the changes in the placebo group. There was no intergroup differences in the prevalence of adverse events. The accumulation of excess body fat improved through the intake of 500 mg/day of SUN-CA containing 100 mg of chlorogenic acids for 12 weeks in adults with obesity without causing serious adverse side effects. SUN-CA could be an effective and safe management option for obesity. The trial was registered at Clinical Research Information Service (CRIS: https://cris.nih.go.kr/cris/index/index.do) as KCT0005733.
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Affiliation(s)
- Ha-Na Kim
- Department of Family Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yun-Ah Lee
- Department of Family Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Sang-Wook Song
- Department of Family Medicine, St. Vincent's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
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20
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Amin U, Huang D, Dhir A, Shindler AE, Franks AE, Thomas CJ. Effects of gastric bypass bariatric surgery on gut microbiota in patients with morbid obesity. Gut Microbes 2024; 16:2427312. [PMID: 39551972 PMCID: PMC11581163 DOI: 10.1080/19490976.2024.2427312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 10/11/2024] [Accepted: 11/04/2024] [Indexed: 11/19/2024] Open
Abstract
The Western diet is associated with gastrointestinal dysbiosis, an active contributor to the pathophysiology of obesity and its comorbidities. Gastrointestinal dysbiosis is strongly linked to increased adiposity, low-grade inflammation, dyslipidaemia, and insulin resistance in individuals with morbid obesity. Bariatric bypass surgery remains the most effective treatment for achieving significant weight loss and alleviating obesity-related comorbidities. A growing body of evidence indicates that traditional Roux-en-Y Gastric Bypass (RYGB) improves the disrupted gut microbiota linked with obesity, potentially contributing to sustained weight loss and reduction of comorbidities. One Anastomosis Gastric Bypass (OAGB), a relatively new and technically simpler bariatric procedure, has shown both safety and efficacy in promoting weight loss and improving comorbidities. Few studies have investigated the impact of OAGB on gut microbiota. This review provides insights into the pathogenesis of obesity, current treatment strategies and our current understanding of the gut microbiota in health and disease, including modulating the gut microbiota as a promising and novel way to alleviate the burden of obesity and cardiometabolic conditions. By exploring the impact of gastric bypass surgery on gut microbiota-host interactions, we aim to shed light on this evolving field of research and uncover potential therapeutic targets for elevating outcomes in bariatric surgery.
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Affiliation(s)
- Urja Amin
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, Victoria, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Bundoora, Victoria, Australia
| | - Dora Huang
- Department of Surgery, Austin Health, Heidelberg, Victoria, Australia
- Body Genesis Institute, Bundoora, Victoria, Australia
| | - Arun Dhir
- Department of Surgery, Austin Health, Heidelberg, Victoria, Australia
- Body Genesis Institute, Bundoora, Victoria, Australia
| | - Anya E Shindler
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, Victoria, Australia
| | - Ashley E Franks
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, Victoria, Australia
| | - Colleen J Thomas
- Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, Victoria, Australia
- Centre for Cardiovascular Biology and Disease Research, La Trobe University, Bundoora, Victoria, Australia
- Pre-Clinical Critical Care Unit, Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
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21
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Yan M, Man S, Sun B, Ma L, Guo L, Huang L, Gao W. Gut liver brain axis in diseases: the implications for therapeutic interventions. Signal Transduct Target Ther 2023; 8:443. [PMID: 38057297 PMCID: PMC10700720 DOI: 10.1038/s41392-023-01673-4] [Citation(s) in RCA: 65] [Impact Index Per Article: 32.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 09/10/2023] [Accepted: 09/28/2023] [Indexed: 12/08/2023] Open
Abstract
Gut-liver-brain axis is a three-way highway of information interaction system among the gastrointestinal tract, liver, and nervous systems. In the past few decades, breakthrough progress has been made in the gut liver brain axis, mainly through understanding its formation mechanism and increasing treatment strategies. In this review, we discuss various complex networks including barrier permeability, gut hormones, gut microbial metabolites, vagus nerve, neurotransmitters, immunity, brain toxic metabolites, β-amyloid (Aβ) metabolism, and epigenetic regulation in the gut-liver-brain axis. Some therapies containing antibiotics, probiotics, prebiotics, synbiotics, fecal microbiota transplantation (FMT), polyphenols, low FODMAP diet and nanotechnology application regulate the gut liver brain axis. Besides, some special treatments targeting gut-liver axis include farnesoid X receptor (FXR) agonists, takeda G protein-coupled receptor 5 (TGR5) agonists, glucagon-like peptide-1 (GLP-1) receptor antagonists and fibroblast growth factor 19 (FGF19) analogs. Targeting gut-brain axis embraces cognitive behavioral therapy (CBT), antidepressants and tryptophan metabolism-related therapies. Targeting liver-brain axis contains epigenetic regulation and Aβ metabolism-related therapies. In the future, a better understanding of gut-liver-brain axis interactions will promote the development of novel preventative strategies and the discovery of precise therapeutic targets in multiple diseases.
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Affiliation(s)
- Mengyao Yan
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, 300457, Tianjin, China
| | - Shuli Man
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, 300457, Tianjin, China.
| | - Benyue Sun
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, 300457, Tianjin, China
| | - Long Ma
- State Key Laboratory of Food Nutrition and Safety, Key Laboratory of Industrial Microbiology, Ministry of Education, Tianjin Key Laboratory of Industry Microbiology, National and Local United Engineering Lab of Metabolic Control Fermentation Technology, China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, 300457, Tianjin, China
| | - Lanping Guo
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, 100700, Beijing, China.
| | - Luqi Huang
- National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, 100700, Beijing, China
| | - Wenyuan Gao
- Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Weijin Road, 300072, Tianjin, China.
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22
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Khemka S, Reddy A, Garcia RI, Jacobs M, Reddy RP, Roghani AK, Pattoor V, Basu T, Sehar U, Reddy PH. Role of diet and exercise in aging, Alzheimer's disease, and other chronic diseases. Ageing Res Rev 2023; 91:102091. [PMID: 37832608 PMCID: PMC10842571 DOI: 10.1016/j.arr.2023.102091] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 10/10/2023] [Indexed: 10/15/2023]
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disease, characterized by memory loss and multiple cognitive impairments. Genetic mutations cause a small proportion (1-2%) of early-onset AD, with mutations in amyloid precursor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2). Major contributing factors of late-onset AD are ApoE4 genotype, traumatic brain injury, diabetes, obesity, hypertension, cardiovascular conditions, in addition to lifestyle factors, such as unhealthy diet and lack of physical exercise. Disease progression can be delayed and/or prevented to a greater extent by adopting healthy lifestyle with balanced and antioxidant enriched diet and daily exercise. The interaction and interplay of diet, exercise, age, and pharmacological interventions holds a crucial role in the progression, pathogenesis and management of AD and its comorbidities, including diabetes, obesity, hypertension and cardiovascular conditions. Antioxidant enriched diet contributes to brain health, glucose control, weight management, and cardiovascular well-being. Regular exercise removes toxins including free radicals and enhances insulin sensitivity, and supports cardiovascular function. In the current article, we discussed, the role of diet, and exercise in aging, AD and other conditions including diabetes, obesity, hypertension, cardiovascular conditions. This article also highlights the impact of medication, socioeconomic and lifestyle factors, and pharmacological interventions. These aspects were discussed in different races and ethnic groups in Texas, and the US.
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Affiliation(s)
- Sachi Khemka
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Aananya Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Lubbock High School, Lubbock, TX 79401, USA
| | - Ricardo Isaiah Garcia
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Micheal Jacobs
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department of Biology, The University of Texas at San Antonio, San Antonio, TX 78249, USA
| | - Ruhananhad P Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Lubbock High School, Lubbock, TX 79401, USA
| | - Aryan Kia Roghani
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Frenship High School, Lubbock, TX 79382, USA
| | - Vasanthkumar Pattoor
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; University of South Florida, Tampa, FL 33620, USA
| | - Tanisha Basu
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - Ujala Sehar
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA
| | - P Hemachandra Reddy
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Nutritional Sciences Department, College of Human Medicine, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Public Health Department of Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA; Department pf Speech, Language and Hearing Services, School Health Professions, Texas Tech University Healthy Sciences Center, Lubbock, TX 79430, USA; Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX 79430, USA.
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23
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Carnell S, Thapaliya G, Jansen E, Chen L. Biobehavioral susceptibility for obesity in childhood: Behavioral, genetic and neuroimaging studies of appetite. Physiol Behav 2023; 271:114313. [PMID: 37544571 PMCID: PMC10591980 DOI: 10.1016/j.physbeh.2023.114313] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 06/06/2023] [Accepted: 07/31/2023] [Indexed: 08/08/2023]
Abstract
Modern food environments are conducive to overeating and weight gain, but not everyone develops obesity. One reason for this may be that individuals differ in appetitive characteristics, or traits, that manifest early in life and go on to influence their behavioral susceptibility to gain and maintain excess weight. Classic studies showing that eating behavior in children can be measured by behavioral paradigms such as tests of caloric compensation and eating in the absence of hunger inspired the development and validation of psychometric instruments to assess appetitive characteristics in children and infants. A large body of evidence now suggests that food approach traits increase obesity risk, while food avoidant traits, such as satiety responsiveness, decrease obesity risk. Twin studies and genetic association studies have demonstrated that appetitive characteristics are heritable, consistent with a biological etiology. However, family environment factors are also influential, with mounting evidence suggesting that genetic and environmental risk factors interact and correlate with consequences for child eating behavior and weight. Further, neuroimaging studies are revealing that individual differences in responses to visual food cues, as well as to small tastes and larger amounts of food, across a number of brain regions involved in reward/motivation, cognitive control and other functions, may contribute to individual variation in appetitive behavior. Growing evidence also suggests that variation on psychometric measures of appetite is associated with regional differences in brain structure, and differential patterns of resting state functional connectivity. Large prospective studies beginning in infancy promise to enrich our understanding of neural and other biological underpinnings of appetite and obesity development in early life, and how the interplay between genetic and environmental factors affects appetitive systems. The biobehavioral susceptibility model of obesity development and maintenance outlined in this narrative review has implications for prevention and treatment of obesity in childhood.
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Affiliation(s)
- Susan Carnell
- Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD, USA.
| | - Gita Thapaliya
- Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD, USA
| | - Elena Jansen
- Division of Child and Adolescent Psychiatry, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD, USA
| | - Liuyi Chen
- Division of Psychiatric Neuroimaging, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore MD, USA
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24
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Alalalmeh SO, Hegazi OE, Shahwan M, Alshehri FS, Ashour AM, Algarni AS, Alorfi NM. Amphetamines in child medicine: a review of ClinicalTrials.gov. Front Pharmacol 2023; 14:1280562. [PMID: 37854716 PMCID: PMC10579567 DOI: 10.3389/fphar.2023.1280562] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Accepted: 09/18/2023] [Indexed: 10/20/2023] Open
Abstract
Background: Globally, the use of amphetamines as therapeutic agents in pediatric medicine is a crucial area of concern, especially given the population's vulnerability. Methods: On 6 August 2023, a search was conducted on ClinicalTrials.gov using "amphetamine" as the keyword. Two independent examiners screened trials against set criteria, including a focus on amphetamine, completion status, an interventional approach, and included children. Ongoing or observational studies were excluded. Data extracted from the qualified trials encompassed primary objectives, participant counts, study duration, and outcomes, with the aim of analyzing children disorders treated by amphetamine. Results: On 6 August 2023, a search of the ClinicalTrials.gov database with the term "amphetamines" identified 179 clinical trials. After extensive exclusion criteria, 19 trials were ultimately selected for analysis. The predominant condition under investigation was attention deficit hyperactivity disorder (ADHD), present in 84.2% of studies. Key study characteristics included: phase 4 trials (36.8%), randomized allocation (63.2%), and the parallel intervention model (42.1%). Masking techniques varied, with no masking in 42.1% of studies, and double and quadruple masking both accounting for 21.1%. Geographically, 78.9% of the studies' participants were from the United States. Conclusion: This study highlights the notable therapeutic potential of amphetamines in pediatric ADHD populations and emphasizes the importance of recognizing potential side effects and addiction risks. As pharmacogenomics offers the prospect of personalized treatments, there is potential to increase therapeutic efficacy and decrease adverse reactions. It is vital to balance these benefits against the inherent risks, understanding the need for continued research to optimize the use of amphetamines in medicine.
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Affiliation(s)
- Samer O. Alalalmeh
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Omar E. Hegazi
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Moyad Shahwan
- Center of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
- Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, United Arab Emirates
| | - Fahad S. Alshehri
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Ahmed M. Ashour
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Alanood S. Algarni
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Nasser M. Alorfi
- Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
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Novograd J, Mullally JA, Frishman WH. Tirzepatide for Weight Loss: Can Medical Therapy "Outweigh" Bariatric Surgery? Cardiol Rev 2023; 31:278-283. [PMID: 36688833 DOI: 10.1097/crd.0000000000000515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
The worldwide prevalence of obesity has been increasing progressively over the past few decades and is predicted to continue to rise in coming years. Unfortunately, this epidemic is also affecting increasing rates of children and adolescents, posing a serious global health concern. Increased adiposity is associated with various comorbidities and increased mortality risk. Conversely, weight loss and chronic weight management are associated with improvements in overall morbidity and mortality. The pathophysiology of obesity is multifactorial with complex interactions between genetic and environmental factors. The foundation of most weight loss plans is lifestyle modification including dietary change and exercise. However, lifestyle modification alone is often insufficient to achieve clinically meaningful weight loss due to physiological mechanisms that limit weight reduction and promote weight regain. Therefore, research has focused on adjunctive pharmacotherapy to enable patients to achieve greater weight loss and improved chronic weight maintenance compared to lifestyle modification alone. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin hormone analogs that have proven effective for the management of type 2 diabetes mellitus as well as obesity and overweight. Tirzepatide is a novel "twincretin" that functions as a dual glucose-dependent insulinotropic polypeptide and GLP-1 RA. Tirzepatide was recently approved by the Food and Drug Administration for the management of type 2 diabetes. Similar to previously approved GLP-1RAs, weight loss is a common side effect of tirzepatide which prompted research focused on its use as a primary weight loss therapy. Although this drug has not yet been approved as an antiobesity medication, there are several phase 3 clinical trials that have demonstrated superior weight loss efficacy compared with previously approved medications. This review article will discuss the discovery and mechanism of tirzepatide, as well as the completed and ongoing trials that may lead to its approval as an adjunctive pharmacotherapy for weight loss.
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Pati B, Sendh S, Sahu B, Pani S, Jena N, Bal NC. Recent advancements in pharmacological strategies to modulate energy balance for combating obesity. RSC Med Chem 2023; 14:1429-1445. [PMID: 37593583 PMCID: PMC10429841 DOI: 10.1039/d3md00107e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 06/06/2023] [Indexed: 08/19/2023] Open
Abstract
The prevalence of obesity along with its related metabolic diseases has increased globally in recent decades. Obesity originates from a heterogeneous physiological state, which is further complicated by the influence of factors such as genetic, behavioural, and environmental. Lifestyle interventions including exercise and diet have limited success, necessitating the development of pharmacological approaches. Mechanistically, strategies target either reducing energy intake or increasing consumption through metabolism boosting. Current drugs lower energy intake via inducing satiety or inhibiting substrate absorption, while targeting mitochondria or cytosolic energy sensors has shown limited success due to toxicity. Nonshivering thermogenesis (NST) has provided hope for activating these processes selectively without significant side effects. The internet-based marketing of plant-based formulations for enhancing metabolism has surged. This review compiles scientific articles, magazines, newspapers, and online resources on anti-obesity drug development. Combination therapy of metabolic boosters and established anti-obesity compounds appears to be a promising future approach that requires further research.
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Affiliation(s)
- Benudhara Pati
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Satyabrata Sendh
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Bijayashree Sahu
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Sunil Pani
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
| | - Nivedita Jena
- Institute of Life Science, DBT ILS Bioincubator Bhubaneswar Odisha 751021-India
| | - Naresh Chandra Bal
- School of Biotechnology, KIIT University Bhubaneswar Odisha 751024 India
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27
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Li Y, Zhou Q, Dai A, Zhao F, Chang R, Ying T, Wu B, Yang D, Wang MW, Cong Z. Structural analysis of the dual agonism at GLP-1R and GCGR. Proc Natl Acad Sci U S A 2023; 120:e2303696120. [PMID: 37549266 PMCID: PMC10438375 DOI: 10.1073/pnas.2303696120] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Accepted: 06/15/2023] [Indexed: 08/09/2023] Open
Abstract
Glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR), two members of class B1 G protein-coupled receptors, play important roles in glucose homeostasis and energy metabolism. They share a high degree of sequence homology but have different functionalities. Unimolecular dual agonists of both receptors developed recently displayed better clinical efficacies than that of monotherapy. To study the underlying molecular mechanisms, we determined high-resolution cryo-electron microscopy structures of GLP-1R or GCGR in complex with heterotrimeric Gs protein and three GLP-1R/GCGR dual agonists including peptide 15, MEDI0382 (cotadutide) and SAR425899 with variable activating profiles at GLP-1R versus GCGR. Compared with related structures reported previously and supported by our published pharmacological data, key residues responsible for ligand recognition and dual agonism were identified. Analyses of peptide conformational features revealed a difference in side chain orientations within the first three residues, indicating that distinct engagements in the deep binding pocket are required to achieve receptor selectivity. The middle region recognizes extracellular loop 1 (ECL1), ECL2, and the top of transmembrane helix 1 (TM1) resulting in specific conformational changes of both ligand and receptor, especially the dual agonists reshaped ECL1 conformation of GLP-1R relative to that of GCGR, suggesting an important role of ECL1 interaction in executing dual agonism. Structural investigation of lipid modification showed a better interaction between lipid moiety of MEDI0382 and TM1-TM2 cleft, in line with its increased potency at GCGR than SAR425899. Together, the results provide insightful information for the design and development of improved therapeutics targeting these two receptors simultaneously.
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Affiliation(s)
- Yang Li
- Department of Medical Microbiology and Parasitology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
| | - Qingtong Zhou
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
| | - Antao Dai
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Fenghui Zhao
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Rulue Chang
- School of Pharmacy, Fudan University, Shanghai201203, China
| | - Tianlei Ying
- Department of Medical Microbiology and Parasitology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
| | - Beili Wu
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
| | - Dehua Yang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai201203, China
- Research Center for Deepsea Bioresources, Sanya, Hainan572025, China
| | - Ming-Wei Wang
- Department of Medical Microbiology and Parasitology, Shanghai Institute of Infectious Disease and Biosecurity, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
- Research Center for Deepsea Bioresources, Sanya, Hainan572025, China
- Department of Chemistry, School of Science, The University of Tokyo, Tokyo113-0033, Japan
- School of Pharmacy, Hainan Medical College, Haikou570228, China
| | - Zhaotong Cong
- Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai200032, China
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28
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Haspula D, Cui Z. Neurochemical Basis of Inter-Organ Crosstalk in Health and Obesity: Focus on the Hypothalamus and the Brainstem. Cells 2023; 12:1801. [PMID: 37443835 PMCID: PMC10341274 DOI: 10.3390/cells12131801] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 06/23/2023] [Accepted: 07/03/2023] [Indexed: 07/15/2023] Open
Abstract
Precise neural regulation is required for maintenance of energy homeostasis. Essential to this are the hypothalamic and brainstem nuclei which are located adjacent and supra-adjacent to the circumventricular organs. They comprise multiple distinct neuronal populations which receive inputs not only from other brain regions, but also from circulating signals such as hormones, nutrients, metabolites and postprandial signals. Hence, they are ideally placed to exert a multi-tier control over metabolism. The neuronal sub-populations present in these key metabolically relevant nuclei regulate various facets of energy balance which includes appetite/satiety control, substrate utilization by peripheral organs and glucose homeostasis. In situations of heightened energy demand or excess, they maintain energy homeostasis by restoring the balance between energy intake and expenditure. While research on the metabolic role of the central nervous system has progressed rapidly, the neural circuitry and molecular mechanisms involved in regulating distinct metabolic functions have only gained traction in the last few decades. The focus of this review is to provide an updated summary of the mechanisms by which the various neuronal subpopulations, mainly located in the hypothalamus and the brainstem, regulate key metabolic functions.
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Affiliation(s)
- Dhanush Haspula
- Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA
| | - Zhenzhong Cui
- Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA;
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Skovbjerg G, Roostalu U, Salinas CG, Skytte JL, Perens J, Clemmensen C, Elster L, Frich CK, Hansen HH, Hecksher-Sørensen J. Uncovering CNS access of lipidated exendin-4 analogues by quantitative whole-brain 3D light sheet imaging. Neuropharmacology 2023:109637. [PMID: 37391028 DOI: 10.1016/j.neuropharm.2023.109637] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 07/02/2023]
Abstract
Peptide-based drug development for CNS disorders is challenged by poor blood-brain barrier (BBB) penetrability of peptides. While acylation protractions (lipidation) have been successfully applied to increase circulating half-life of therapeutic peptides, little is known about the CNS accessibility of lipidated peptide drugs. Light-sheet fluorescence microscopy (LSFM) has emerged as a powerful method to visualize whole-brain 3D distribution of fluorescently labelled therapeutic peptides at single-cell resolution. Here, we applied LSFM to map CNS distribution of the clinically relevant GLP-1 receptor agonist (GLP-1RA) exendin-4 (Ex4) and lipidated analogues following peripheral administration. Mice received an intravenous dose (100 nmol/kg) of IR800 fluorophore-labelled Ex4 (Ex4), Ex4 acylated with a C16-monoacid (Ex4_C16MA) or C18-diacid (Ex4_C18DA). Other mice were administered C16MA-acylated exendin 9-39 (Ex9-39_C16MA), a selective GLP-1R antagonist, serving as negative control for GLP-1R mediated agonist internalization. Two hours post-dosing, brain distribution of Ex4 and analogues was predominantly restricted to the circumventricular organs, notably area postrema and nucleus of the solitary tract. Ex4_C16MA and Ex9-39_C16MA also distributed to the paraventricular hypothalamic nucleus and medial habenula. Notably, Ex4_C18DA was detected in deeper-lying brain structures such as dorsomedial/ventromedial hypothalamic nuclei and the dentate gyrus. Similar CNS distribution maps of Ex4-C16MA and Ex9-39_C16MA suggest that brain access of lipidated Ex4 analogues is independent on GLP-1 receptor internalization. The cerebrovasculature was devoid of specific labelling, hence not supporting a direct role of GLP-1 RAs in BBB function. In conclusion, peptide lipidation increases CNS accessibility of Ex4. Our fully automated LSFM pipeline is suitable for mapping whole-brain distribution of fluorescently labelled drugs.
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Affiliation(s)
- Grethe Skovbjerg
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Urmas Roostalu
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | | | - Jacob L Skytte
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Johanna Perens
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
| | - Christoffer Clemmensen
- Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark
| | - Lisbeth Elster
- Gubra ApS, Hørsholm Kongevej 11B, 2970, Hørsholm, Denmark
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30
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Liu J, Zhou X, Feng C, Zheng W, Chen P, Zhang X, Hou P. Glucagon-modified Liposomes Delivering Thyroid Hormone for Anti-obesity Therapy. Arch Med Res 2023:S0188-4409(23)00057-7. [PMID: 37121791 DOI: 10.1016/j.arcmed.2023.04.001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 03/24/2023] [Accepted: 04/18/2023] [Indexed: 05/02/2023]
Abstract
BACKGROUND Thyroid hormones (active form T3) are naturally potent compounds that influence energy expenditure, cholesterol metabolism, and fat oxidation. T3 would be an effective anti-obesity drug if it would not be delivered to the heart and bones, which leads to serious side effects, such as cardiovascular and bone thyrotoxicity, muscle wasting, and so on. METHODS In this study, we designed a targeted drug delivery system that is a glucagon-modified liposome to deliver T3 to the liver and adipose tissues. RESULTS The liposomes exhibited excellent properties, including uniform nanoscale particle size, good physicochemical stability, and adequate drug release behavior. More importantly, the glucagon-modified liposomes were enriched in the liver, which minimized the undesired bone and cardiovascular thyrotoxicity of T3. Compared to the control group, T3-loading glucagon-modified liposomes could effectively decrease body weight, reverse hepatic steatosis, and correct hyperlipidemia and hyperglycemia in ob/ob mice, without the undesired cardiovascular and bone thyrotoxicity. CONCLUSION These findings indicate that delivery of thyroid hormone by glucagon-modified liposomes may provide an effective strategy for anti-obesity therapy.
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Affiliation(s)
- Juan Liu
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xinrui Zhou
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Chao Feng
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Wenfang Zheng
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Pu Chen
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Xiaozhi Zhang
- Department of Radiation Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China
| | - Peng Hou
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, People's Republic of China.
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Coulter AA, Greenway FL, Zhang D, Ghosh S, Coulter CR, James SL, He Y, Cusimano LA, Rebello CJ. Naringenin and β-carotene convert human white adipocytes to a beige phenotype and elevate hormone- stimulated lipolysis. Front Endocrinol (Lausanne) 2023; 14:1148954. [PMID: 37143734 PMCID: PMC10153092 DOI: 10.3389/fendo.2023.1148954] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 03/20/2023] [Indexed: 05/06/2023] Open
Abstract
Introduction Naringenin, a peroxisome proliferator-activated receptor (PPAR) activator found in citrus fruits, upregulates markers of thermogenesis and insulin sensitivity in human adipose tissue. Our pharmacokinetics clinical trial demonstrated that naringenin is safe and bioavailable, and our case report showed that naringenin causes weight loss and improves insulin sensitivity. PPARs form heterodimers with retinoic-X-receptors (RXRs) at promoter elements of target genes. Retinoic acid is an RXR ligand metabolized from dietary carotenoids. The carotenoid β-carotene reduces adiposity and insulin resistance in clinical trials. Our goal was to examine if carotenoids strengthen the beneficial effects of naringenin on human adipocyte metabolism. Methods Human preadipocytes from donors with obesity were differentiated in culture and treated with 8µM naringenin + 2µM β-carotene (NRBC) for seven days. Candidate genes involved in thermogenesis and glucose metabolism were measured as well as hormone-stimulated lipolysis. Results We found that β-carotene acts synergistically with naringenin to boost UCP1 and glucose metabolism genes including GLUT4 and adiponectin, compared to naringenin alone. Protein levels of PPARα, PPARγ and PPARγ-coactivator-1α, key modulators of thermogenesis and insulin sensitivity, were also upregulated after treatment with NRBC. Transcriptome sequencing was conducted and the bioinformatics analyses of the data revealed that NRBC induced enzymes for several non-UCP1 pathways for energy expenditure including triglyceride cycling, creatine kinases, and Peptidase M20 Domain Containing 1 (PM20D1). A comprehensive analysis of changes in receptor expression showed that NRBC upregulated eight receptors that have been linked to lipolysis or thermogenesis including the β1-adrenergic receptor and the parathyroid hormone receptor. NRBC increased levels of triglyceride lipases and agonist-stimulated lipolysis in adipocytes. We observed that expression of RXRγ, an isoform of unknown function, was induced ten-fold after treatment with NRBC. We show that RXRγ is a coactivator bound to the immunoprecipitated PPARγ protein complex from white and beige human adipocytes. Discussion There is a need for obesity treatments that can be administered long-term without side effects. NRBC increases the abundance and lipolytic response of multiple receptors for hormones released after exercise and cold exposure. Lipolysis provides the fuel for thermogenesis, and these observations suggest that NRBC has therapeutic potential.
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Affiliation(s)
- Ann A. Coulter
- Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Frank L. Greenway
- Clinical Trials, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Dachuan Zhang
- Biostatistics, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Sujoy Ghosh
- Adjunct Faculty, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Cathryn R. Coulter
- Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Sarah L. James
- Computational Biology, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Yanlin He
- Brain Glycemic and Metabolism Control, Pennington Biomedical Research Center, Baton Rouge, LA, United States
| | - Luke A. Cusimano
- Cusimano Plastic and Reconstructive Surgery, Baton Rouge, LA, United States
| | - Candida J. Rebello
- Nutrition and Chronic Disease, Pennington Biomedical Research Center, Baton Rouge, LA, United States
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Pharmacological Treatments and Natural Biocompounds in Weight Management. Pharmaceuticals (Basel) 2023; 16:ph16020212. [PMID: 37139804 PMCID: PMC9962258 DOI: 10.3390/ph16020212] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/25/2023] [Accepted: 01/26/2023] [Indexed: 01/31/2023] Open
Abstract
The obesity pandemic is one of society’s most urgent public health concerns. One-third of the global adult population may fall under obese or overweight by 2025, suggesting a rising demand for medical care and an exorbitant cost of healthcare expenditure in the coming years. Generally, the treatment strategy for obese patients is largely patient-centric and needs dietary, behavioral, pharmacological, and sometimes even surgical interventions. Given that obesity cases are rising in adults and children and lifestyle modifications have failed to produce the desired results, the need for medical therapy adjunct to lifestyle modifications is vital for better managing obesity. Most existing or past drugs for obesity treatment target satiety or monoamine pathways and induce a feeling of fullness in patients, while drugs such as orlistat are targeted against intestinal lipases. However, many medications targeted against neurotransmitters showed adverse events in patients, thus being withdrawn from the market. Alternatively, the combination of some drugs has been successfully tested in obesity management. However, the demand for novel, safer, and more efficacious pharmaceutical medicines for weight management does exist. The present review elucidates the current understanding of the available anti-obesity medicines of synthetic and natural origin, their main mechanisms of action, and the shortcomings associated with current weight management drugs.
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Migliolo L, de A. Boleti A, de O. Cardoso P, Frihling BF, e Silva P, de Moraes LRN. Adipose tissue, systematic inflammation, and neurodegenerative diseases. Neural Regen Res 2023; 18:38-46. [PMID: 35799506 PMCID: PMC9241402 DOI: 10.4103/1673-5374.343891] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Song EJ, Shin NR, Jeon S, Nam YD, Kim H. Impact of the herbal medicine, Ephedra sinica stapf , on gut microbiota and body weight in a diet-induced obesity model. Front Pharmacol 2022; 13:1042833. [PMID: 36457710 PMCID: PMC9706310 DOI: 10.3389/fphar.2022.1042833] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 10/31/2022] [Indexed: 10/21/2024] Open
Abstract
Obesity is a chronic metabolic disease caused by excessive body fat and has become a global public health problem. Evidence suggests that obesity and obesity-induced metabolic disorders are closely related to gut microbiota. Bupropion (BP), an antidepressant medicine, and Ephedra sinica Stapf [Ephedraceae; Ephedrae Herba], a herbal medicine, are sympathetic stimulants and have weight loss effects. However, to our best knowledge, no studies have simultaneously assessed the effects of drugs and herbal medicines on obesity and gut microbiota. This study aimed to determine the effects of BP and ES on weight loss and re-modulation of host gut microbiota. To test this hypothesis, we fed C57BL/6J mice with a high-fat diet supplemented with bupropion (BP; 30 mg/kg/day) and Ephedra sinica Stapf extract (ES; 150 mg/kg/day) via oral gavage for eight weeks. Further, we evaluated the effects of BP and ES on body weight and fat accumulation. In addition, we evaluated the effects of BP and ES on gut microbiota using 16S rRNA amplicon sequencing. Our results showed that weight loss was confirmed in both BP and ES; however, it was more pronounced in ES. ES changed the overall composition of the gut microbiota by restoring the relative abundance of Oscillospiraceae, Lachnospiraceae, and the Firmicutes/Bacteroidetes ratio, an indicator of gut microbiota dysbiosis. Nine amplicon sequence variants (ASVs) of the gut microbiome were significantly recovered by BP and ES treatment, of which eight ASVs correlated with body weight and fat accumulation. Additionally, three ASVs were significantly recovered by ES treatment alone. In conclusion, the anti-obesity effects of BP and ES, especially fat accumulation, are related to the regulation of gut microbiota. Moreover, ES had a greater influence on the gut microbiota than BP.
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Affiliation(s)
- Eun-Ji Song
- Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, Jeollabuk-do, South Korea
| | - Na Rae Shin
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, Goyang-si, Gyeonggi-do, South Korea
| | - Songhee Jeon
- Department of Biomedical Sciences, Center for Global Future Biomedical Scientists at Chonnam National University, Gwangju, South Korea
| | - Young-Do Nam
- Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, Jeollabuk-do, South Korea
| | - Hojun Kim
- Department of Rehabilitation Medicine of Korean Medicine, Dongguk University, Goyang-si, Gyeonggi-do, South Korea
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Abstract
Obesity is a major public health issue with an increasing prevalence worldwide. Excess body fat is associated with various comorbidities, as well as increased overall mortality risk. The benefits of weight loss are evident by the reductions in morbidity and mortality. The foundation for most weight loss programs involves strict lifestyle modification, including dietary change and exercise. Unfortunately, many individuals struggle with weight loss and chronic weight management due to difficulty adhering to long-term lifestyle modification and the metabolic adaptations that promote weight regain. The use of adjunctive pharmacotherapy has been employed to help patients not only achieve greater weight loss than lifestyle modification alone but also to assist with long-term weight management. Historically, antiobesity drugs have produced only modest weight loss and required at least once daily administration. Glucagon-like peptide-1 (GLP-1), a hormone with significant effects on glycemic control and weight regulation, has been explored for use as adjunctive pharmacotherapy for weight loss. Semaglutide, a GLP-1 receptor agonist, was recently approved by the Food and Drug Administration for chronic weight management in adults with obesity or who are overweight. The approval came after the publication of the Semaglutide Treatment Effect in People with Obesity clinical trials. In these 68-week trials, semaglutide 2.4 mg was associated with significantly greater weight loss compared to placebo. Semaglutide differs from other GLP-1 receptor agonists by having a longer half-life and producing greater weight loss. This article provides an overview of the discovery and mechanism of action of semaglutide 2.4 mg, and the clinical trials that led to its approval.
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Affiliation(s)
- Joel Novograd
- From the New York Medical College (student) Valhalla, NY
| | - Jaime Mullally
- Department of Medicine, Division of Endocrinology, New York Medical College/Westchester Medical Center, Valhalla, NY
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The In Vitro Inhibitory Effect of Selected Asteraceae Plants on Pancreatic Lipase Followed by Phenolic Content Identification through Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS). Int J Mol Sci 2022; 23:ijms231911204. [PMID: 36232503 PMCID: PMC9569725 DOI: 10.3390/ijms231911204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Revised: 09/12/2022] [Accepted: 09/19/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic lipase (PNLIP, EC 3.1.1.3) plays a pivotal role in the digestion of dietary lipids, a metabolic pathway directly related to obesity. One of the effective strategies in obesity treatment is the inhibition of PNLIP, which is possible to be achieved by specific phenolic compounds occurring in high abundance in some plants. In this study, a multidisciplinary approach is presented investigating the PNLIP inhibitory effect of 33 plants belonging in the Asteraceae botanical family. In the first stage of the study, a rapid and cost-efficient PNLIP assay in a 96-microwell plate format was developed and important parameters were optimized, e.g., the enzyme substrate. Upon PNLIP assay optimization, aqueous and dichloromethane Asteraceae plant extracts were tested and a cut-off inhibition level was set to further analyze only the samples with a significant inhibitory effect (inhibitory rate > 40%), using an ultra-high-performance liquid chromatography hybrid quadrupole time-of-flight mass spectrometry (UHPLC-q-TOF-MS) method. Specifically, a metabolomic suspect screening was performed and 69 phenolic compounds were tentatively identified, including phenolic acids, flavonoids, flavonoid-3-O-glycosides, and flavonoid-7-O-glycosides, amongst others. In the case of aqueous extracts, phytochemicals known for inducing PNLIP inhibitory effect, e.g., compounds containing galloyl molecules or caffeoylquinic acids, were monitored in Chrysanthemum morifolium, Grindella camporum and Hieracium pilosella extracts. All in all, the presented approach combines in vitro bioactivity measurements to high-end metabolomics to identify phenolic compounds with potential medicinal and/or dietary applications.
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Anti-obesity weight loss medications: Short-term and long-term use. Life Sci 2022; 306:120825. [PMID: 35870619 DOI: 10.1016/j.lfs.2022.120825] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/21/2022]
Abstract
As obesity prevalence increases, more and more drugs that assist with weight loss have been developed. Numerous weight loss drugs had been approved, but many have also been withdrawn based on their lack of efficacy as well as safety concerns. Initial approaches in developing weight loss drugs was by increasing physiological energy expenditure and suppressing the appetite. Subsequently, as more physiological mechanisms for weight gain has been unearthed, drugs targeting newly discovered receptors and/or enzymes have been introduced with improved safety profiles and fewer psychological adverse events. Additionally, drugs targeting hunger or satiety signaling have been actively studied, and have shown increased adoption by physicians. Studies have also evaluated drugs that target metabolic tissues-such as adipose tissue or muscle-to promote weight loss, however to-date nothing has carried on into clinical practice. Starting with a brief history of early obesity treatments, this review evaluates current weight loss pharmaceutical options based on their duration of therapy status.
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Ferrulli A, Terruzzi I, Senesi P, Succi M, Cannavaro D, Luzi L. Turning the clock forward: New pharmacological and non pharmacological targets for the treatment of obesity. Nutr Metab Cardiovasc Dis 2022; 32:1320-1334. [PMID: 35354547 DOI: 10.1016/j.numecd.2022.02.016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 11/26/2022]
Abstract
AIMS Obesity and its main metabolic complication, type 2 diabetes, have attained the status of a global pandemic; there is need for novel strategies aimed at treating obesity and preventing the development of diabetes. A healthy diet and exercise are basic for treatment of obesity but often not enough. Pharmacotherapy can be helpful in maintaining compliance, ameliorating obesity-related health risks, and improving quality of life. In the last two decades, the knowledge of central and peripheral mechanisms underlying homeostatic and hedonic aspects of food intake has significantly increased. Dysregulation of one or more of these components could lead to obesity. DATA SYNTHESIS In order to better understand how potential innovative treatment options can affect obesity, homeostatic and reward mechanisms that regulate energy balance has been firstly illustrated. Then, an overview of potential therapeutic targets for obesity, distinguished according to the level of regulation of feeding behavior, has been provided. Moreover, several non-drug therapies have been recently tested in obesity, such as non-invasive neurostimulation: Transcranial Magnetic Stimulation or Transcranial Direct Current Stimulation. All of them are promising for obesity treatment and are almost devoid of side effects, constituting a potential resource for the prevention of metabolic diseases. CONCLUSIONS The plethora of current anti-obesity therapies creates the unique challenge for physicians to customize the intervention, according to the specific obesity characteristics and the intervention side effect profiles; moreover, it allows multimodal approaches addressed to treat obesity and metabolic adaptation with complementary mechanisms.
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Affiliation(s)
- Anna Ferrulli
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Ileana Terruzzi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Pamela Senesi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Massimiliano Succi
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Daniele Cannavaro
- Department of Biomedical Sciences for Health, University of Milan, Milan, Italy
| | - Livio Luzi
- Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Sesto San Giovanni, MI, Italy; Department of Biomedical Sciences for Health, University of Milan, Milan, Italy.
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The Role of Glp-1 Receptor Agonists in Insulin Resistance with Concomitant Obesity Treatment in Polycystic Ovary Syndrome. Int J Mol Sci 2022; 23:ijms23084334. [PMID: 35457152 PMCID: PMC9029608 DOI: 10.3390/ijms23084334] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 02/01/2023] Open
Abstract
Insulin resistance is documented in clamp studies in 75% of women with polycystic ovary syndrome (PCOS). Although it is not included in the diagnostic criteria of PCOS, there is a crucial role of this metabolic impairment, which along with hormonal abnormalities, increase each other in a vicious circle of PCOS pathogenesis. Insulin resistance in this group of patients results from defects at the molecular level, including impaired insulin receptor-related signaling pathways enhanced by obesity and its features: Excess visceral fat, chronic inflammation, and reactive oxygen species. While lifestyle intervention has a first-line role in the prevention and management of excess weight in PCOS, the role of anti-obesity pharmacological agents in achieving and maintaining weight loss is being increasingly recognized. Glucagon-like peptide-1 receptor agonists (GLP1-RAs) not only act by reducing body weight but also can affect the mechanisms involved in insulin resistance, like an increasing expression of glucose transporters in insulin-dependent tissues, decreasing inflammation, reducing oxidative stress, and modulating lipid metabolism. They also tend to improve fertility either by increasing LH surge in hypothalamus-pituitary inhibition due to estrogen excess connected with obesity or decreasing too high LH levels accompanying hyperinsulinemia. GLP1-RAs seem promising for effective treatment of obese PCOS patients, acting on one of the primary causes of PCOS at the molecular level.
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Janssen LK, Horstmann A. Molecular Imaging of Central Dopamine in Obesity: A Qualitative Review across Substrates and Radiotracers. Brain Sci 2022; 12:486. [PMID: 35448017 PMCID: PMC9031606 DOI: 10.3390/brainsci12040486] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 04/05/2022] [Accepted: 04/06/2022] [Indexed: 02/04/2023] Open
Abstract
Dopamine is a neurotransmitter that plays a crucial role in adaptive behavior. A wealth of studies suggests obesity-related alterations in the central dopamine system. The most direct evidence for such differences in humans comes from molecular neuroimaging studies using positron emission tomography (PET) and single-photon emission computed tomography (SPECT). The aim of the current review is to give a comprehensive overview of molecular neuroimaging studies that investigated the relation between BMI or weight status and any dopamine target in the striatal and midbrain regions of the human brain. A structured literature search was performed and a summary of the extracted findings are presented for each of the four available domains: (1) D2/D3 receptors, (2) dopamine release, (3) dopamine synthesis, and (4) dopamine transporters. Recent proposals of a nonlinear relationship between severity of obesity and dopamine imbalances are described while integrating findings within and across domains, after which limitations of the review are discussed. We conclude that despite many observed associations between obesity and substrates of the dopamine system in humans, it is unlikely that obesity can be traced back to a single dopaminergic cause or consequence. For effective personalized prevention and treatment of obesity, it will be crucial to identify possible dopamine (and non-dopamine) profiles and their functional characteristics.
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Affiliation(s)
- Lieneke Katharina Janssen
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany;
- Institute of Psychology, Otto von Guericke University Magdeburg, 39106 Magdeburg, Germany
| | - Annette Horstmann
- Department of Neurology, Max Planck Institute for Human Cognitive and Brain Sciences, 04103 Leipzig, Germany;
- Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, 00014 Helsinki, Finland
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Barritt AS, Marshman E, Noureddin M. Review article: role of glucagon-like peptide-1 receptor agonists in non-alcoholic steatohepatitis, obesity and diabetes-what hepatologists need to know. Aliment Pharmacol Ther 2022; 55:944-959. [PMID: 35266164 PMCID: PMC9310586 DOI: 10.1111/apt.16794] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/13/2022] [Accepted: 01/14/2022] [Indexed: 02/06/2023]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH) is characterised by hepatic lipid accumulation, cell injury, inflammation and fibrosis. Insulin resistance, a hallmark of type 2 diabetes (T2D) and obesity, is a key pathogenic driver of NASH. Other than difficult-to-maintain lifestyle changes, there are no approved treatments for NASH. Due to their effects on multiple pathophysiological processes, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been tested in disorders related to insulin resistance and metabolic defects. AIMS To summarise studies of GLP-1RAs relevant to the treatment of NASH. METHODS PubMed searches were performed and results were compiled. RESULTS Large trials with GLP-1RAs in T2D demonstrate highly effective glucose lowering, with body weight loss, and in some cases, reduced cardiovascular events and improved liver transaminases. The GLP-1RAs, liraglutide and semaglutide, were associated with clinically relevant, sustained body weight reduction in individuals with overweight or obesity and without T2D. In a phase II trial in NASH, liraglutide reduced metabolic dysfunction, insulin resistance and lipotoxicity in key organs associated with NASH pathogenesis. Furthermore, liraglutide and semaglutide led to histological resolution of NASH in ~40% to 60% of patients, although a statistically significant effect on fibrosis has not been confirmed. Regarding safety, GLP-1RAs are associated with gastrointestinal and gallbladder-related adverse events, with the latter perhaps related to weight loss. Meta-analyses do not indicate increased risk of acute pancreatitis, pancreatic cancer or other malignancies with GLP-1RAs. CONCLUSIONS These studies support the use of GLP-1RAs for the improvement of underlying metabolic dysfunction observed in NASH and suggest further long-term phase III trials are warranted.
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Affiliation(s)
- A. Sidney Barritt
- Division of Gastroenterology and Hepatology, UNC Liver CenterUniversity of North Carolina at Chapel HillChapel HillNCUSA
| | | | - Mazen Noureddin
- Department of MedicineCedars‐Sinai Medical CenterLos AngelesCAUSA
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Chen T, Sun T, Bian Y, Pei Y, Feng F, Chi H, Li Y, Tang X, Sang S, Du C, Chen Y, Chen Y, Sun H. The Design and Optimization of Monomeric Multitarget Peptides for the Treatment of Multifactorial Diseases. J Med Chem 2022; 65:3685-3705. [DOI: 10.1021/acs.jmedchem.1c01456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Tingkai Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Tianyu Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Yaoyao Bian
- College of Acupuncture and Massage, College of Regimen and Rehabilitation, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Yuqiong Pei
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Feng Feng
- Food and Pharmaceutical Research Institute, Jiangsu Food and Pharmaceuticals Science College, Huaian 223003, People’s Republic of China
| | - Heng Chi
- Food and Pharmaceutical Research Institute, Jiangsu Food and Pharmaceuticals Science College, Huaian 223003, People’s Republic of China
| | - Yuan Li
- Department of Pharmaceutical Engineering, Jiangsu Food and Pharmaceuticals Science College, Huaian 223005, People’s Republic of China
| | - Xu Tang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Shenghu Sang
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Chenxi Du
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Ying Chen
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
| | - Yao Chen
- School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, People’s Republic of China
| | - Haopeng Sun
- School of Pharmacy, China Pharmaceutical University, Nanjing 211198, People’s Republic of China
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Discriminative stimulus effects of an imidazolidine-derived appetite suppressant. Med Chem Res 2022. [DOI: 10.1007/s00044-022-02853-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Del Prato S, Gallwitz B, Holst JJ, Meier JJ. The incretin/glucagon system as a target for pharmacotherapy of obesity. Obes Rev 2022; 23:e13372. [PMID: 34713962 PMCID: PMC9286339 DOI: 10.1111/obr.13372] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/14/2022]
Abstract
Obesity is a chronic, multifactorial, relapsing disease. Despite multicomponent lifestyle interventions, including pharmacotherapy, maintaining bodyweight loss is challenging for many people. The pathophysiology of obesity is complex, and currently approved pharmacotherapies only target a few of the many pathways involved; thus, single-targeting agents have limited efficacy. Proglucagon-derived peptides, glucagon, and the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), represent attractive targets for managing obesity and metabolic disorders because they may have direct roles in multiple mechanisms including satiety, energy homeostasis, and lipolytic activity. Unimolecular dual and triple agonists targeting glucagon and incretin hormone receptors have been shown to promote bodyweight loss, lower glucose levels, and reduce food intake in animal models of obesity. Multiple dual receptor agonists are in clinical development for the treatment of obesity, including GLP-1/GIP and GLP-1/glucagon receptor agonists. The extent to which glucagon contributes to treatment effects remains to be understood, but it may promote bodyweight loss by reducing food intake, while concomitant GLP-1 receptor agonism ensures normal glucose control. Further research is required to fully understand the molecular mechanisms of action and metabolic effects of both dual and triple receptor agonists.
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Affiliation(s)
- Stefano Del Prato
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | - Baptist Gallwitz
- Department of Internal Medicine IVEberhard Karls UniversityTübingenGermany
- Institute for Diabetes Research and Metabolic Diseases of the Helmholtz Center MunichUniversity of TübingenTübingenGermany
| | - Jens Juul Holst
- Department of Biomedical Sciences, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Juris J. Meier
- Division of Diabetology, Katholisches Klinikum Bochum, St. Josef HospitalRuhr UniversityBochumGermany
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Ugwoke CK, Cvetko E, Umek N. Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives. Int J Mol Sci 2022; 23:ijms23020847. [PMID: 35055038 PMCID: PMC8778410 DOI: 10.3390/ijms23020847] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/09/2022] [Accepted: 01/11/2022] [Indexed: 02/04/2023] Open
Abstract
Obesity is a worrisomely escalating public health problem globally and one of the leading causes of morbidity and mortality from noncommunicable disease. The epidemiological link between obesity and a broad spectrum of cardiometabolic disorders has been well documented; however, the underlying pathophysiological mechanisms are only partially understood, and effective treatment options remain scarce. Given its critical role in glucose metabolism, skeletal muscle has increasingly become a focus of attention in understanding the mechanisms of impaired insulin function in obesity and the associated metabolic sequelae. We examined the current evidence on the relationship between microvascular dysfunction and insulin resistance in obesity. A growing body of evidence suggest an intimate and reciprocal relationship between skeletal muscle microvascular and glucometabolic physiology. The obesity phenotype is characterized by structural and functional changes in the skeletal muscle microcirculation which contribute to insulin dysfunction and disturbed glucose homeostasis. Several interconnected etiologic molecular mechanisms have been suggested, including endothelial dysfunction by several factors, extracellular matrix remodelling, and induction of oxidative stress and the immunoinflammatory phenotype. We further correlated currently available pharmacological agents that have deductive therapeutic relevance to the explored pathophysiological mechanisms, highlighting a potential clinical perspective in obesity treatment.
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Yang ZY, Wu YY, Zhou Y, Yang YQ, Zhang JH, He T, Liu S. N-linoleyltyrosine ameliorates high-fat diet-induced obesity in C57BL/6 mice via cannabinoid receptor regulation. Front Endocrinol (Lausanne) 2022; 13:938527. [PMID: 36111301 PMCID: PMC9468927 DOI: 10.3389/fendo.2022.938527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 08/05/2022] [Indexed: 11/23/2022] Open
Abstract
OBJECTIVES N-linoleyltyrosine (NITyr) showed mild effects in preclinical studies. The research discussed the effect of NITyr on a high-fat diet (HFD) induced obese (DIO) mice, and preliminarily explored its mechanism. METHODS The DIO mice were established by feeding an HFD for 12 weeks and subsequently administrated orally with NITyr (30, 60 and 100 mg/kg) for four weeks. The indexes of serum and liver samples were determined by ELISA kit. The pathological status of adipose and liver were detected by HE staining. The factors related to energy and lipid metabolism were measured via western blot. RESULTS NITyr at 60 and 100 mg/kg/day suppressed the weight gain without affecting water and food intake. Accordingly, NITyr reduced adipose weight and the area of individual adipocytes and increased the number of adipocytes. Moreover, NITyr didn't affect the appetite-related indexes such as ghrelin, peptide YY and brain-derived neurotrophic factor. Besides, NITyr didn't affect other organ coefficients except for the liver. Correspondingly, NITyr reduced alanine aminotransferase and aspartate aminotransferase levels, yet didn't influence IL-1β and TNF-α levels, and the liver injury. The levels of triacylglycerol (TG), total cholesterol (TC), glucose, insulin, adiponectin and leptin in serum were assessed to evaluate the effect of NITyr on glucose and lipid metabolism. NITyr decreased the levels of TG, TC and glucose, and didn't affect insulin, adiponectin and leptin levels. Meanwhile, NITyr up-regulated p-AMPK and the cannabinoid receptor 2 (CB2) expressions, and down-regulated PPAR, FAS and cannabinoid receptor 1 (CB1) expressions.Overall, NITyr suppressed lipid accumulation via improving lipid and glucose metabolism involving CB1 and CB2 receptors.
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Affiliation(s)
- Zheng-yu Yang
- Department of Pharmacy, Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, China
| | - Yi-ying Wu
- Department of Pharmacy, Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, China
| | - Yi Zhou
- Research and Development Center, Sichuan Yuanda Shuyang Pharmaceutical Co., Ltd, Chengdu, China
| | - Yun-qi Yang
- Department of Pharmacy, Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, China
| | - Jia-hui Zhang
- Department of Pharmacy, Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, China
| | - Tao He
- Department of Thoracic Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
- *Correspondence: Sha Liu, ; Tao He,
| | - Sha Liu
- Department of Pharmacy, Sichuan Province College Key Laboratory, Chengdu Medical College, Chengdu, China
- Department of Thoracic Surgery, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
- *Correspondence: Sha Liu, ; Tao He,
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Huang J, Pham M, Panenka WJ, Honer WG, Barr AM. Chronic Treatment With Psilocybin Decreases Changes in Body Weight in a Rodent Model of Obesity. Front Psychiatry 2022; 13:891512. [PMID: 35664477 PMCID: PMC9157591 DOI: 10.3389/fpsyt.2022.891512] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/27/2022] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND There are currently relatively few effective pharmacological treatments for obesity, and existing ones may be associated with limiting side-effects. In the search for novel anti-obesity agents, drugs that modify central serotonergic systems have historically proven to be effective in promoting weight loss. Psilocin, which is rapidly metabolized from psilocybin, is an agonist at multiple serotonin receptors. In the present study we assessed the effects of psilocybin and a positive control (metformin) on changes in body weight in a rat model of obesity. METHODS Five groups of adult male rats were pre-conditioned with a cafeteria diet until obese (>600 g) and then treated with either psilocybin (0.1, 1, or 5 mg/kg, i.p.), metformin (300 mg/kg, p.o.) or vehicle control. Treatments were for 27 consecutive weekdays, and body weights and high calorie food intake were recorded daily. Fasting glucose levels were recorded after 11 days of treatment. At the end of treatment rats completed a glucose tolerance test, and multiple fat pads were dissected out to assess adiposity. RESULTS The medium dose psilocybin group had to be terminated from the study prematurely. Both the low and high dose psilocybin groups caused a significant decrease in changes in body weight compared to controls. The metformin group produced a greater decrease in change in body weight than either psilocybin groups or controls. Both high dose psilocybin and metformin decreased consumption of the high calorie diet, and exhibited decreased central adiposity. CONCLUSION Psilocybin demonstrated modest but significant effects on weight gain. Further study is recommended.
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Affiliation(s)
- Joyce Huang
- Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - Michelle Pham
- Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada
| | - William J Panenka
- Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.,British Columbia Mental Health & Substance Use Services Research Institute, Vancouver, BC, Canada
| | - William G Honer
- Department of Psychiatry, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.,British Columbia Mental Health & Substance Use Services Research Institute, Vancouver, BC, Canada
| | - Alasdair M Barr
- Department of Anesthesiology, Pharmacology and Therapeutics, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.,British Columbia Mental Health & Substance Use Services Research Institute, Vancouver, BC, Canada
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Dimitri P. Treatment of Acquired Hypothalamic Obesity: Now and the Future. Front Endocrinol (Lausanne) 2022; 13:846880. [PMID: 35464063 PMCID: PMC9019363 DOI: 10.3389/fendo.2022.846880] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
The hypothalamus is the centre of neuroendocrine regulation of energy homeostasis and appetite. Maldevelopment of, or damage to, the key hypothalamic nuclei disrupts the coordinated balance between energy intake and expenditure leading, to rapid and excessive weight gain. Hypothalamic obesity is compounded by a disruption of the hypothalamic-pituitary axis, sleep disruption, visual compromise, and neurological and vascular sequalae. Amongst suprasellar tumors, craniopharyngioma is the most common cause of acquired hypothalamic obesity, either directly or following surgical or radiotherapeutic intervention. At present, therapy is limited to strategies to manage obesity but with a modest and variable impact. Current approaches include optimizing pituitary hormone replacement, calorie restriction, increased energy expenditure through physical activity, behavioral interventions, pharmacotherapy and bariatric surgery. Current pharmacotherapeutic approaches include stimulants that increase energy consumption, anti-diabetic agents, hypothalamic-pituitary substitution therapy, octreotide, and methionine aminopeptidase 2 (MetAP2) inhibitors. Some pharmacological studies of hypothalamic obesity report weight loss or stabilization but reported intervention periods are short, and others report no effect. The impact of bariatric surgery on weight loss in hypothalamic obesity again is variable. Novel or combined approaches to manage hypothalamic obesity are thus required to achieve credible and sustained weight loss. Identifying etiological factors contributing hypothalamic obesity may lead to multi-faceted interventions targeting hyperphagia, insulin resistance, decreased energy expenditure, sleep disturbance, hypopituitarism and psychosocial morbidity. Placebo-controlled trials using current single, or combination therapies are required to determine the impact of therapeutic agents. A well-defined approach to defining the location of hypothalamic damage may support the use of future targeted therapies. Intranasal oxytocin is currently being investigated as an anorexogenic agent. Novel agents including those targeting pro-opimelanocortin-C and AgRP/NPY expressing neurons and the MC4 receptor may result in better outcomes. This article discusses the current challenges in the management of hypothalamic obesity in children and young people and future therapeutic approaches to increasing weight loss and quality of life in these patients.
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Affiliation(s)
- Paul Dimitri
- The Department of Paediatric Endocrinology, Sheffield Children’s NHS Foundation Trust, Sheffield, United Kingdom
- College of Health, Wellbeing and Life Sciences, Sheffield Hallam University, Sheffield, United Kingdom
- *Correspondence: Paul Dimitri,
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A Single Dose of Ginkgo biloba Extract Induces Gene Expression of Hypothalamic Anorexigenic Effectors in Male Rats. Brain Sci 2021; 11:brainsci11121602. [PMID: 34942904 PMCID: PMC8699374 DOI: 10.3390/brainsci11121602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/29/2021] [Accepted: 10/29/2021] [Indexed: 11/17/2022] Open
Abstract
Previous studies have shown that Ginkgo biloba extract (GbE) reduces food intake and body mass gain and regulates proteins related to lipid metabolism in obese rats. In ovariectomized rats, GbE restored the hippocampal and hypothalamic serotonergic system activity, favoring the spontaneous feeding decrement. Considering the promising hypophagic effect of GbE, this study aimed to investigate the effect of a single acute dose on hypothalamic pathways that regulate feeding behavior in male rats. Four-month-old Wistar male rats received either a single acute oral GbE dose (500 mg/kg) or vehicle. Food intake and body mass were measured after 1, 4, 12, and 24 h. Rats were euthanized, and hypothalami were removed for mRNA quantification of anorexigenic (POMC/CART) and orexigenic (AgRP/NPY) neuropeptides, leptin/serotonin receptors (5HT1A, 5HT1B, 5HT2C), and serotonin transporters. We also investigated POMC, 5-HT1B, and 5-HT2C protein levels. A single acute GbE dose induced the hypothalamic POMC, CART, and 5-HT2C gene expression but failed to modify orexigenic effectors. No alterations in food intake, body mass, and hypothalamic protein levels were observed. In summary, the present findings demonstrate the rapid stimulation of pivotal hypothalamic anorexigenic pathways in response to a single GbE administration, reinforcing the GbE hypophagic activity. However, more studies are necessary to evaluate its potential as an appetite modulator.
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Munafò A, Frara S, Perico N, Di Mauro R, Cortinovis M, Burgaletto C, Cantarella G, Remuzzi G, Giustina A, Bernardini R. In search of an ideal drug for safer treatment of obesity: The false promise of pseudoephedrine. Rev Endocr Metab Disord 2021; 22:1013-1025. [PMID: 33945051 PMCID: PMC8724077 DOI: 10.1007/s11154-021-09658-w] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/27/2021] [Indexed: 12/14/2022]
Abstract
Obesity is a major public health problem worldwide. Only relatively few treatment options are, at present, available for the management of obese patients. Furthermore, treatment of obesity is affected by the widespread misuse of drugs and food supplements. Ephedra sinica is an old medicinal herb, commonly used in the treatment of respiratory tract diseases. Ephedra species contain several alkaloids, including pseudoephedrine, notably endowed with indirect sympathomimetic pharmacodynamic properties. The anorexigenic effect of pseudoephedrine is attributable primarily to the inhibition of neurons located in the hypothalamic paraventricular nucleus (PVN), mediating satiety stimuli. Pseudoephedrine influences lipolysis and thermogenesis through interaction with β3 adrenergic receptors and reduces fat accumulation through down-regulation of transcription factors related to lipogenesis. However, its use is associated with adverse events that involve to a large extent the cardiovascular and the central nervous system. Adverse events of pseudoephedrine also affect the eye, the intestine, and the skin, and, of relevance, sudden cardiovascular death related to dietary supplements containing Ephedra alkaloids has also been reported. In light of the limited availability of clinical data on pseudoephedrine in obesity, along with its significantly unbalanced risk/benefit profile, as well as of the psychophysical susceptibility of obese patients, it appears reasonable to preclude the prescription of pseudoephedrine in obese patients of any order and degree.
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Affiliation(s)
- Antonio Munafò
- Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy
| | - Stefano Frara
- Institute of Endocrine and Metabolic Sciences (IEMS), San Raffaele Vita-Salute University, Milano, Milano, Italy
| | - Norberto Perico
- Istituto Di Ricerche Farmacologiche "Mario Negri", Bergamo, Italy
| | - Rosaria Di Mauro
- Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy
| | | | - Chiara Burgaletto
- Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy
| | - Giuseppina Cantarella
- Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy
| | - Giuseppe Remuzzi
- Istituto Di Ricerche Farmacologiche "Mario Negri", Bergamo, Italy
| | - Andrea Giustina
- Institute of Endocrine and Metabolic Sciences (IEMS), San Raffaele Vita-Salute University, Milano, Milano, Italy
| | - Renato Bernardini
- Department of Biomedical and Biotechnological Sciences, University of Catania School of Medicine, Catania, Italy.
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