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Jeczmien-Lazur JS, Sanetra AM, Pradel K, Izowit G, Chrobok L, Palus-Chramiec K, Piggins HD, Lewandowski MH. Metabolic cues impact non-oscillatory intergeniculate leaflet and ventral lateral geniculate nucleus: standard versus high-fat diet comparative study. J Physiol 2023; 601:979-1016. [PMID: 36661095 DOI: 10.1113/jp283757] [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: 08/19/2022] [Accepted: 01/12/2023] [Indexed: 01/21/2023] Open
Abstract
The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) are subcortical structures involved in entrainment of the brain's circadian system to photic and non-photic (e.g. metabolic and arousal) cues. Both receive information about environmental light from photoreceptors, exhibit infra-slow oscillations (ISO) in vivo, and connect to the master circadian clock. Although current evidence demonstrates that the IGL/VLG communicate metabolic information and are crucial for entrainment of circadian rhythms to time-restricted feeding, their sensitivity to food intake-related peptides has not been investigated yet. We examined the effect of metabolically relevant peptides on the spontaneous activity of IGL/VLG neurons. Using ex vivo and in vivo electrophysiological recordings as well as in situ hybridisation, we tested potential sensitivity of the IGL/VLG to anorexigenic and orexigenic peptides, such as cholecystokinin, glucagon-like peptide 1, oxyntomodulin, peptide YY, orexin A and ghrelin. We explored neuronal responses to these drugs during day and night, and in standard vs. high-fat diet conditions. We found that IGL/VLG neurons responded to all the substances tested, except peptide YY. Moreover, more neurons responded to anorexigenic drugs at night, while a high-fat diet affected the IGL/VLG sensitivity to orexigenic peptides. Interestingly, ISO neurons responded to light and orexin A, but did not respond to the other food intake-related peptides. In contrast, non-ISO cells were activated by metabolic peptides, with only some being responsive to light. Our results show for the first time that peptides involved in the body's energy homeostasis stimulate the thalamus and suggest functional separation of the IGL/VLG cells. KEY POINTS: The intergeniculate leaflet and ventral lateral geniculate nucleus (IGL/VLG) of the rodent thalamus process various signals and participate in circadian entrainment. In both structures, cells exhibiting infra-slow oscillatory activity as well as non-rhythmically firing neurons being observed. Here, we reveal that only one of these two groups of cells responds to anorexigenic (cholecystokinin, glucagon-like peptide 1 and oxyntomodulin) and orexigenic (ghrelin and orexin A) peptides. Neuronal responses vary depending on the time of day (day vs. night) and on the diet (standard vs. high-fat diet). Additionally, we visualised receptors to the tested peptides in the IGL/VLG using in situ hybridisation. Our results suggest that two electrophysiologically different subpopulations of IGL/VLG neurons are involved in two separate functions: one related to the body's energy homeostasis and one associated with the subcortical visual system.
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Affiliation(s)
- Jagoda S Jeczmien-Lazur
- Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
| | - Anna M Sanetra
- Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
| | - Kamil Pradel
- Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
| | - Gabriela Izowit
- Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
| | - Lukasz Chrobok
- Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland.,School of Physiology, Pharmacology, and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Katarzyna Palus-Chramiec
- Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
| | - Hugh D Piggins
- School of Physiology, Pharmacology, and Neuroscience, Faculty of Life Sciences, University of Bristol, Bristol, UK
| | - Marian H Lewandowski
- Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University in Krakow, Krakow, Poland
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Khalil HE, Abdelwahab MF, Ibrahim HIM, AlYahya KA, Altaweel AA, Alasoom AJ, Burshed HA, Alshawush MM, Waz S. Cichoriin, a Biocoumarin, Mitigates Oxidative Stress and Associated Adverse Dysfunctions on High-Fat Diet-Induced Obesity in Rats. Life (Basel) 2022; 12:1731. [PMID: 36362887 PMCID: PMC9694194 DOI: 10.3390/life12111731] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Revised: 10/18/2022] [Accepted: 10/24/2022] [Indexed: 08/27/2023] Open
Abstract
Metabolic dysfunctions linked to obesity carry the risk of co-morbidities such as diabetes, hepatorenal, and cardiovascular diseases. Coumarins are believed to display several biological effects on diverse adverse health conditions. This study was conducted to uncover the impact of cichoriin on high-fat diet (HFD)-induced obese rats. Methods: Obesity was induced in twenty rats by exposure to an HFD for six weeks. The rats were randomly divided into five groups; group I comprised five healthy rats and was considered the control one. On the other hand, the HFD-induced rats were divided into the following (five per each group): group II (the HFD group), groups III (cichoriin 50 mg/kg) and IV (cichoriin 100 mg/kg) as the treatment groups, and group V received atorvastatin (10 mg/kg) (as a standard). Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT), aspartate transaminase (AST), creatine kinase MB (CK-MB), urea, creatinine, the hepatic and renal malondialdehyde (MDA) as well as reduced glutathione (GSH) levels were assessed. Histopathological analysis of the heart, kidney, and liver tissues was investigated. mRNA and protein expressions of the peroxisome proliferator-activated receptor gamma (PPAR-γ) were estimated. Results: The administration of cichoriin alleviated HFD-induced metabolic dysfunctions and improved the histopathological characteristics of the heart, kidney, and liver. Additionally, the treatment improved the lipid profile and hepatic and renal functions, as well as the oxidative balance state. Cichoriin demonstrated an upregulation of the mRNA and protein expressions of PPAR-γ. Taken together, these findings are the first report on the beneficial role of cichoriin in alleviating adverse metabolic effects in HFD-induced obesity and adapting it into an innovative obesity management strategy.
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Affiliation(s)
- Hany Ezzat Khalil
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Miada F. Abdelwahab
- Department of Pharmacognosy, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Hairul-Islam Mohamed Ibrahim
- Department of Biological Sciences, College of Science, King Faisal University, Al-Ahsa 31982, Saudi Arabia
- Pondicherry Centre for Biological Science and Educational Trust, Puducherry 605004, India
| | - Khalid A. AlYahya
- Department of Surgery, College of Medicine, King Faisal University, Al-Ahsa 36363, Saudi Arabia
| | - Abdullah Abdulhamid Altaweel
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Abdullah Jalal Alasoom
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Hussein Ali Burshed
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Marwan Mohamed Alshawush
- Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa 31982, Saudi Arabia
| | - Shaimaa Waz
- Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia 61511, Egypt
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Azlan A, Sultana S, Huei CS, Razman MR. Antioxidant, Anti-Obesity, Nutritional and Other Beneficial Effects of Different Chili Pepper: A Review. Molecules 2022; 27:898. [PMID: 35164163 PMCID: PMC8839052 DOI: 10.3390/molecules27030898] [Citation(s) in RCA: 54] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/25/2022] [Accepted: 01/26/2022] [Indexed: 01/28/2023] Open
Abstract
Fruits and vegetables are important components of a healthy diet. They are rich sources of vitamins and minerals, dietary fibre and a host of beneficial non-nutrient substances including plant sterols, flavonoids and other antioxidants. It has been reported that reduced intake of fruits and vegetables may increase the risk of non-communicable diseases (NCDs). Chili pepper, is a common and important spice used to enhance taste and nutrition. Over the years, reports have shown its potential as antioxidant and an anti-obesity agent. Obesity is a serious health concern as it may initiate other common chronic diseases. Due to the side effects of synthetic antioxidants and anti-obesity drugs, scientists are now focusing on natural products which produce similar effects to synthetic chemicals. This up-to-date review addresses this research gap and presents, in an accessible format, the nutritional, antioxidant and anti-obesity properties of different chili peppers. This review article serves as a reference guide for use of chili peppers as anti-obesity agents.
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Affiliation(s)
- Azrina Azlan
- Department of Nutrition, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia;
- Research Centre of Excellence for Nutrition and Non-Communicable Diseases, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia
- Halal Products Research Institute, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia
| | - Sharmin Sultana
- Grain Quality Testing Laboratory, International Rice Research Institute (IRRI), Dhaka 1213, Bangladesh;
| | - Chan Suk Huei
- Department of Nutrition, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia (UPM), Serdang 43400, Selangor, Malaysia;
| | - Muhammad Rizal Razman
- Research Centre for Sustainability Science and Governance (SGK), Institute for Environment and Development (LESTARI), Universiti Kebangsaan Malaysia (UKM), Bangi 43600, Selangor, Malaysia
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Ke W, Reed JN, Yang C, Higgason N, Rayyan L, Wählby C, Carpenter AE, Civelek M, O’Rourke EJ. Genes in human obesity loci are causal obesity genes in C. elegans. PLoS Genet 2021; 17:e1009736. [PMID: 34492009 PMCID: PMC8462697 DOI: 10.1371/journal.pgen.1009736] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2021] [Revised: 09/24/2021] [Accepted: 07/23/2021] [Indexed: 12/13/2022] Open
Abstract
Obesity and its associated metabolic syndrome are a leading cause of morbidity and mortality. Given the disease's heavy burden on patients and the healthcare system, there has been increased interest in identifying pharmacological targets for the treatment and prevention of obesity. Towards this end, genome-wide association studies (GWAS) have identified hundreds of human genetic variants associated with obesity. The next challenge is to experimentally define which of these variants are causally linked to obesity, and could therefore become targets for the treatment or prevention of obesity. Here we employ high-throughput in vivo RNAi screening to test for causality 293 C. elegans orthologs of human obesity-candidate genes reported in GWAS. We RNAi screened these 293 genes in C. elegans subject to two different feeding regimens: (1) regular diet, and (2) high-fructose diet, which we developed and present here as an invertebrate model of diet-induced obesity (DIO). We report 14 genes that promote obesity and 3 genes that prevent DIO when silenced in C. elegans. Further, we show that knock-down of the 3 DIO genes not only prevents excessive fat accumulation in primary and ectopic fat depots but also improves the health and extends the lifespan of C. elegans overconsuming fructose. Importantly, the direction of the association between expression variants in these loci and obesity in mice and humans matches the phenotypic outcome of the loss-of-function of the C. elegans ortholog genes, supporting the notion that some of these genes would be causally linked to obesity across phylogeny. Therefore, in addition to defining causality for several genes so far merely correlated with obesity, this study demonstrates the value of model systems compatible with in vivo high-throughput genetic screening to causally link GWAS gene candidates to human diseases.
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Affiliation(s)
- Wenfan Ke
- Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia, United States of America
| | - Jordan N. Reed
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, Virginia, United States of America
| | - Chenyu Yang
- Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia, United States of America
| | - Noel Higgason
- Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia, United States of America
| | - Leila Rayyan
- Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia, United States of America
| | - Carolina Wählby
- Department of Information Technology and SciLifeLab, Uppsala University, Uppsala, Sweden
| | - Anne E. Carpenter
- Imaging Platform, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
| | - Mete Civelek
- Department of Biomedical Engineering, School of Engineering and Applied Science, University of Virginia, Charlottesville, Virginia, United States of America
- Center for Public Health Genomics, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America
| | - Eyleen J. O’Rourke
- Department of Biology, College of Arts and Sciences, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail:
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Venkatakrishnan K, Chiu HF, Wang CK. Extensive review of popular functional foods and nutraceuticals against obesity and its related complications with a special focus on randomized clinical trials. Food Funct 2019; 10:2313-2329. [PMID: 31041963 DOI: 10.1039/c9fo00293f] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Obesity is a multifactorial chronic disease or syndrome mainly caused by an imbalance in energy expenditure and intake. Obesity and its associated complications make it the fifth leading cause of global mortality. The benefits of the current anti-obesity treatment regimen have been marked by high cost and numerous adverse effects. Therefore, many researchers focus on plant-derived/natural products or altered dietary patterns for the management of obesity and its related complications (co-morbidities). Several epidemiological studies have confirmed that the consumption of functional foods/nutraceuticals could considerably lower the risk of various chronic diseases, like obesity, diabetic mellitus, and cancer, but the underpinning mechanism is still unclear. This comprehensive review briefs on the prevalence of obesity, the complications related to obesity, the current treatment regimen and the importance of functional foods and nutraceuticals (molecular mechanism) for the management of body weight and alleviation of its co-morbid conditions. This is the first comprehensive review revealing the in-depth anti-obesity mechanisms of various popular functional foods and nutraceuticals with a special reference to randomized clinical trials (RCTs). Overall, this contribution highlights the importance and beneficial role of functional foods/nutraceuticals on weight management (anti-obesity) and their contributions to the current treatment status, especially related to clinical trials, which could help in the development of novel functional foods/nutraceuticals for combatting obesity and its co-morbidities.
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Affiliation(s)
- Kamesh Venkatakrishnan
- School of Nutrition, Chung Shan Medical University, 110, Sec. 1, Jianguo North Road, Taichung City-40201, TaiwanRepublic of China.
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Khodeer DM, Bilasy SE, Farag NE, Mehana AE, Elbaz AA. Sitagliptin protects diabetic rats with acute myocardial infarction through induction of angiogenesis: role of IGF-1 and VEGF. Can J Physiol Pharmacol 2019; 97:1053-1063. [PMID: 31116952 DOI: 10.1139/cjpp-2018-0670] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Angiogenesis is regulated in a tissue-specific manner in all patients, especially those with diabetes. In this study, we describe a novel molecular pathway of angiogenesis regulation in diabetic rats with myocardial infarction (MI) and examine the cardioprotective effects of different doses of sitagliptin. Male rats were divided into 5 groups: normal vehicle group, diabetic group, diabetic + MI, diabetic + MI + 5 mg/kg sitagliptin, and diabetic + MI + 10 mg/kg sitagliptin. Isoproterenol in diabetic rats resulted in significant (p < 0.05) disturbance to the electrocardiogram, cardiac histopathological manifestations, and an increase in inflammatory markers compared with the vehicle and diabetic groups. Treatment with sitagliptin improved the electrocardiogram and histopathological sections, upregulated vascular endothelial growth factor (VEGF) and transmembrane phosphoglycoprotein protein (CD34) in cardiac tissues, and increased serum insulin-like growth factor 1 (IGF-1) and decreased cardiac tissue homogenate for interleukin 6 (IL-6) and cyclooxygenase 2 (COX-2). A relationship was found between serum IGF-1 and cardiac VEGF and CD34 accompanied by an improvement in cardiac function of diabetic rats with MI. Therefore, the observed effects of sitagliptin occurred at least partly through an improvement in angiogenesis and the mitigation of inflammation. Consequently, these data suggest that sitagliptin may contribute, in a dose-dependent manner, to protection against acute MI in diabetic individuals.
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Affiliation(s)
- Dina M Khodeer
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Shymaa E Bilasy
- Department of Biochemistry, Faculty of Pharmacy, Suez Canal University, Ismailia 41522, Egypt
| | - Noha E Farag
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Amir E Mehana
- Department of Zoology, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
| | - Amani A Elbaz
- Department of Physiology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
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Tillner J, Posch MG, Wagner F, Teichert L, Hijazi Y, Einig C, Keil S, Haack T, Wagner M, Bossart M, Larsen PJ. A novel dual glucagon-like peptide and glucagon receptor agonist SAR425899: Results of randomized, placebo-controlled first-in-human and first-in-patient trials. Diabetes Obes Metab 2019; 21:120-128. [PMID: 30091218 DOI: 10.1111/dom.13494] [Citation(s) in RCA: 127] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 07/27/2018] [Accepted: 08/05/2018] [Indexed: 12/11/2022]
Abstract
AIMS To evaluate the safety, pharmacokinetics and pharmacodynamics of SAR425899, a novel polypeptide, active as an agonist at both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCR), in healthy volunteers and in overweight/obese patients with type 2 diabetes (T2D). METHODS Subcutaneous administrations of SAR425899 were tested in two randomized, placebo-controlled, double-blind clinical trials. In the first trial, healthy overweight volunteers (body mass index [BMI] 25-30 kg/m2 ; n = 32) received single-ascending doses (0.01-0.1 mg) of SAR425899 or placebo. In the second, a multiple-ascending-dose trial (NCT02411825), healthy normal- to overweight volunteers (BMI 20-30 kg/m2 ; n = 40) and overweight/obese patients with T2D (BMI 28-42 kg/m2 ; n = 36) received daily doses of SAR425899 or placebo over 21 or 28 days, respectively. RESULTS The most frequently reported adverse events were gastrointestinal; gastrointestinal side effects were less pronounced in patients with T2D compared with healthy volunteers. SAR425899 significantly reduced levels of fasting plasma glucose (P < 0.05 vs. placebo) and glycated haemoglobin (P < 0.001 versus placebo) in patients with T2D. Additionally, SAR425899 led to reductions in body weight, with a maximal reduction of 5.32 kg in healthy volunteers and 5.46 kg in patients with T2D (P < 0.001 vs. placebo) at end of treatment. CONCLUSIONS SAR425899 was well tolerated and led to favourable glycaemic effects in patients with T2D and weight reduction in both healthy volunteers and patients. Whether dual GLP-1R/GCR agonism represents a treatment method that is superior to pure GLP-1R agonists for obesity and diabetes treatment remains to be confirmed.
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Affiliation(s)
| | | | - Frank Wagner
- Charité Research Organisation GmbH, Berlin, Germany
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Xu H, Zhuang X. Atypical antipsychotics-induced metabolic syndrome and nonalcoholic fatty liver disease: a critical review. Neuropsychiatr Dis Treat 2019; 15:2087-2099. [PMID: 31413575 PMCID: PMC6659786 DOI: 10.2147/ndt.s208061] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 07/02/2019] [Indexed: 02/05/2023] Open
Abstract
The atypical antipsychotics (AAPs) have been used as first-line drugs in psychiatric practice for a wide range of psychotic disorders, including schizophrenia and bipolar mania. While effectively exerting therapeutic effects on positive and negative symptoms, as well as cognitive impairments in schizophrenia patients, these drugs are less likely to induce extrapyramidal symptoms compared to typical antipsychotics. However, the increasing application of them has raised questions on their tolerability and adverse effects over the endocrine, metabolic, and cardiovascular axes. Specifically, AAPs are associated to different extents, with weight gain, metabolic syndrome (MetS), and nonalcoholic fatty liver disease (NAFLD). This article summarized clinical evidence showing the metabolic side effects of AAPs in patients with schizophrenia, and experimental evidence of AAPs-induced metabolic side effects observed in animals and cell culture studies. In addition, it discussed potential mechanisms involved in the APPs-induced MetS and NAFLD.
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Affiliation(s)
- Haiyun Xu
- The Mental Health Center, Shantou University Medical College, Shantou, People’s Republic of China
- Correspondence: Haiyun XuThe Mental Health Center, Shantou University Medical College, Shantou 515041, People’s Republic of ChinaEmail
| | - Xiaoyin Zhuang
- The Mental Health Center, Shantou University Medical College, Shantou, People’s Republic of China
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Attenuation of High-Fat Diet-Induced Rat Liver Oxidative Stress and Steatosis by Combined Hydroxytyrosol- (HT-) Eicosapentaenoic Acid Supplementation Mainly Relies on HT. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2018; 2018:5109503. [PMID: 30057681 PMCID: PMC6051008 DOI: 10.1155/2018/5109503] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 04/18/2018] [Accepted: 04/26/2018] [Indexed: 12/11/2022]
Abstract
Pharmacological therapy for nonalcoholic fatty liver disease (NAFLD) is not approved at the present time. For this purpose, the effect of combined eicosapentaenoic acid (EPA; 50 mg/kg/day) modulating hepatic lipid metabolism and hydroxytyrosol (HT; 5 mg/kg/day) exerting antioxidant actions was evaluated on hepatic steatosis and oxidative stress induced by a high-fat diet (HFD; 60% fat, 20% protein, and 20% carbohydrates) compared to a control diet (CD; 10% fat, 20% protein, and 70% carbohydrates) in mice fed for 12 weeks. HFD-induced liver steatosis (i) was reduced by 32% by EPA, without changes in oxidative stress-related parameters and mild recovery of Nrf2 functioning affording antioxidation and (ii) was decreased by 42% by HT, concomitantly with total regain of the glutathione status diminished by HFD, 42% to 59% recovery of lipid peroxidation and protein oxidation enhanced by HFD, and regain of Nrf2 functioning, whereas (iii) combined EPA + HT supplementation elicited 74% reduction in liver steatosis, with total recovery of the antioxidant potential in a similar manner than HT. It is concluded that combined HT + EPA drastically decreases NAFLD development, an effect that shows additivity in HT and EPA effects that mainly relies on HT, strengthening the impact of oxidative stress as a central mechanism underlying liver steatosis in obesity.
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Shankar SS, Shankar RR, Mixson LA, Miller DL, Pramanik B, O'Dowd AK, Williams DM, Frederick CB, Beals CR, Stoch SA, Steinberg HO, Kelley DE. Native Oxyntomodulin Has Significant Glucoregulatory Effects Independent of Weight Loss in Obese Humans With and Without Type 2 Diabetes. Diabetes 2018; 67:1105-1112. [PMID: 29545266 DOI: 10.2337/db17-1331] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Accepted: 03/06/2018] [Indexed: 12/20/2022]
Abstract
Oxyntomodulin (OXM), an enteroendocrine hormone, causes appetite suppression, increased energy expenditure, and weight loss in obese humans via activation of GLP-1 and glucagon receptors. However, the effects of OXM on glucose homeostasis remain ill defined. To address this gap, we evaluated the effects of an i.v. infusion of native OXM on insulin secretion rates (ISRs) and glycemic excursion in a graded glucose infusion (GGI) procedure in two separate randomized, placebo (PBO)-controlled, single-dose crossover trials in 12 overweight and obese subjects without diabetes and in 12 obese subjects with type 2 diabetes mellitus (T2DM), using the GLP-1 analog liraglutide (LIRA) as a comparator in T2DM. In both groups, in the GGI, 3.0 pmol/kg/min of OXM significantly increased ISR and blunted glycemic excursion relative to PBO. In T2DM, the effects of OXM were comparable to those of LIRA, including restoration of β-cell glucose responsiveness to that of nonobese subjects without diabetes. Our findings indicate that native OXM significantly augments glucose-dependent insulin secretion acutely in obese subjects with and without diabetes, with effects comparable to pharmacologic GLP-1 receptor activation and independent of weight loss. Native OXM has potential to improve hyperglycemia via complementary and independent induction of insulin secretion and weight loss.
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Systemic and vascular inflammation in an in-vitro model of central obesity. PLoS One 2018; 13:e0192824. [PMID: 29438401 PMCID: PMC5811040 DOI: 10.1371/journal.pone.0192824] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 01/31/2018] [Indexed: 12/31/2022] Open
Abstract
Metabolic disorders due to over-nutrition are a major global health problem, often associated with obesity and related morbidities. Obesity is peculiar to humans, as it is associated with lifestyle and diet, and so difficult to reproduce in animal models. Here we describe a model of human central adiposity based on a 3-tissue system consisting of a series of interconnected fluidic modules. Given the causal link between obesity and systemic inflammation, we focused primarily on pro-inflammatory markers, examining the similarities and differences between the 3-tissue model and evidence from human studies in the literature. When challenged with high levels of adiposity, the in-vitro system manifests cardiovascular stress through expression of E-selectin and von Willebrand factor as well as systemic inflammation (expressing IL-6 and MCP-1) as observed in humans. Interestingly, most of the responses are dependent on the synergic interaction between adiposity and the presence of multiple tissue types. The set-up has the potential to reduce animal experiments in obesity research and may help unravel specific cellular mechanisms which underlie tissue response to nutritional overload.
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Distribution of Pancreatic Polypeptide–secreting Endocrine Cells in Nondiabetic and Diabetic Cases. Appl Immunohistochem Mol Morphol 2017; 25:422-431. [DOI: 10.1097/pai.0000000000000310] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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13
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Rodgers R. Bench to bedside in appetite research: Lost in translation? Neurosci Biobehav Rev 2017; 76:163-173. [DOI: 10.1016/j.neubiorev.2016.08.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2016] [Revised: 08/22/2016] [Accepted: 08/24/2016] [Indexed: 12/19/2022]
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Martel J, Ojcius DM, Chang CJ, Lin CS, Lu CC, Ko YF, Tseng SF, Lai HC, Young JD. Anti-obesogenic and antidiabetic effects of plants and mushrooms. Nat Rev Endocrinol 2017; 13:149-160. [PMID: 27636731 DOI: 10.1038/nrendo.2016.142] [Citation(s) in RCA: 192] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Obesity is reaching global epidemic proportions as a result of factors such as high-calorie diets and lack of physical exercise. Obesity is now considered to be a medical condition, which not only contributes to the risk of developing type 2 diabetes mellitus, cardiovascular disease and cancer, but also negatively affects longevity and quality of life. To combat this epidemic, anti-obesogenic approaches are required that are safe, widely available and inexpensive. Several plants and mushrooms that are consumed in traditional Chinese medicine or as nutraceuticals contain antioxidants, fibre and other phytochemicals, and have anti-obesogenic and antidiabetic effects through the modulation of diverse cellular and physiological pathways. These effects include appetite reduction, modulation of lipid absorption and metabolism, enhancement of insulin sensitivity, thermogenesis and changes in the gut microbiota. In this Review, we describe the molecular mechanisms that underlie the anti-obesogenic and antidiabetic effects of these plants and mushrooms, and propose that combining these food items with existing anti-obesogenic approaches might help to reduce obesity and its complications.
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Affiliation(s)
- Jan Martel
- Center for Molecular and Clinical Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
| | - David M Ojcius
- Center for Molecular and Clinical Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Department of Biomedical Sciences, University of the Pacific, Arthur Dugoni School of Dentistry, 155 Fifth Street, San Francisco, California 94103, USA
| | - Chih-Jung Chang
- Center for Molecular and Clinical Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Department of Microbiology and Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Research Center of Bacterial Pathogenesis, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
| | - Chuan-Sheng Lin
- Center for Molecular and Clinical Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Department of Microbiology and Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Research Center of Bacterial Pathogenesis, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
| | - Chia-Chen Lu
- Department of Respiratory Therapy, Fu Jen Catholic University, 510 Zhong-Zheng Street, New Taipei City 24205, Taiwan, Republic of China
| | - Yun-Fei Ko
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Chang Gung Biotechnology Corporation, 201 Tung-Hua North Road, Taipei 10508, Taiwan, Republic of China
- Biochemical Engineering Research Center, Ming Chi University of Technology, 84 Gungjuan Road, New Taipei City 24301, Taiwan, Republic of China
| | - Shun-Fu Tseng
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Research Center of Bacterial Pathogenesis, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
| | - Hsin-Chih Lai
- Center for Molecular and Clinical Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Department of Microbiology and Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Research Center of Bacterial Pathogenesis, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Research Center for Industry of Human Ecology, College of Human Ecology, Chang Gung University of Science and Technology, 261 Wen-Hua First Road, Taoyuan 33303, Taiwan, Republic of China
- Graduate Institute of Health Industry and Technology, College of Human Ecology, Chang Gung University of Science and Technology, 261 Wen-Hua First Road, Taoyuan 33303, Taiwan, Republic of China
| | - John D Young
- Center for Molecular and Clinical Immunology, Chang Gung University, 259 Wen-Hua First Road, Taoyuan 33302, Taiwan, Republic of China
- Chang Gung Immunology Consortium, Linkou Chang Gung Memorial Hospital, 5 Fu-Hsing Street, Taoyuan 33305, Taiwan, Republic of China
- Chang Gung Biotechnology Corporation, 201 Tung-Hua North Road, Taipei 10508, Taiwan, Republic of China
- Biochemical Engineering Research Center, Ming Chi University of Technology, 84 Gungjuan Road, New Taipei City 24301, Taiwan, Republic of China
- Laboratory of Cellular Physiology and Immunology, Rockefeller University, 1230 York Avenue, New York, New York 10021, USA
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15
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Gonçalves P, Araújo JR, Martel F. Antipsychotics-induced metabolic alterations: focus on adipose tissue and molecular mechanisms. Eur Neuropsychopharmacol 2015; 25:1-16. [PMID: 25523882 DOI: 10.1016/j.euroneuro.2014.11.008] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Revised: 10/14/2014] [Accepted: 11/13/2014] [Indexed: 12/19/2022]
Abstract
The use of antipsychotic drugs for the treatment of mood disorders and psychosis has increased dramatically over the last decade. Despite its consumption being associated with beneficial neuropsychiatric effects in patients, atypical antipsychotics (which are the most frequently prescribed antipsychotics) use is accompanied by some secondary adverse metabolic effects such as weight gain, dyslipidemia and glucose intolerance. The molecular mechanisms underlying these adverse effects are not fully understood but have been suggested to involve a dysregulation of adipose tissue homeostasis. As such, the aim of this paper is to review and discuss the role of adipose tissue in the development of secondary adverse metabolic effects induced by atypical antipsychotics. Data analyzed in this article suggest that atypical antipsychotics may increase adipose tissue (particularly visceral adipose tissue) lipogenesis, differentiation/hyperplasia, pro-inflammatory mediator secretion and insulin resistance and decrease adipose tissue lipolysis. Consequently, patients receiving antipsychotic medication could be at risk of developing obesity, type 2 diabetes and cardiovascular disease. A better knowledge of the impact of these drugs on adipose tissue homeostasis may unveil strategies to develop novel antipsychotic drugs with less adverse metabolic effects and to develop adjuvant therapies (e.g. behavioral and nutritional therapies) to neuropsychiatric patients receiving antipsychotic medication.
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Affiliation(s)
- Pedro Gonçalves
- INSERM (French Institute of Health and Medical Research), Unit 1151, INEM (Research Center in Molecular Medicine), Faculty of Medicine of Paris Descartes University, Paris, France
| | - João Ricardo Araújo
- INSERM (French Institute of Health and Medical Research), Unit 786, Molecular Microbial Pathogenesis Unit, Institut Pasteur, Paris, France
| | - Fátima Martel
- Department of Biochemistry (U38-FCT), Faculty of Medicine, University of Porto, Porto, Portugal.
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16
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Inhibitory Effects of 4-(4-Methylbenzamino)benzoate on Adipocyte Differentiation. J CHEM-NY 2015. [DOI: 10.1155/2015/171570] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
The potent suppression of adipocyte differentiation by 4-(4-methylbenzamino)benzoate was discovered during the search for new antiobesity compounds. 4-(4-methylbenzamino)benzoate was observed to suppress adipocyte differentiation in 3T3-L1 cells by 96.8% at 50 μM without cytotoxicity. In addition, 4-(4-methylbenzamino)benzoate reduced the cellular expression of fatty acid synthase in a concentration-dependent manner, as well as suppressing PPAR-gamma activity, which controls fatty acid storage and glucose metabolism. Based on these results, 4-(4-methylbenzamino)benzoate shows potential as an antiobesity material.
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17
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Finelli C, Padula MC, Martelli G, Tarantino G. Could the improvement of obesity-related co-morbidities depend on modified gut hormones secretion? World J Gastroenterol 2014; 20:16649-16664. [PMID: 25469034 PMCID: PMC4248209 DOI: 10.3748/wjg.v20.i44.16649] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 05/27/2014] [Accepted: 06/25/2014] [Indexed: 02/06/2023] Open
Abstract
Obesity and its associated diseases are a worldwide epidemic disease. Usual weight loss cures - as diets, physical activity, behavior therapy and pharmacotherapy - have been continuously implemented but still have relatively poor long-term success and mainly scarce adherence. Bariatric surgery is to date the most effective long term treatment for morbid obesity and it has been proven to reduce obesity-related co-morbidities, among them nonalcoholic fatty liver disease, and mortality. This article summarizes such variations in gut hormones following the current metabolic surgery procedures. The profile of gut hormonal changes after bariatric surgery represents a strategy for the individuation of the most performing surgical procedures to achieve clinical results. About this topic, experts suggest that the individuation of the crosslink among the gut hormones, microbiome, the obesity and the bariatric surgery could lead to new and more specific therapeutic interventions for severe obesity and its co-morbidities, also non surgical.
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18
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Day JW, Gelfanov V, Smiley D, Carrington PE, Eiermann G, Chicchi G, Erion MD, Gidda J, Thornberry NA, Tschöp MH, Marsh DJ, SinhaRoy R, DiMarchi R, Pocai A. Optimization of co-agonism at GLP-1 and glucagon receptors to safely maximize weight reduction in DIO-rodents. Biopolymers 2014. [PMID: 23203689 DOI: 10.1002/bip.22072] [Citation(s) in RCA: 106] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
The ratio of GLP-1/glucagon receptor (GLP1R/GCGR) co-agonism that achieves maximal weight loss without evidence of hyperglycemia was determined in diet-induced obese (DIO) mice chronically treated with GLP1R/GCGR co-agonist peptides differing in their relative receptor agonism. Using glucagon-based peptides, a spectrum of receptor selectivity was achieved by a combination of selective incorporation of GLP-1 sequences, C-terminal modification, backbone lactam stapling to stabilize helical structure, and unnatural amino acid substitutions at the N-terminal dipeptide. In addition to α-amino-isobutyric acid (Aib) substitution at position two, we show that α,α'-dimethyl imidazole acetic acid (Dmia) can serve as a potent replacement for the highly conserved histidine at position one. Selective site-specific pegylation was used to further minimize enzymatic degradation and provide uniform, extended in vivo duration of action. Maximal weight loss devoid of any sign of hyperglycemia was achieved with a co-agonist comparably balanced for in vitro potency at murine GLP1R and GCGR. This peptide exhibited superior weight loss and glucose lowering compared to a structurally matched pure GLP1R agonist, and to co-agonists of relatively reduced GCGR tone. Any further enhancement of the relative GCGR agonist potency yielded increased weight loss but at the expense of elevated blood glucose. We conclude that GCGR agonism concomitant with GLP1R agonism constitutes a promising approach to treatment of the metabolic syndrome. However, the relative ratio of GLP1R/GCGR co-agonism needs to be carefully chosen for each species to maximize weight loss efficacy and minimize hyperglycemia.
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Affiliation(s)
- Jonathan W Day
- Department of Chemistry, Indiana University, Bloomington, IN, USA
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19
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Nikolic D, Toth PP, Ferlita A, Bartolo VD, Montalto G, Banach M, Rizzo M. Novel anti-obesity drugs and plasma lipids. ACTA ACUST UNITED AC 2014. [DOI: 10.2217/clp.14.7] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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20
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Abstract
Obesity is one of the largest and fastest growing public health problems in the world. Last century social changes have set an obesogenic milieu that calls for micro and macro environment interventions for disease prevention, while treatment is mandatory for individuals already obese. The cornerstone of overweight and obesity treatment is diet and physical exercise. However, many patients find lifestyle modifications difficult to comply and prone to failure in the long-term; therefore many patients consider anti-obesity drugs an important adjuvant if not a better alternative to behavioral approach or obesity surgery. Since the pharmacological options for obesity treatment remain quite limited, this is an exciting research area, with new treatment targets and strategies on the horizon. This review discusses the development of innovative therapeutic agents, focusing in energy homeostasis regulation and the use of molecular vaccines, targeting hormones such as somatostatin, GIP and ghrelin, to reduce body weight.
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Affiliation(s)
- Mariana P Monteiro
- Department of Anatomy; Unit for Multidisciplinary Biomedical Research (UMIB); Institute for Biomedical Sciences Abel Salazar (ICBAS); University of Porto; Porto, Portugal
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21
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Abstract
Over the past 30 years, it has been established that hormones produced by the gut, pancreas, and adipose tissue are key players in the control of body weight. These hormones act through a complex neuroendocrine system, including the hypothalamus, to regulate metabolism and energy homeostasis. In obesity, this homeostatic balance is disrupted, either through alterations in the levels of these hormones or through resistance to their actions. Alterations in gut hormone secretion following gastric bypass surgery are likely to underlie the dramatic and persistent loss of weight following this procedure, as well as the observed amelioration in type 2 diabetes mellitus. Medications based on the gut hormone GLP-1 are currently in clinical use to treat type 2 diabetes mellitus and have been shown to produce weight loss. Further therapies for obesity based on other gut hormones are currently in development.
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Affiliation(s)
- Rebecca Scott
- Division of Diabetes, Endocrinology, Metabolism, Hammersmith Hospital, Imperial College London, London, United Kingdom.
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22
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Development of a neuromedin U-human serum albumin conjugate as a long-acting candidate for the treatment of obesity and diabetes. Comparison with the PEGylated peptide. J Pept Sci 2013; 20:7-19. [DOI: 10.1002/psc.2582] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2013] [Revised: 10/11/2013] [Accepted: 10/11/2013] [Indexed: 12/12/2022]
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23
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Misra M. Obesity pharmacotherapy: current perspectives and future directions. Curr Cardiol Rev 2013; 9:33-54. [PMID: 23092275 PMCID: PMC3584306 DOI: 10.2174/157340313805076322] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 07/31/2012] [Accepted: 08/27/2012] [Indexed: 02/06/2023] Open
Abstract
The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis
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Affiliation(s)
- Monika Misra
- Department of Pharmacology, Jawaharlal Nehru Medical College, Aligarh Muslim University, Aligarh, Uttar Pradesh, 202002, India.
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24
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Ueda SY, Miyamoto T, Nakahara H, Shishido T, Usui T, Katsura Y, Yoshikawa T, Fujimoto S. Effects of exercise training on gut hormone levels after a single bout of exercise in middle-aged Japanese women. SPRINGERPLUS 2013; 2:83. [PMID: 23504454 PMCID: PMC3597337 DOI: 10.1186/2193-1801-2-83] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/25/2012] [Accepted: 02/25/2013] [Indexed: 01/15/2023]
Abstract
The purpose of this study was to investigate the effects of 12 weeks of exercise training on gut hormone levels after a single bout of exercise in middle-aged Japanese women. Twenty healthy middle-aged women were recruited for this study. Several measurements were performed pre and post exercise training, including: body weight and composition, peak oxygen consumption (peak VO2), energy intake after the single bout of exercise, and the release of gut hormones with fasting and after the single bout of exercise. Exercise training resulted in significant increases in acylated ghrelin fasting levels (from 126.6 ± 5.6 to 135.9 ± 5.4 pmol/l, P < 0.01), with no significant changes in GLP-1 (from 0.54 ± 0.04 to 0.55 ± 0.03 pmol/ml) and PYY (from 1.20 ± 0.07 to 1.23 ± 0.06 pmol/ml) fasting levels. GLP-1 levels post exercise training after the single bout of exercise were significantly higher than those pre exercise training (areas under the curve (AUC); from 238.4 ± 65.2 to 286.5 ± 51.2 pmol/ml x 120 min, P < 0.001). There was a tendency for higher AUC for the time courses of PYY post exercise training than for those pre exercise training (AUC; from 519.5 ± 135.5 to 551.4 ± 128.7 pmol/ml x 120 min, P = 0.06). Changes in (delta) GLP-1 AUC were significantly correlated with decreases in body weight (r = -0.743, P < 0.001), body mass index (r = -0.732, P < 0.001), percent body fat (r = -0.731, P < 0.001), and energy intake after a single bout exercise (r = -0.649, P < 0.01) and increases in peak VO2 (r = 0.558, P < 0.05). These results suggest that the ability of exercise training to create a negative energy balance relies not only directly on its impact on energy expenditure, but also indirectly on its potential to modulate energy intake.
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Affiliation(s)
- Shin-Ya Ueda
- Department of Acupuncture, Morinomiya University of Medical Sciences, 1-26-16, Nankokita, Suminoe-ku, Osaka City, Osaka, 559-8611 Japan
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25
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Avraham Y, Katzhendler J, Vorobeiv L, Merchavia S, Listman C, Kunkes E, Harfoush F, Salameh S, Ezra AF, Grigoriadis NC, Berry EM, Najajreh Y. Novel Acylethanolamide Derivatives That Modulate Body Weight through Enhancement of Hypothalamic Pro-Opiomelanocortin (POMC) and/or Decreased Neuropeptide Y (NPY). J Med Chem 2013; 56:1811-29. [DOI: 10.1021/jm300484d] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Yosefa Avraham
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Jehoshua Katzhendler
- Institute of Drug Research,
School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, 91120 Jerusalem, Israel
| | - Lia Vorobeiv
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shira Merchavia
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Chana Listman
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Eithan Kunkes
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Fida’ Harfoush
- Anticancer Drugs Research Lab,
Faculty of Pharmacy, Al-Quds University, Abu-Dies, P.O. Box 20002, Jerusalem, Palestinian Authority
| | - Sawsan Salameh
- Anticancer Drugs Research Lab,
Faculty of Pharmacy, Al-Quds University, Abu-Dies, P.O. Box 20002, Jerusalem, Palestinian Authority
| | - Aviva F. Ezra
- Institute of Drug Research,
School of Pharmacy, Faculty of Medicine, Hebrew University of Jerusalem, 91120 Jerusalem, Israel
| | - Nikolaos C. Grigoriadis
- Department of Neurology, AHEPA University Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Elliot M. Berry
- Department of Human Nutrition
and Metabolism, Braun School of Public Health, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yousef Najajreh
- Anticancer Drugs Research Lab,
Faculty of Pharmacy, Al-Quds University, Abu-Dies, P.O. Box 20002, Jerusalem, Palestinian Authority
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26
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Noyan-Ashraf MH, Shikatani EA, Schuiki I, Mukovozov I, Wu J, Li RK, Volchuk A, Robinson LA, Billia F, Drucker DJ, Husain M. A Glucagon-Like Peptide-1 Analog Reverses the Molecular Pathology and Cardiac Dysfunction of a Mouse Model of Obesity. Circulation 2013. [DOI: 10.1161/circulationaha.112.091215] [Citation(s) in RCA: 213] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Background—
Cardiac consequences of obesity include inflammation, hypertrophy, and compromised energy metabolism. Glucagon-like peptide-1 is an incretin hormone capable of cytoprotective actions that reduces inflammation and endoplasmic reticulum stress in other tissues. Here we examine the cardiac effects of the glucagon-like peptide-1 analog liraglutide in a model of obesity, independent of changes in body weight.
Methods and Results—
C57Bl6 mice were placed on a 45% high-fat diet (HFD) or a regular chow diet. Mice on HFD developed 46±2% and 60±2% greater body weight relative to regular chow diet–fed mice at 16 and 32 weeks, respectively (both
P
<0.0001), manifesting impaired glucose tolerance, insulin resistance, and cardiac ceramide accumulation by 16 weeks. One-week treatment with liraglutide (30 µg/kg twice daily) did not reduce body weight, but reversed insulin resistance, cardiac tumor necrosis factor-α expression, nuclear factor kappa B translocation, obesity-induced perturbations in cardiac endothelial nitric oxide synthase, connexin-43, and markers of hypertrophy and fibrosis, in comparison with placebo-treated HFD controls. Liraglutide improved the cardiac endoplasmic reticulum stress response and also improved cardiac function in animals on HFD by an AMP-activated protein kinase–dependent mechanism. Supporting a direct mechanism of action, liraglutide (100 nmol/L) prevented palmitate-induced lipotoxicity in isolated mouse cardiomyocytes and primary human coronary smooth muscle cells and prevented adhesion of human monocytes to tumor necrosis factor-α–activated human endothelial cells in vitro.
Conclusions—
Weight-neutral treatment with a glucagon-like peptide-1 analog activates several cardioprotective pathways, prevents HFD-induced insulin resistance and inflammation, reduces monocyte vascular adhesion, and improves cardiac function in vivo by activating AMP-activated protein kinase. These data support a role for glucagon-like peptide-1 analogs in limiting the cardiovascular risks of obesity.
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Affiliation(s)
- Mohammad Hossein Noyan-Ashraf
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Eric Akihiko Shikatani
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Irmgard Schuiki
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Ilya Mukovozov
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Jun Wu
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Ren-Ke Li
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Allen Volchuk
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Lisa Annette Robinson
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Filio Billia
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Daniel J. Drucker
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
| | - Mansoor Husain
- From the Toronto General Research Institute, Toronto, Canada (M.H.N.-A., E.A.S., I.S., J.W., R.-K.L., A.V., F.B., M.H.); Hospital for Sick Children, Toronto, Canada (I.M., L.A.R.); Samuel Lunenfeld Research Institute, Toronto Canada (D.J.D.); Heart & Stroke Richard Lewar Centre of Excellence, University of Toronto, Toronto, Canada (D.J.D., M.H.)
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Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome. Proc Natl Acad Sci U S A 2012; 110:141-6. [PMID: 23248313 DOI: 10.1073/pnas.1216801110] [Citation(s) in RCA: 81] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Synthetic biology has significantly advanced the design of genetic devices that can reprogram cellular activities and provide novel treatment strategies for future gene- and cell-based therapies. However, many metabolic disorders are functionally linked while developing distinct diseases that are difficult to treat using a classic one-drug-one-disease intervention scheme. For example, hypertension, hyperglycemia, obesity, and dyslipidemia are interdependent pathologies that are collectively known as the metabolic syndrome, the prime epidemic of the 21st century. We have designed a unique therapeutic strategy in which the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin. Therefore, the signal transduction of a chimeric trace-amine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements. Based on this designer signaling cascade, it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc(mIgG)-Leptin, a bifunctional therapeutic peptide hormone that combines the glucagon-like peptide 1 (GLP-1) and leptin via an IgG-Fc linker. In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia. Using a clinically licensed drug to coordinate expression of therapeutic transgenes combines drug- and gene-based therapies for coordinated treatment of functionally related metabolic disorders.
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Abstract
The increasing global prevalence of obesity urgently requires an implementation of efficient preventive and therapeutic measures. Weight loss and its maintenance should be considered one of the most important strategies to reduce the incidence of obesity-related co-morbidities such as diabetes and cardiovascular diseases. Lifestyle modification focused on diet and physical activity represents the essential component of any kind of weight management. However, only an intensive lifestyle intervention can be efficient in terms of long-term weight loss. Anti-obesity drugs affect different targets in the central nervous system or peripheral tissues and improve regulatory and metabolic disturbances that contribute to the development of obesity. Anti-obesity medications provide modest additional fat loss to that achieved by lifestyle modification alone, reduce visceral fat stores, improve programme adherence, weight loss maintenance, diminish obesity-related health risks and improve a quality of life. Anti-obesity drugs do play a role in weight management. Their replacement with placebo is followed by weight regain. Due to adverse events, several anti-obesity drugs were withdrawn from the market over the past few years and currently only orlistat remains available for long-term obesity management. Drug withdrawals, failure of clinical trials with several new anti-obesity compounds as well as inappropriate demands of drug regulating agencies concerning the study protocol led to scepticism about the perspectives in the pharmacotherapy of obesity. However, recently developed anti-obesity medications such as gut hormone analogues and drug combinations provided encouraging results in terms of weight loss, safety and improvement of cardio-metabolic health risks.
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Abstract
Oxyntomodulin (OXM) is a peptide secreted from the L cells of the gut following nutrient ingestion. OXM is a dual agonist of the glucagon-like peptide-1 receptor (GLP1R) and the glucagon receptor (GCGR) combining the effects of GLP1 and glucagon to act as a potentially more effective treatment for obesity than GLP1R agonists. Injections of OXM in humans cause a significant reduction in weight and appetite, as well as an increase in energy expenditure. Activation of GCGR is classically associated with an elevation in glucose levels, which would be deleterious in patients with T2DM, but the antidiabetic properties of GLP1R agonism would be expected to counteract this effect. Indeed, OXM administration improved glucose tolerance in diet-induced obese mice. Thus, dual agonists of the GCGR and GLP1R represent a new therapeutic approach for diabetes and obesity with the potential for enhanced weight loss and improvement in glycemic control beyond those of GLP1R agonists.
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Affiliation(s)
- Alessandro Pocai
- Diabetes and Endocrinology, Merck Research Laboratories, Merck Sharp and Dohme Corp., Rahway, New Jersey 07065, USA.
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Abstract
The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent regulatory experience suggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss.
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Affiliation(s)
- R John Rodgers
- Behavioural Neuroscience Laboratory, Institute of Psychological Sciences, University of Leeds, LS2 9JT, UK.
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31
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Roth JD, Erickson MR, Chen S, Parkes DG. GLP-1R and amylin agonism in metabolic disease: complementary mechanisms and future opportunities. Br J Pharmacol 2012; 166:121-36. [PMID: 21671898 DOI: 10.1111/j.1476-5381.2011.01537.x] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Abstract
The discoveries of the incretin hormone glucagon-like peptide-1 (GLP-1) and the β-cell hormone amylin have translated into hormone-based therapies for diabetes. Both classes of molecules also exhibit weight-lowering effects and have been investigated for their anti-obesity potential. In the present review, we explore the mechanisms underlying the physiological and pharmacological actions of GLP-1 and amylin agonism. Despite their similarities (e.g. both molecular classes slow gastric emptying, decrease glucagon and inhibit food intake), there are important distinctions between the central and/or peripheral pathways that mediate their effects on glycaemia and energy balance. We suggest that understanding the similarities and differences between these molecules holds important implications for the development of novel, combination-based therapies, which are increasingly the norm for diabetes/metabolic disease. Finally, the future of GLP-1- and amylin agonist-based therapeutics is discussed.
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32
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Ingallinella P, Peier AM, Pocai A, Marco AD, Desai K, Zytko K, Qian Y, Du X, Cellucci A, Monteagudo E, Laufer R, Bianchi E, Marsh DJ, Pessi A. PEGylation of Neuromedin U yields a promising candidate for the treatment of obesity and diabetes. Bioorg Med Chem 2012; 20:4751-9. [DOI: 10.1016/j.bmc.2012.06.003] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2012] [Revised: 05/31/2012] [Accepted: 06/01/2012] [Indexed: 12/13/2022]
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Finger BC, Dinan TG, Cryan JF. Diet-induced obesity blunts the behavioural effects of ghrelin: studies in a mouse-progressive ratio task. Psychopharmacology (Berl) 2012; 220:173-81. [PMID: 21892647 DOI: 10.1007/s00213-011-2468-0] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2011] [Accepted: 08/22/2011] [Indexed: 10/17/2022]
Abstract
RATIONAL The ghrelinergic system is implicated in the development of obesity and in modulating central reward systems. It has been reported that diet-induced obesity causes blunted responding on food intake to ghrelin administration, associated with central ghrelin resistance. Here we investigate whether the stimulatory effects of ghrelin on the reward system are altered in diet-induced obese mice. METHODS Obesity was induced in C57BL/6J mice by feeding high-fat diet for 13 weeks. Mice were trained in an operant fixed and exponential progressive ratio task to respond for sucrose rewards. In an ad libitum fed state, ghrelin and a ghrelin receptor antagonist were administered in the progressive ratio. Alterations in the central ghrelin system in diet-induced obese mice were assessed. RESULTS Obese mice showed attenuated acquisition and performance in the fixed and progressive ratio paradigm. Most importantly, diet-induced obesity inhibited the stimulatory effects of ghrelin (2 nmol, 3 nmol/10 g) on progressive ratio responding whereas lean animals presented with increased responding. Administration of the ghrelin-receptor antagonist (D-Lys(3))-GHRP-6 (66.6 nmol/10 g) decreased performance in lean but not obese mice. This insensitivity to ghrelin receptor ligands in mice on high-fat diet was further supported by decreased mRNA expression of the ghrelin receptor in the hypothalamus and the nucleus accumbens in obese mice. CONCLUSIONS This study demonstrates that the modulatory effects of ghrelin receptor ligands are blunted in a mouse model of diet-induced obesity in a progressive ratio task. Thereby, our data extend the previously described ghrelin resistance in these mice from food intake to reward-associated behaviours.
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Affiliation(s)
- Beate C Finger
- Food for Health Ireland, University College Cork, Cork, Ireland
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Rubino DM, Gadde KM. A review of topiramate and phentermine: a combined therapeutic approach for obesity. ACTA ACUST UNITED AC 2012. [DOI: 10.2217/clp.11.65] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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Peier AM, Desai K, Hubert J, Du X, Yang L, Qian Y, Kosinski JR, Metzger JM, Pocai A, Nawrocki AR, Langdon RB, Marsh DJ. Effects of peripherally administered neuromedin U on energy and glucose homeostasis. Endocrinology 2011; 152:2644-54. [PMID: 21586559 DOI: 10.1210/en.2010-1463] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Neuromedin U (NMU) is a highly conserved peptide reported to modulate energy homeostasis. Pharmacological studies have shown that centrally administered NMU inhibits food intake, reduces body weight, and increases energy expenditure. NMU-deficient mice develop obesity, whereas transgenic mice overexpressing NMU become lean and hypophagic. Two high-affinity NMU receptors, NMUR1 and NMUR2, have been identified. NMUR1 is found primarily in the periphery and NMUR2 primarily in the brain, where it mediates the anorectic effects of centrally administered NMU. Given the broad expression pattern of NMU, we evaluated whether peripheral administration of NMU has effects on energy homeostasis. We observed that acute and chronic peripheral administration of NMU in rodents dose-dependently reduced food intake and body weight and that these effects required NMUR1. The anorectic effects of NMU appeared to be partly mediated by vagal afferents. NMU treatment also increased core body temperature and metabolic rate in mice, suggesting that peripheral NMU modulates energy expenditure. Additionally, peripheral administration of NMU significantly improved glucose excursion. Collectively, these data suggest that NMU functions as a peripheral regulator of energy and glucose homeostasis and the development of NMUR1 agonists may be an effective treatment for diabetes and obesity.
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Affiliation(s)
- Andrea M Peier
- Merck Research Laboratories, Rahway, New Jersey 07065, USA.
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Hainer V. Comparative efficiency and safety of pharmacological approaches to the management of obesity. Diabetes Care 2011; 34 Suppl 2:S349-54. [PMID: 21525481 PMCID: PMC3632205 DOI: 10.2337/dc11-s255] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Vojtech Hainer
- Institute of Endocrinology, Obesity Management Center, Prague, Czech Republic.
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38
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Targeting 5-HT receptors for the treatment of obesity. Curr Opin Pharmacol 2011; 11:52-8. [DOI: 10.1016/j.coph.2011.01.005] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2010] [Revised: 01/24/2011] [Accepted: 01/25/2011] [Indexed: 01/09/2023]
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39
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Current world literature. Curr Opin Endocrinol Diabetes Obes 2011; 18:83-98. [PMID: 21178692 DOI: 10.1097/med.0b013e3283432fa7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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40
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Correll CU, Lencz T, Malhotra AK. Antipsychotic drugs and obesity. Trends Mol Med 2011; 17:97-107. [PMID: 21185230 PMCID: PMC3053585 DOI: 10.1016/j.molmed.2010.10.010] [Citation(s) in RCA: 221] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2010] [Revised: 10/26/2010] [Accepted: 10/26/2010] [Indexed: 12/15/2022]
Abstract
Mechanisms underlying antipsychotic cardiometabolic adverse effects are incompletely understood. This hampers the identification of high-risk patients, low-risk antipsychotics and preventive/ameliorative treatments. Recent clinical, molecular and genetic data suggest that: (i) antipsychotic-naïve samples provide the greatest power for mechanistic studies; (ii) weight and metabolic effects can be discordant, pointing to overlapping and distinct mechanisms; (iii) antipsychotics affect satiety and energy homeostasis signaling; (iv) the specific peptides mediating these effects are unknown but probably overlap with those involved in idiopathic obesity; and (v) single nucleotide polymorphisms in genes encoding known neurotransmitter receptors and metabolic proteins are promising pharmacogenomic targets for countering adverse affects. However, sophisticated molecular studies and genome-wide association studies, ideally in antipsychotic-naïve/first episode samples, are needed to further advance the field.
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Dal-Pan A, Blanc S, Aujard F. Resveratrol suppresses body mass gain in a seasonal non-human primate model of obesity. BMC PHYSIOLOGY 2010; 10:11. [PMID: 20569453 PMCID: PMC2903570 DOI: 10.1186/1472-6793-10-11] [Citation(s) in RCA: 79] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/21/2009] [Accepted: 06/22/2010] [Indexed: 01/21/2023]
Abstract
Background Resveratrol, a natural polyphenolic compound, was shown to protect rodents against high-fat-diet induced diabesity by boosting energy metabolism. To the best of our knowledge, no data is yet available on the effects of resveratrol in non-human primates. Six non-human heterotherm primates (grey mouse lemurs, Microcebus murinus) were studied during four weeks of dietary supplementation with resveratrol (200 mg/kg/day) during their winter body-mass gain period. Body mass, spontaneous energy intake, resting metabolic rate, spontaneous locomotor activity and daily variations in body temperature were measured. In addition, the plasma levels of several gut hormones involved in satiety control were evaluated. Results Resveratrol reduced the seasonal body-mass gain by concomitantly decreasing energy intake by 13% and increasing resting metabolic rate by 29%. Resveratrol supplementation inhibited the depth of daily torpor, an important energy-saving process in this primate. The daily amount of locomotor activity remained unchanged. Except for an increase in the glucose-dependent insulinotropic polypeptide, a gut hormone known to promote mobilization of fat stores, no major change in satiety hormone plasma levels was observed under resveratrol supplementation. Conclusions These results suggest that in a non-human primate, resveratrol reduces body-mass gain by increasing satiety and resting metabolic rate, and by inhibiting torpor expression. The measured anorectic gut hormones did not seem to play a major role in these observations.
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Affiliation(s)
- Alexandre Dal-Pan
- Mécanismes Adaptatifs et Evolution, UMR 7179 Centre National de la Recherche Scientifique, Muséum National d'Histoire Naturelle, Paris, France
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Suzuki K, Simpson KA, Minnion JS, Shillito JC, Bloom SR. The role of gut hormones and the hypothalamus in appetite regulation. Endocr J 2010; 57:359-72. [PMID: 20424341 DOI: 10.1507/endocrj.k10e-077] [Citation(s) in RCA: 194] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The World Health Organisation has estimated that by 2015 approximately 2.3 billion adults will be overweight and more than 700 million obese. Obesity is associated with an increased risk of diabetes, cardiovascular events, stroke and cancer. The hypothalamus is a crucial region for integrating signals from central and peripheral pathways and plays a major role in appetite regulation. In addition, there are reciprocal connections with the brainstem and higher cortical centres. In the arcuate nucleus of the hypothalamus, there are two major neuronal populations which stimulate or inhibit food intake and influence energy homeostasis. Within the brainstem, the dorsal vagal complex plays a role in the interpretation and relaying of peripheral signals. Gut hormones act peripherally to modulate digestion and absorption of nutrients. However, they also act as neurotransmitters within the central nervous system to control food intake. Peptide YY, pancreatic polypeptide, glucagon-like peptide-1 and oxyntomodulin suppress appetite, whilst ghrelin increases appetite through afferent vagal fibres to the caudal brainstem or directly to the hypothalamus. A better understanding of the role of these gut hormones may offer the opportunity to develop successful treatments for obesity. Here we review the current understanding of the role of gut hormones and the hypothalamus on food intake and body weight control.
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Affiliation(s)
- Keisuke Suzuki
- Section of Investigative Medicine, Imperial College London, London, UK
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43
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Glucagon regulation of energy metabolism. Physiol Behav 2010; 100:545-8. [PMID: 20381509 DOI: 10.1016/j.physbeh.2010.03.019] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2010] [Revised: 03/17/2010] [Accepted: 03/19/2010] [Indexed: 11/24/2022]
Abstract
Glucagon has long been known as a counter-regulatory hormone to insulin of fundamental importance to glucose homeostasis. Its prominent ability to stimulate glycogenolysis and gluconeogenesis, has historically cast this peptide as one hormone where the metabolic consequences of increasing blood glucose levels, especially in obesity, are viewed largely as being deleterious. This perspective may be changing in light of emerging data and reconsideration of historic studies, which suggest that glucagon has beneficial effects on body fat mass, food intake, and energy expenditure. In this review, we discuss the mechanisms of glucagon-mediated body weight regulation as well as possible novel therapeutic approaches in the treatment of obesity and glucose intolerance that may arise from these findings. The paper represents an invited review by a symposium, award winner or keynote speaker at the Society for the Study of Ingestive Behavior [SSIB] Annual Meeting in Portland, July 2009.
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Somogyi A, Loke YK, Ferro A, Lewis LD, Cohen AF, Ritter JM. Editors' pick 2009. Br J Clin Pharmacol 2010; 69:107-10. [DOI: 10.1111/j.1365-2125.2009.03606.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
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Park A. Editorial for BJCP Special Obesity Edition. Br J Clin Pharmacol 2009; 68:801-3. [PMID: 20002074 DOI: 10.1111/j.1365-2125.2009.03582.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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