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Xiao Y, Wu W, Liu F, Jin L, Jia Y, Qiao N, Cai K, Ru S, Cao L, Gui S. Inflammatory mediator contributes to leptin resistance and obesity in craniopharyngioma. FASEB J 2024; 38:e70242. [PMID: 39655658 PMCID: PMC11629452 DOI: 10.1096/fj.202402216rr] [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] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 11/24/2024] [Accepted: 11/27/2024] [Indexed: 12/13/2024]
Abstract
Obesity presents a significant challenge in managing patients with craniopharyngioma (CP). Cyst fluid (CF), rich in inflammatory mediators, is implicated in CP-related obesity, though the precise mechanism remains unclear. This study investigated the impact of CF or C-X-C motif chemokine ligand-1 (CXCL1) injections on body weight, Lee index, plasma lipid profiles, hepatic lipid accumulation, leptin levels, NF-κB pathway, the suppressor of cytokine signaling 3 (SOCS3) expression, and leptin sensitivity in rats. Bioinformatics was employed to identify differentially expressed genes (DEGs) between CF/CXCL1-treated and control SY5Y cells, as well as to confirm enriched pathways. Western blotting was used for experimental validation, including the effects of sodium salicylate (SS) on leptin sensitivity in SY5Y cells. Injecting CF or CXCL1 into the brain, without hypothalamic damage, led to increased body weight, Lee index, and hepatic lipid accumulation in rats, alongside elevated fasting blood glucose, triglycerides, and total cholesterol, while high-density lipoprotein cholesterol levels decreased. Additionally, CF and CXCL1 could induce elevated leptin levels, a higher leptin-to-body weight ratio, and resistance to exogenous leptin by activating the NF-κB pathway and upregulating the expression of SOCS3 in rats. Further validation confirmed that CF and CXCL1 suppress leptin signaling by activating the NF-κB pathway and upregulating SOCS3. Moreover, SS mitigated the inhibitory effects of CF or CXCL1 on leptin signaling, preserving leptin sensitivity in SY5Y cells. These results highlight the obesogenic role of CF and CXCL1, offering insights into the development of morbid obesity through inflammatory factor-mediated leptin resistance, independent of hypothalamic damage. SS may serve as a promising therapeutic approach for CP-associated obesity, though additional clinical studies are necessary to confirm its efficacy.
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Affiliation(s)
- Youchao Xiao
- Department of NeurosurgeryThe First Affiliated Hospital of Ningbo UniversityZhejiangChina
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Wentao Wu
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Fangzheng Liu
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Lu Jin
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Yanfei Jia
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Ning Qiao
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Kefan Cai
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Siming Ru
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Lei Cao
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Songbai Gui
- Department of Neurosurgery, Beijing Tiantan HospitalCapital Medical UniversityBeijingChina
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Bai Y, Zhao Y, Jin J, Ye Z, Fan H, Zhao D, Gao S. Jiang Tang San Hao Formula exerts its anti-diabetic effect by affecting the gut-microbiota-brain axis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 135:156100. [PMID: 39388919 DOI: 10.1016/j.phymed.2024.156100] [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: 05/04/2024] [Revised: 08/27/2024] [Accepted: 09/26/2024] [Indexed: 10/12/2024]
Abstract
BACKGROUND Type 2 diabetes is a complex metabolic disorder characterized by insulin resistance and impaired insulin secretion, with growing evidence highlighting the critical role of the gut-microbiota-brain axis in modulating glucose and lipid metabolism. OBJECTIVE To evaluate the effects of Jiang Tang San Hao Formula (JTSHF) on blood glucose control in type 2 diabetic mouse model and to explore its mechanism through the gut- microbiota-brain axis. METHODS A type 2 diabetes model was established using six-week-old male C57BL6/J mice, induced by a high-fat diet combined with streptozotocin injection. The diabetic mice then randomly assigned to the model group, metformin (Glucophage) group and JTSHF group, receiving 11 weeks of treatment by gavage. Body weight and fasting blood glucose were monitored biweekly. The oral glucose tolerance test was performed during the fifth and 10th weeks of the intervention. The measurements of body composition were conducted pre- and post-treatment. After the intervention, serum insulin, lipid levels, glucagon like peptide-1 (GLP-1), peptide YY, ghrelin, and leptin were detected. The fresh feces of mice were collected before sacrifice for gut microbiota analysis and short chain fatty acids quantification. The colon tissues of mice in each group were collected to observe the morphological structure and to measure the expression levels of GPR41 and GPR43. The hypothalamus was collected to assess the expression of POMC, AgRP and NPY. RESULTS JTSHF significantly boosted sugar and lipid metabolism and contributed to weight reduction in diabetic mice (p < 0.05). At the genus level, JTSHF increased the relative abundance of Bacteroides, Prevotella, and Parabacteroides, and decreased Clostridium, Lactobacillus, and Oscillibacter in the gut microbiota. JTSHF enhanced the content of short chain fatty acids, improved the expression level of GPR43/41 in colonic tissue (p < 0.05), and increased POMC expression while decreasing AgRP and NPY expression in the hypothalamus (p < 0.05). Serum GLP-1 was increased, and ghrelin was decreased significantly after JTSHF intervention (p < 0.05). CONCLUSION By affecting the composition, relative abundance, and metabolites of gut microbiota, JTSHF regulates various gut brain peptides, affects the hypothalamic feeding center, improves glucose and lipid metabolism, and thus plays the anti-diabetic role. The study provides novel insights into how traditional Chinese medicine modulates the gut-brain connection to exert anti-diabetic effects, highlighting the innovative potential of JTSHF in metabolic disease management.
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Affiliation(s)
- Ying Bai
- Department of Traditional Chinese Medicine, Peking Union Medical College Hospital, Beijing, China
| | - Yi Zhao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Jialin Jin
- China Science and Technology Development Center for Chinese Medicine, Beijing, China
| | - Zimengwei Ye
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Hui Fan
- Guangdong Pharmaceutical University, Guangdong, China
| | - Dandan Zhao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
| | - Sihua Gao
- College of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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Kasim RH, Chillon TS, Eleftheriadou AM, Rijntjes E, Minich WB, Zechmann S, Schomburg L. Detection of natural autoimmunity to ghrelin in diabetes mellitus. FRONTIERS IN MEDICAL TECHNOLOGY 2024; 6:1407409. [PMID: 39070294 PMCID: PMC11272539 DOI: 10.3389/fmedt.2024.1407409] [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: 04/28/2024] [Accepted: 06/28/2024] [Indexed: 07/30/2024] Open
Abstract
Objective Ghrelin is an orexigenic peptide that becomes post-translationally modified. Natural autoantibodies to ghrelin (ghrelin-aAb) have been described in healthy subjects, in eating disorders and rheumatic diseases, with potential clinical relevance. Despite these important reports, the data base on the prevalence and physiological role is small and technical approaches for assessing ghrelin-aAb are few, encouraging respective research for improving knowledge on the potential endocrine significance. Methods A novel immunoprecipitation assay was generated based on a fusion protein of human ghrelin with a reporter gene. Assay quality was verified with commercial antibodies. Assay characteristics and matrix effects were determined, including stability of natural ghrelin-aAb to freezing, signal linearity in dilution experiments, and comparison of different matrices. Three groups of serum samples were analyzed for ghrelin-aAb, comprising commercial sera from healthy subjects and patients with type 1 or type 2 diabetes mellitus. Results The newly generated ghrelin-aAb assay proved sensitive, robust and reliable over a broad concentration range. Results from serum and plasma differed slightly. The signals from serum remained stable towards freezing and thawing, and in dilution experiments. Applying a mathematical criterion for outliers (P75 + 1.5-times IQR), an average prevalence of 11%-12% of positive samples was identified in the different human cohorts, with no significant sex-or disease-related difference. General significance A novel diagnostic autoantibody assay detected ghrelin-aAb with a similar prevalence in diabetic patients and controls, suggesting that autoimmunity to ghrelin plays little role in diabetes mellitus, but may be of relevance in other diseases where ghrelin signaling is essential.
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Affiliation(s)
- Rega H. Kasim
- Institute for Experimental Endocrinology, Charité—Universitätsmedizin Berlin, Berlin, Germany
- Division of Diabetes and Endocrinology, GZO Zurich Regional Health Center, Wetzikon, Switzerland
| | - Thilo Samson Chillon
- Institute for Experimental Endocrinology, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | | | - Eddy Rijntjes
- Institute for Experimental Endocrinology, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Waldemar B. Minich
- Institute for Experimental Endocrinology, Charité—Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Zechmann
- Division of Diabetes and Endocrinology, GZO Zurich Regional Health Center, Wetzikon, Switzerland
| | - Lutz Schomburg
- Institute for Experimental Endocrinology, Charité—Universitätsmedizin Berlin, Berlin, Germany
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van Aken GA. Computer modeling of digestive processes in the alimentary tract and their physiological regulation mechanisms: closing the gap between digestion models and in vivo behavior. Front Nutr 2024; 11:1339711. [PMID: 38606020 PMCID: PMC11007706 DOI: 10.3389/fnut.2024.1339711] [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: 11/16/2023] [Accepted: 02/15/2024] [Indexed: 04/13/2024] Open
Abstract
Introduction A model has been developed for in silico simulation of digestion and its physiological feedback mechanisms. Methods The model is based on known physiology described in the literature and is able to describe the complexity of many simultaneous processes related to food digestion. Results Despite the early stage of development of the model, it already encompasses a large number of processes that occur simultaneously, enabling the prediction of a large number of post-prandial physiological markers, which can be highly functional in combination with in vitro, organ-on-a-chip and digital twin models purposed to measure the physiological properties of organs and to predict the effect of adjusted food composition in normal and diseased states. Discussion Input from and collaboration between science fileds is needed to further develop and refine the model and to connect with in vitro, in vivo, and ex vivo (organ-on-a-chip) models.
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Bornath DPD, McKie GL, McCarthy SF, Vanderheyden LW, Howe GJ, Medeiros PJ, Hazell TJ. Interleukin-6 is not involved in appetite regulation following moderate-intensity exercise in males with normal weight and obesity. Obesity (Silver Spring) 2023; 31:2315-2324. [PMID: 37551724 DOI: 10.1002/oby.23841] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 04/13/2023] [Accepted: 05/16/2023] [Indexed: 08/09/2023]
Abstract
OBJECTIVE In obesogenic states and after exercise, interleukin (IL)-6 elevations are established, and IL-6 is speculated to be an appetite-regulating mechanism. This study examined the role of IL-6 on exercise-induced appetite regulation in sedentary normal weight (NW) males and those with obesity (OB). METHODS Nine NW participants and eight participants with OB completed one non-exercise control (CTRL) and one moderate-intensity continuous training (MICT; 60 minutes, 65% V̇O2max ) session. IL-6, acylated ghrelin, active peptide tyrosine-tyrosine3-36 , active glucagon-like peptide-1, and overall appetite perceptions were measured fasted, pre exercise, and 30, 90, and 150 minutes post exercise. RESULTS Fasted IL-6 concentrations were elevated in OB (p = 0.005,η p 2 = 0.419); however, increases following exercise were similar between groups (p = 0.934,η p 2 = 0.000). Acylated ghrelin was lower in OB versus NW (p < 0.017, d > 0.84), and OB did not respond to MICT (p > 0.512, d < 0.44) although NW had a decrease versus CTRL (p < 0.034, d > 0.61). IL-6 did not moderate/mediate acylated ghrelin release after exercise (p > 0.251). There were no observable effects of MICT on tyrosine-tyrosine3-36 , glucagon-like peptide-1, or overall appetite (p > 0.334,η p 2 < 0.062). CONCLUSIONS These results suggest that IL-6 is not involved in exercise-induced appetite suppression. Despite blunted appetite-regulatory peptide responses to MICT in participants with OB, NW participants exhibited decreased acylated ghrelin; however, no differences in appetite perceptions existed between CTRL and MICT or NW and OB.
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Affiliation(s)
- Derek P D Bornath
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada
| | - Greg L McKie
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada
| | - Seth F McCarthy
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada
| | - Luke W Vanderheyden
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada
| | - Greg J Howe
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada
| | - Philip J Medeiros
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada
| | - Tom J Hazell
- Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, Ontario, Canada
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Aukan MI, Coutinho S, Pedersen SA, Simpson MR, Martins C. Differences in gastrointestinal hormones and appetite ratings between individuals with and without obesity-A systematic review and meta-analysis. Obes Rev 2023; 24:e13531. [PMID: 36416279 PMCID: PMC10078575 DOI: 10.1111/obr.13531] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/26/2022] [Accepted: 10/27/2022] [Indexed: 11/24/2022]
Abstract
Determining if gastrointestinal (GI) hormone response to food intake differs between individuals with, and without, obesity may improve our understanding of obesity pathophysiology. A systematic review and meta-analysis of studies assessing the concentrations of GI hormones, as well as appetite ratings, following a test meal, in individuals with and without obesity was undertaken. Systematic searches were conducted in the databases MEDLINE, Embase, Cochrane Library, PsycINFO, Web of Science, and ClinicalTrials.gov. A total of 7514 unique articles were retrieved, 115 included in the systematic review, and 70 in the meta-analysis. The meta-analysis compared estimated standardized mean difference in GI hormones' concentration, as well as appetite ratings, between individuals with and without obesity. Basal and postprandial total ghrelin concentrations were lower in individuals with obesity compared with controls, and this was reflected by lower postprandial hunger ratings in the former. Individuals with obesity had a lower postprandial concentration of total peptide YY compared with controls, but no significant differences were found for glucagon-like peptide 1, cholecystokinin, or other appetite ratings. A large methodological and statistical heterogeneity among studies was found. More comprehensive studies are needed to understand if the differences observed are a cause or a consequence of obesity.
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Affiliation(s)
- Marthe Isaksen Aukan
- Obesity Research Group, Department of Clinical and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Centre of Obesity and Innovation (ObeCe), Clinic of Surgery, St. Olav University Hospital, Trondheim, Norway
| | - Silvia Coutinho
- Obesity Research Group, Department of Clinical and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Department of Public Health Nutrition at the Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo (UiO), Oslo, Norway
| | - Sindre Andre Pedersen
- Library Section for Research Support, Data and Analysis, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
| | - Melanie Rae Simpson
- Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim, Norway.,Clinical Research Unit Central Norway, St. Olavs Hospital, Trondheim, Norway
| | - Catia Martins
- Obesity Research Group, Department of Clinical and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.,Centre of Obesity and Innovation (ObeCe), Clinic of Surgery, St. Olav University Hospital, Trondheim, Norway.,Department of Nutrition Sciences, the University of Alabama at Birmingham (UAB), Birmingham, Alabama, USA
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Valinejad A, Khodaei K. Does exercise during a ketogenic diet effectively alter appetite sensation, appetite-regulating hormones, and body composition? Exp Biol Med (Maywood) 2022; 247:1898-1906. [PMID: 35920294 PMCID: PMC9742743 DOI: 10.1177/15353702221113862] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Exercise and diet are two essential interventions in weight control. The purpose of this study was to compare the effectiveness of two exercise training types during a ketogenic diet (KD) on appetite sensation, appetite-regulating hormones, and body composition in overweight or obese man. Thirty-six men, overweight or with obesity, voluntarily participated in this study. The participants were randomly assigned into three groups, including KD (n = 12), aerobic training during KD (AT-KD) (n = 12), and resistance training during KD (RT-KD) (n = 12) groups. The participants followed a low-carbohydrate diet for 6 weeks. Exercise training programs consisted of three sessions per week over 6 weeks. Appetite sensation was analyzed using a visual analogue scale (VAS) in fasting and postprandial states. The Enzyme-Linked Immunosorbent Assay (ELISA) method analyzed appetite-regulating hormones, including spexin, leptin, and acylated ghrelin, in a fasting state. Body composition was measured using bioelectrical impedance analysis (BIA). Furthermore, the ketosis state was monitored by measuring urinary ketones weekly. The results indicated that in both AT-KD and RT-KD groups, spexin and acylated ghrelin increased while leptin decreased without any between-group differences. Hunger and prospective food consumption (PFC) declined while satiety and fullness increased in all groups. The AT-KD group experienced a significant decrease in hunger and PFC, while fullness increased compared with the KD group. Fat mass, weight, and body mass index (BMI) decreased in all groups. Lean body mass increased in the RT-KD group (+2.66 kg) compared with both AT-KD and KD groups (-1.71 and -1.33 kg, respectively). This study demonstrated that AT-KD and RT-KD effectively altered appetite-regulating hormones and suppressed appetite sensation. In addition, both interventions had a favorable effect on weight loss and body fat reduction, with a more pronounced effect of RT-KD on maintaining lean body mass in overweight or obese men.
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Fukunaga N, Ribeiro RVP, Bissoondath V, Billia F, Rao V. Ghrelin May Inhibit Inflammatory Response and Apoptosis During Ischemia-Reperfusion Injury. Transplant Proc 2022; 54:2357-2363. [PMID: 36180256 DOI: 10.1016/j.transproceed.2022.08.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/26/2022] [Accepted: 08/29/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Ghrelin, a novel growth hormone-releasing peptide, has both anti-inflammatory and anti-apoptotic effects on human endothelial cells. We evaluated the protective effects of ghrelin against ischemia-reperfusion injury (IRI) in a murine heterotopic cervical heart transplantation model. METHODS Donor hearts from C57BL/6J wild-type mice, which were kept in cold saline for 60 minutes, were heterotopically transplanted into C57BL/6J wild-type recipients. A day prior to heterotopic cervical heart transplantation, donor animals received either ghrelin (300 nmol/kg) or saline (0.3 mL) intraperitoneally. Upon reperfusion and postoperative day 1, ghrelin or saline was administered to the recipients. Donor hearts were procured on day 2. RESULTS Ghrelin injection did not result in any adverse effects in donors or recipients. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive cells were significantly decreased in the ghrelin group (0.38% ± 0.21% vs 5.74% ± 3.68%; P < .001). Both cleaved caspase-3 activity and Bcl-2/Bax ratio from the ghrelin group were significantly reduced compared to those in the control. Furthermore, the phosphorylated Akt/Akt ratio was higher in the ghrelin group (0.44 ± 0.21 vs 0.14 ± 0.03; P = .043). Nuclear factor-kappa B p65 nuclear translocation was reduced in the ghrelin hearts compared to the controls (3.17% ± 1.84% vs 19.28% ± 13.14%; P = .009). Vascular cell adhesion molecule-1, intracellular adhesion molecule-1, nuclear factor-kappa B, and tumor necrosis factor alpha levels were also significantly reduced in the ghrelin-treated group. No significant difference was observed in 8-isoprostane production between groups. CONCLUSION Ghrelin inhibits the inflammatory response and apoptosis during transplant-related IRI. This study demonstrates the protective effects of ghrelin against IRI.
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Affiliation(s)
- Naoto Fukunaga
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Canada
| | - Roberto Vanin Pinto Ribeiro
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Canada
| | - Ved Bissoondath
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Canada
| | - Filio Billia
- Division of Cardiology, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Canada
| | - Vivek Rao
- Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, University Health Network, University of Toronto, Toronto, Canada.
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Müller TD, Blüher M, Tschöp MH, DiMarchi RD. Anti-obesity drug discovery: advances and challenges. Nat Rev Drug Discov 2022; 21:201-223. [PMID: 34815532 PMCID: PMC8609996 DOI: 10.1038/s41573-021-00337-8] [Citation(s) in RCA: 526] [Impact Index Per Article: 175.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/06/2021] [Indexed: 12/27/2022]
Abstract
Enormous progress has been made in the last half-century in the management of diseases closely integrated with excess body weight, such as hypertension, adult-onset diabetes and elevated cholesterol. However, the treatment of obesity itself has proven largely resistant to therapy, with anti-obesity medications (AOMs) often delivering insufficient efficacy and dubious safety. Here, we provide an overview of the history of AOM development, focusing on lessons learned and ongoing obstacles. Recent advances, including increased understanding of the molecular gut-brain communication, are inspiring the pursuit of next-generation AOMs that appear capable of safely achieving sizeable and sustained body weight loss.
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Affiliation(s)
- Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center, Helmholtz Zentrum München, Neuherberg, Germany.
- German Center for Diabetes Research (DZD), Neuherberg, Germany.
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
| | - Matthias H Tschöp
- Helmholtz Zentrum München, Neuherberg, Germany
- Division of Metabolic Diseases, Department of Medicine, Technische Universität München, München, Germany
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Masule MV, Rathod S, Agrawal Y, Patil CR, Nakhate KT, Ojha S, Goyal SN, Mahajan UB. Ghrelin mediated regulation of neurosynaptic transmitters in depressive disorders. CURRENT RESEARCH IN PHARMACOLOGY AND DRUG DISCOVERY 2022; 3:100113. [PMID: 35782191 PMCID: PMC9240712 DOI: 10.1016/j.crphar.2022.100113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 06/07/2022] [Accepted: 06/07/2022] [Indexed: 11/16/2022] Open
Abstract
Ghrelin is a peptide released by the endocrine cells of the stomach and the neurons in the arcuate nucleus of the hypothalamus. It modulates both peripheral and central functions. Although ghrelin has emerged as a potent stimulator of growth hormone release and as an orexigenic neuropeptide, the wealth of literature suggests its involvement in the pathophysiology of affective disorders including depression. Ghrelin exhibits a dual role through the advancement and reduction of depressive behavior with nervousness in the experimental animals. It modulates depression-related signals by forming neuronal networks with various neuropeptides and classical neurotransmitter systems. The present review emphasizes the integration and signaling of ghrelin with other neuromodulatory systems concerning depressive disorders. The role of ghrelin in the regulation of neurosynaptic transmission and depressive illnesses implies that the ghrelin system modulation can yield promising antidepressive therapies.
Ghrelin is the orexigenic type of neuropeptide. It binds with the growth hormone secretagogue receptor (GHSR). GHSR is ubiquitously present in the various brain regions. Ghrelin is involved in the regulation of depression-related behavior. The review focuses on the neurotransmission and signaling of ghrelin in neuropsychiatric and depressive disorders.
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Affiliation(s)
- Milind V. Masule
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Maharashtra, India
| | - Sumit Rathod
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Yogeeta Agrawal
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Chandragouda R. Patil
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Maharashtra, India
| | - Kartik T. Nakhate
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
| | - Shreesh Ojha
- Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
| | - Sameer N. Goyal
- Shri Vile Parle Kelavani Mandal's Institute of Pharmacy, Dhule, 424001, Maharashtra, India
- Corresponding author.
| | - Umesh B. Mahajan
- Department of Pharmacology, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, 425405, Maharashtra, India
- Corresponding author.
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Luo Q, Hu J, Yang G, Yuan X, Chen Z, Wang D, Lu Y, Zhu L, Wang G. Fasting Increases Iron Export by Modulating Ferroportin 1 Expression Through the Ghrelin/GHSR1α/MAPK Pathway in the Liver. Biol Trace Elem Res 2021; 199:267-277. [PMID: 32215811 DOI: 10.1007/s12011-020-02114-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 03/08/2020] [Indexed: 11/29/2022]
Abstract
The liver is contributed to maintaining body iron homeostasis and controlling of body adaptation to fasting. Although previous studies implied a negative relationship between iron and ghrelin in both mice and humans, it remains to be explored whether fasting or ghrelin has a functional effect on iron homeostasis in the liver. In this study, we examined the roles of fasting and ghrelin in modulating the protein expression of Fpn1, transferrin receptor 1 (TfR1), and ferritin light chain (Ft-L), as well as the mRNA expression of ghrelin, hepcidin, ghrelin O-acyltransferase (GOAT), and growth hormone secretagogue receptor 1 alpha (GHSR1α) in mouse liver and cultured hepatocytes. Our in vivo results suggested that fasting significantly upregulated the mRNA expression of ghrelin, GOAT, and GHSR1α, as well as the protein levels of ghrelin, Fpn1, and Ft-L, but not TfR1, in mouse liver. Interestingly, mRNA expression of hepcidin did not change significantly after fasting. Meanwhile, in cultured hepatocytes, ghrelin significantly increased the protein expression of Fpn1 but not Ft-L and TfR1 and significantly enhanced ERK phosphorylation. Furthermore, the pretreatment of cultured hepatocytes with either a pERK inhibitor or a GHSR1α antagonist abolished the effects of ghrelin on Fpn1 expression and ERK phosphorylation. Our findings confirmed that fasting increases iron export in the liver by upregulating Fpn1 expression through the ghrelin/GHSR1α/MAPK signaling pathway.
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Affiliation(s)
- Qianqian Luo
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Jianan Hu
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Guang Yang
- Department of Geriatrics, Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei, China
- Hubei Provincial Academy of Traditional Chinese Medicine, Wuhan, Hubei, China
| | - Xiaoyu Yuan
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Zhongping Chen
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Dan Wang
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Yapeng Lu
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China
| | - Li Zhu
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China.
| | - Guohua Wang
- Department of Physiology and Hypoxic Biomedicine, Institute of Special Environmental Medicine and Co-innovation Center of Neuroregeneration, Nantong University, 9 Seyuan Road, Chongchuan District, Nantong, 226019, Jiangsu, China.
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Armistead B, Johnson E, VanderKamp R, Kula-Eversole E, Kadam L, Drewlo S, Kohan-Ghadr HR. Placental Regulation of Energy Homeostasis During Human Pregnancy. Endocrinology 2020; 161:5838263. [PMID: 32417921 DOI: 10.1210/endocr/bqaa076] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 05/08/2020] [Indexed: 02/07/2023]
Abstract
Successful pregnancies rely on sufficient energy and nutrient supply, which require the mother to metabolically adapt to support fetal needs. The placenta has a critical role in this process, as this specialized organ produces hormones and peptides that regulate fetal and maternal metabolism. The ability for the mother to metabolically adapt to support the fetus depends on maternal prepregnancy health. Two-thirds of pregnancies in the United States involve obese or overweight women at the time of conception. This poses significant risks for the infant and mother by disrupting metabolic changes that would normally occur during pregnancy. Despite well characterized functions of placental hormones, there is scarce knowledge surrounding placental endocrine regulation of maternal metabolic trends in pathological pregnancies. In this review, we discuss current efforts to close this gap of knowledge and highlight areas where more research is needed. As the intrauterine environment predetermines the health and wellbeing of the offspring in later life, adequate metabolic control is essential for a successful pregnancy outcome. Understanding how placental hormones contribute to aberrant metabolic adaptations in pathological pregnancies may unveil disease mechanisms and provide methods for better identification and treatment. Studies discussed in this review were identified through PubMed searches between the years of 1966 to the present. We investigated studies of normal pregnancy and metabolic disorders in pregnancy that focused on energy requirements during pregnancy, endocrine regulation of glucose metabolism and insulin resistance, cholesterol and lipid metabolism, and placental hormone regulation.
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Affiliation(s)
- Brooke Armistead
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan
| | - Eugenia Johnson
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan
| | - Robert VanderKamp
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan
| | - Elzbieta Kula-Eversole
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan
| | - Leena Kadam
- Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan
| | - Sascha Drewlo
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan
| | - Hamid-Reza Kohan-Ghadr
- Department of Obstetrics, Gynecology and Reproductive Biology, College of Human Medicine, Michigan State University, Grand Rapids, Michigan
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Hu X, You L, Hu C, Wu J, Ai M, He X, Huang W, Wu Z. Effects of β‑hydroxybutyric acid and ghrelin on the motility and inflammation of gastric antral smooth muscle cells involving the regulation of growth hormone secretagogue receptor. Mol Med Rep 2019; 20:5050-5058. [PMID: 31638214 PMCID: PMC6854601 DOI: 10.3892/mmr.2019.10739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Accepted: 07/03/2019] [Indexed: 11/06/2022] Open
Abstract
Ghrelin is an orexigenic hormone that is produced by gastric cells. Ghrelin stimulates food intake and increases gastric movement. In rat model, injected β‑hydroxybutyric acid (β‑HB) leads to a decrease in body weight. It has been reported that patients with gastric erosions are slower to evacuate the stomach. The aim of the present study was to investigate the effects of ghrelin and β‑HB on motility and inflammation in rat gastric antral smooth muscle cells (GASMCs). GASMCs were extracted from rat gastric antrum. Cell viability was determined using the Cell Counting Kit‑8 assay. A reactive oxygen species (ROS) assay kit was used to analyze the levels of ROS using flow cytometry. Protein levels were determined using western blotting, and the expression levels of mRNAs were evaluated using reverse transcription‑quantitative PCR. β‑HB inhibited the expression of myosin regulatory light polypeptide 9 (MYL9), myosin light chain kinase (MLCK), transforming protein RhoA (RhoA), Rho‑associated protein kinase‑1 (ROCK‑1) and growth hormone secretagogue receptor (GHS‑R). By contrast, ghrelin increased the expression of MYL9, MLCK, RhoA, ROCK‑1 and GHS‑R in β‑HB‑treated GASMCs. β‑HB increased the levels of tumor necrosis factor (TNF)‑α, interleukin (IL)‑6 and ROS, and decreased the levels of manganese (Mn) superoxide dismutase (SOD), copper/zinc (Cu/Zn)SOD and catalase. Ghrelin decreased the expression of TNF‑α, IL‑6, ROS and catalase, whereas ghrelin promoted the expression of MnSOD and Cu/ZnSOD in β‑HB‑treated GASMCs. Short interfering RNA targeting GHS‑R inhibited the expression of MYL9, MLCK, RhoA and ROCK‑1, and increased the levels of TNF‑α, IL‑6 and ROS in β‑HB‑treated or ghrelin‑treated GASMCs. The present study provided preliminary evidence that β‑HB inhibits the motility of GASMCs and promotes inflammation in GASMCs, whereas ghrelin decreases these effects. GHS‑R acted as a primary regulator of motility and inflammation in GASMCs treated with β‑HB and ghrelin.
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Affiliation(s)
- Xiaolin Hu
- Department of Internal Medicine, Southwest University Hospital, Chongqing 400715, P.R. China
| | - Li You
- Department of Pharmacy, Southwest University Hospital, Chongqing 400715, P.R. China
| | - Changhua Hu
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P.R. China
| | - Juan Wu
- Department of Internal Medicine, Southwest University Hospital, Chongqing 400715, P.R. China
| | - Min Ai
- Department of Internal Medicine, Southwest University Hospital, Chongqing 400715, P.R. China
| | - Xiaoyan He
- College of Pharmaceutical Sciences, Southwest University, Chongqing 400715, P.R. China
| | - Wenjie Huang
- Department of Public Health, Southwest University Hospital, Chongqing 400715, P.R. China
| | - Zonghui Wu
- Health Management Center, Southwest University Hospital, Chongqing 400715, P.R. China
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14
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Blum RA, Mair S, Duus EM. Appetite and food intake results from phase I studies of anamorelin. J Cachexia Sarcopenia Muscle 2019; 10:1027-1035. [PMID: 31074178 PMCID: PMC6818453 DOI: 10.1002/jcsm.12439] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 03/18/2019] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Loss of appetite and body weight are potentially devastating, highly prevalent cancer complications. The ghrelin receptor is a mediator of appetite and metabolism, and anamorelin is a novel, orally administered ghrelin receptor agonist. Effects on appetite and food intake may influence body-weight gain but can be difficult to measure in multi-site studies. Here, we summarize two single-centre trials. METHODS Both trials were phase I, randomized, double-blind, placebo-controlled, partly/wholly crossover studies of healthy young adults. Study 102 tested single anamorelin doses of 1-20 mg. Assessments included post-dose self-ratings on 100 mm visual analogue scales for hunger, anticipated eating pleasure, and anticipated quantity of food consumption. Study 101 tested single 10, 25, and 50 mg doses. Assessments included the same scales plus caloric intake beginning 4 h post-dose. RESULTS Study 102 treated 16 male subjects (mean age, 26.3 years). Mean hunger scores generally increased after all treatments, with significant differences from placebo (P < 0.05) in the 5 mg anamorelin group at 0.5 and 1 h post-dose (+8.2 and +13.2 mm). Results for other scales were similar. Study 101 treated nine male subjects (mean age, 26.3 years). Pooled findings for anamorelin 25 and 50 mg vs. placebo showed significant mean increases in hunger scores at all but 1 pre-prandial time point, including the first assessment, 0.5 h post-dose (+10.9 vs. +0.7 mm, P = 0.0077), and the last assessment, 4 h post-dose (+32.7 vs. +7.0 mm, P = 0.0170), with a significant mean 18.4% increase vs. placebo in caloric intake (P = 0.0148). CONCLUSIONS In single-centre studies of healthy adults, single anamorelin doses of 1-20 mg elicited modest increases in hunger, and single doses of 25 and 50 mg achieved significant increases in hunger and caloric intake. The findings are consistent with dose-related weight gain reported in a prior phase I study as well as multi-centre findings in cachectic cancer patients and expand the evidence supporting anamorelin as a potential intervention.
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Affiliation(s)
- Robert A Blum
- Buffalo Clinical Research Center, LLC, Buffalo, NY, USA
| | | | - Elizabeth M Duus
- Formerly, Helsinn Therapeutics (US), Incorporated, Iselin, NJ, USA
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15
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Witjaksono F, Lukito W, Wijaya A, Annisa NG, Jutamulia J, Nurwidya F, Simadibrata M. The effect of breakfast with different macronutrient composition on PYY, ghrelin, and ad libitum intake 4 h after breakfast in Indonesian obese women. BMC Res Notes 2018; 11:787. [PMID: 30390699 PMCID: PMC6215622 DOI: 10.1186/s13104-018-3895-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Accepted: 10/27/2018] [Indexed: 01/02/2023] Open
Abstract
OBJECTIVES Gut hormones, such as PYY and ghrelin, are associated with appetite control and obesity. Protein is thought to be the most satiating nutrient and could affect the production of several gut hormones. The purpose of the current study was to find the effect of breakfast with different protein composition on PYY, ghrelin, and ad libitum intake 4 h after breakfast. RESULTS This clinical trial involves 22 obese women participants. Subjects were given three types of breakfast: low protein consumption (12.4% protein), medium protein (23.5% protein), and high protein (40.6% protein). PYY and ghrelin levels were measured at 0, 15, 60, 120, and 180 min after breakfast. Ad libitum meal was given 4 h after breakfast and measured after. This study found that there is no significant difference in PYY and ghrelin level at each measurement time between different type of breakfast. This study also found no significant difference of ad libitum energy intake between different type of breakfast. Trial registration ClinicalTrials.gov NCT03697486, 3 December 2018. Retrospectively registered.
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Affiliation(s)
- Fiastuti Witjaksono
- Department of Nutrition, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jl. Salemba Raya No. 6, Jakarta, 10430, Indonesia
| | - Widjaja Lukito
- Southeast Asian Ministers of Education Organization Regional Centre for Food and Nutrition (SEAMEO RECFON), Jl. Salemba Raya No. 6, Jakarta, 10430, Indonesia
| | - Andi Wijaya
- Department of Clinical Chemistry, Faculty of Medicine, Univeritas Hasanuddin, Jl. Perintis Kemerdekaan KM. 10, Makassar, 90245, Indonesia
| | - Nagita Gianty Annisa
- Department of Nutrition, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jl. Salemba Raya No. 6, Jakarta, 10430, Indonesia
| | - Joan Jutamulia
- Department of Nutrition, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jl. Salemba Raya No. 6, Jakarta, 10430, Indonesia
| | - Fariz Nurwidya
- Department of Nutrition, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jl. Salemba Raya No. 6, Jakarta, 10430, Indonesia. .,Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Indonesia, Persahabatan Hospital, Jalan Persahabatan Raya No.1, Jakarta, 13230, Indonesia.
| | - Marcellus Simadibrata
- Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Dr. Cipto Mangunkusumo Hospital, Jl. Salemba Raya No. 6, 10430, Jakarta, Indonesia
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Ghrelin, a gastrointestinal hormone, regulates energy balance and lipid metabolism. Biosci Rep 2018; 38:BSR20181061. [PMID: 30177523 PMCID: PMC6153372 DOI: 10.1042/bsr20181061] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 08/13/2018] [Accepted: 08/28/2018] [Indexed: 01/06/2023] Open
Abstract
Ghrelin, an acylated peptide hormone of 28 amino acids, is an endogenous ligand of the released growth hormone secretagogue receptor (GHSR). Ghrelin has been isolated from human and rat stomach and is also detected in the hypothalamic arcuate nucleus. Ghrelin receptor is primarily located in the neuropeptide Y and agouti-related protein neurons. Many previous studies have shown that ghrelin and GHSR are involved in the regulation of energy homeostasis, and its administration can increase food intake and body weight gain. AMP-activated protein kinase is activated by ghrelin in the hypothalamus, which contributes to lower intracellular long-chain fatty acid level. Ghrelin appears to modulate the response to food cues via a neural network involved in the regulation of feeding and in the appetitive response to food cues. It also increases the response of brain areas involved in visual processing, attention, and memory to food pictures. Ghrelin is also an important factor linking the central nervous system with peripheral tissues that regulate lipid metabolism. It promotes adiposity by the activation of hypothalamic orexigenic neurons and stimulates the expression of fat storage-related proteins in adipocytes. Meanwhile, ghrelin exerts direct peripheral effects on lipid metabolism, including increase in white adipose tissue mass, stimulation of lipogenesis in the liver, and taste sensitivity modulation.
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Morin V, Hozer F, Costemale-Lacoste JF. The effects of ghrelin on sleep, appetite, and memory, and its possible role in depression: A review of the literature. Encephale 2018; 44:256-263. [DOI: 10.1016/j.encep.2017.10.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Revised: 10/01/2017] [Accepted: 10/02/2017] [Indexed: 12/13/2022]
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Koca SS, Kara M, Özgen M, Dayanan R, Demir CF, Aksoy K, İlhan N, Dönder E, Işık A. Low prevalence of obesity in Behçet's disease is associated with high obestatin level. Eur J Rheumatol 2017. [PMID: 28638683 DOI: 10.5152/eurjrheum.2017.160095] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
OBJECTIVE Chronic inflammatory diseases are associated with altered body composition. Ghrelin has anti-inflammatory effects, and its level is altered in obesity and inflammatory diseases. The aim of the study was to evaluate the prevalence of obesity and ghrelin and obestatin levels in patients with Behçet's disease (BD). MATERIAL AND METHODS One hundred and forty-three (143) patients with BD and 112 healthy controls (HC) were enrolled. Participants were subdivided according to the body mass index (BMI) as lean (<18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25-29.9 kg/m2) and obese (≥30 kg/m2). In addition to the routine evaluations (fasting blood glucose, lipid profile, and kidney and liver function tests), serum acylated-ghrelin (AG), unacylated-ghrelin (UAG), total ghrelin (TG) and obestatin levels were analyzed. Student's t-test and chi-square test were used for statistical analysis. RESULTS The prevalence of obesity was relatively lower in the BD group than in the HC group (12.6% vs. 20.5%, p=0.089). Serum ghrelin levels were similar in the BD and HC groups (p>0.05 for all) although the obestatin level was higher in the BD group compared to the HC group (p<0.001). Serum UAG, TG and obestatin levels were lower in obese BD patients (n=18) than non-obese BD patients (p=0.027, p=0.014 and p=0.001, respectively). CONCLUSION The obestatin level was high and the prevalence of obesity was low in the BD group. Moreover, obese BD patients had low obestatin levels. These results suggest that obestatin may protect BD patients from obesity.
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Affiliation(s)
| | - Murat Kara
- Department of Medical Genetics, Sıtkı Koçman University School of Medicine, Muğla, Turkey
| | - Metin Özgen
- Department of Rheumatology, 19 Mayıs University School of Medicine, Samsun, Turkey
| | - Ramazan Dayanan
- Department of Internal Medicine, Fırat University School of Medicine, Elazığ, Turkey
| | - Caner Feyzi Demir
- Department of Neurology, Fırat University School of Medicine, Elazığ, Turkey
| | - Kader Aksoy
- Department of Endocrinology, Fırat University School of Medicine, Elazığ, Turkey
| | - Nevin İlhan
- Department of Biochemistry, Fırat University School of Medicine, Elazığ, Turkey
| | - Emir Dönder
- Department of Internal Medicine, Fırat University School of Medicine, Elazığ, Turkey
| | - Ahmet Işık
- Department of Rheumatology, Fırat University School of Medicine, Elazığ, Turkey
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Sipe LM, Yang C, Ephrem J, Garren E, Hirsh J, Deppmann CD. Differential sympathetic outflow to adipose depots is required for visceral fat loss in response to calorie restriction. Nutr Diabetes 2017; 7:e260. [PMID: 28394360 PMCID: PMC5436093 DOI: 10.1038/nutd.2017.13] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 02/01/2017] [Indexed: 01/10/2023] Open
Abstract
The sympathetic nervous system (SNS) regulates energy homeostasis in part by governing fatty acid liberation from adipose tissue. We first examined whether SNS activity toward discrete adipose depots changes in response to a weight loss diet in mice. We found that SNS activity toward each adipose depot is unique in timing, pattern of activation, and habituation with the most dramatic contrast between visceral and subcutaneous adipose depots. Sympathetic drive toward visceral epididymal adipose is more than doubled early in weight loss and then suppressed later in the diet when weight loss plateaued. Coincident with the decline in SNS activity toward visceral adipose is an increase in activity toward subcutaneous depots indicating a switch in lipolytic sources. In response to calorie restriction, SNS activity toward retroperitoneal and brown adipose depots is unaffected. Finally, pharmacological blockage of sympathetic activity on adipose tissue using the β3-adrenergic receptor antagonist, SR59230a, suppressed loss of visceral adipose mass in response to diet. These findings indicate that SNS activity toward discrete adipose depots is dynamic and potentially hierarchical. This pattern of sympathetic activation is required for energy liberation and loss of adipose tissue in response to calorie-restricted diet.
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Affiliation(s)
- L M Sipe
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - C Yang
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - J Ephrem
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - E Garren
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - J Hirsh
- Department of Biology, University of Virginia, Charlottesville, VA, USA
| | - C D Deppmann
- Department of Biology, University of Virginia, Charlottesville, VA, USA.,Department of Cell Biology, University of Virginia, Charlottesville, VA, USA.,Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA.,Department of Neuroscience, University of Virginia, Charlottesville, VA, USA
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Churm R, Davies JS, Stephens JW, Prior SL. Ghrelin function in human obesity and type 2 diabetes: a concise review. Obes Rev 2017; 18:140-148. [PMID: 27899023 DOI: 10.1111/obr.12474] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2016] [Revised: 09/06/2016] [Accepted: 09/06/2016] [Indexed: 12/12/2022]
Abstract
The 28 amino acid hormone, ghrelin, has been found to have various effects on metabolism. This review will focus on the pathways integrated into ghrelin's effect within the hypothalamus, pancreas and adipocytes. The identification of molecules and pathways that regulate ghrelin-mediated lipid retention could establish new mechanisms underlying cellular energy homeostasis. The impact of acyl-ghrelin on glucose metabolism and lipid homeostasis may allow for novel preventative or early intervention therapeutic strategies to treat obesity related type 2 diabetes and associated metabolic dysfunction.
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Affiliation(s)
- R Churm
- Diabetes Research Group, Institute of Life Science 1, Swansea University, Swansea, UK
| | - J S Davies
- Molecular Neurobiology Research Group, Institute of Life Science 1, Swansea University, Swansea, UK
| | - J W Stephens
- Diabetes Research Group, Institute of Life Science 1, Swansea University, Swansea, UK
| | - S L Prior
- Diabetes Research Group, Institute of Life Science 1, Swansea University, Swansea, UK
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Mikulášková B, Maletínská L, Zicha J, Kuneš J. The role of food intake regulating peptides in cardiovascular regulation. Mol Cell Endocrinol 2016; 436:78-92. [PMID: 27450151 DOI: 10.1016/j.mce.2016.07.021] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 07/07/2016] [Accepted: 07/19/2016] [Indexed: 12/11/2022]
Abstract
Obesity is a risk factor that worsens cardiovascular events leading to higher morbidity and mortality. However, the exact mechanisms of relation between obesity and cardiovascular events are unclear. Nevertheless, it has been demonstrated that pharmacological therapy for obesity has great potential to improve some cardiovascular problems. Therefore, it is important to determine the common mechanisms regulating both food intake and blood pressure. Several hormones produced by peripheral tissues work together with neuropeptides involved in the regulation of both food intake and blood pressure. Anorexigenic (food intake lowering) hormones such as leptin, glucagon-like peptide-1 and cholecystokinin cooperate with α-melanocyte-stimulating hormone, cocaine- and amphetamine-regulated peptide as well as prolactin-releasing peptide. Curiously their collective actions result in increased sympathetic activity, especially in the kidney, which could be one of the factors responsible for the blood pressure increases seen in obesity. On the other hand, orexigenic (food intake enhancing) peptides, especially ghrelin released from the stomach and acting in the brain, cooperates with orexins, neuropeptide Y, melanin-concentrating hormone and galanin, which leads to decreased sympathetic activity and blood pressure. This paradox should be intensively studied in the future. Moreover, it is important to know that the hypothalamus together with the brainstem seem to be major structures in the regulation of food intake and blood pressure. Thus, the above mentioned regions might be essential brain components in the transmission of peripheral signals to the central effects. In this short review, we summarize the current information on cardiovascular effects of food intake regulating peptides.
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Affiliation(s)
- B Mikulášková
- Institute of Physiology AS CR, Prague, Czech Republic; Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic
| | - L Maletínská
- Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic
| | - J Zicha
- Institute of Physiology AS CR, Prague, Czech Republic
| | - J Kuneš
- Institute of Physiology AS CR, Prague, Czech Republic; Institute of Organic Chemistry and Biochemistry AS CR, Prague, Czech Republic.
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Panissa VLG, Julio UF, Hardt F, Kurashima C, Lira FS, Takito MY, Franchini E. Effect of exercise intensity and mode on acute appetite control in men and women. Appl Physiol Nutr Metab 2016; 41:1083-1091. [DOI: 10.1139/apnm-2016-0172] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
The aim of this study was to compare the effects of exercise intensity on appetite control: relative energy intake (energy intake minus the energy expenditure of exercise; REI), hunger scores, and appetite-regulating hormones in men and women. Eleven men and 9 women were submitted to 4 experimental sessions: high-intensity intermittent all-out exercise (HIIE-A) for 60 × 8 s interspersed by 12 s of passive recovery; high-intensity intermittent exercise (HIIE) at 100% of maximal load attained in incremental test; steady-state exercise at 60% of maximal load, matched by work done; and a control session. Exercise was performed 1.5 h after a standardized breakfast, and an ad libitum lunch was offered 4 h after breakfast. Blood concentration of insulin, cortisol, acylated ghrelin, peptideYY3-36, glucose, and hunger scores were measured when fasting, and at 1.5, 2, 3.25, and 4 h of experiment. REI was lower in all exercises than in the control, without differences between exercises and sex showing no compensation in energy intake because of any exercise; the hunger scores were lower only in the exercises performed at higher intensity (HIIE and HIIE-A) compared with the control. The area under the curve of acylated ghrelin was lower in the HIIE-A when compared with the control. PeptideYY3-36 was higher in men than women and cortisol higher in women than men independently of the condition. Although high-intensity exercises promoted a little more pronounced effects in the direction of suppressing the appetite, no differences were observed in REI, demonstrating that these modifications were not sufficient to affect energy intake.
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Affiliation(s)
| | - Ursula Ferreira Julio
- Department of Sport, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Felipe Hardt
- Department of Sport, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Carolina Kurashima
- Department of Human Movement Pedagogy, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Fábio Santos Lira
- Exercise and Immunometabolism Research Group, Department of Physical Education, Paulista State University, UNESP, Presidente Prudente, São Paulo, Brazil
| | - Monica Yuri Takito
- Department of Human Movement Pedagogy, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
| | - Emerson Franchini
- Department of Sport, School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
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Abstract
Background Obesity is a consequence of chronic energy imbalance. We need accurate and precise measurements of energy intake and expenditure, as well as the related behaviors, to fully understand how energy homeostasis is regulated in order to develop interventions and evaluate their effectiveness to combat the global obesity epidemic. Scope of review We provide an in-depth review of the methodologies currently used to measure energy intake and expenditure in humans, including their principles, advantages, and limitations in the clinical research setting. The aim is to provide researchers with a comprehensive guide to conduct obesity research of the highest possible quality. Major conclusions An array of methodologies is available to measure various aspects of energy metabolism and none is perfect under all circumstances. The choice of methods should be specific to particular research questions with practicality and quality of data the priorities for consideration. A combination of complementary measurements may be preferable. There is an imperative need to develop new methodologies to improve the accuracy and precision of energy intake assessments.
Image-based technology is a significant step to improve energy intake measurement. Physical activity informs patterns but not absolute energy expenditure. Combining complementary measurements overcomes shortfalls of individual methods.
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Eslami Z, Torabizadeh M, Talebpour Z, Talebpour M, Ghassempour A, Aboul-Enein HY. Simple and Sensitive Quantification of Ghrelin Hormone in Human Plasma Using SBSE-HPLC/DAD-MS. J Chromatogr Sci 2016; 54:1652-1660. [DOI: 10.1093/chromsci/bmw125] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Revised: 06/15/2016] [Indexed: 11/14/2022]
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Ghrelin Actions on Somatotropic and Gonadotropic Function in Humans. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 138:3-25. [PMID: 26940384 DOI: 10.1016/bs.pmbts.2015.11.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ghrelin, a 28 amino-acid octanoylated peptide predominantly produced by the stomach, was discovered to be the natural ligand of the type 1a GH secretagogue receptor (GHS-R1a). It was thus considered as a natural GHS additional to GHRH, although later on ghrelin has mostly been considered a major orexigenic factor. The GH-releasing action of ghrelin takes place both directly on pituitary cells and through modulation of GHRH from the hypothalamus; some functional antisomatostatin action has also been shown. However, ghrelin is much more than a natural GH secretagogue. In fact, it also modulates lactotroph and corticotroph secretion in humans as well as in animals and plays a relevant role in the modulation of the hypothalamic-pituitary-gonadal function. Several studies have indicated that ghrelin plays an inhibitory effect on gonadotropin pulsatility, is involved in the regulation of puberty onset in animals, and may regulate spermatogenesis, follicular development and ovarian cell functions in humans. In this chapter ghrelin actions on the GH/IGF-I and the gonadal axes will be revised. The potential therapeutic role of ghrelin as a treatment of catabolic conditions will also be discussed.
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Li Z, Mulholland M, Zhang W. Ghrelin O-acyltransferase (GOAT) and energy metabolism. SCIENCE CHINA-LIFE SCIENCES 2016; 59:281-91. [PMID: 26732975 DOI: 10.1007/s11427-015-4973-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/09/2015] [Indexed: 12/16/2022]
Abstract
Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.
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Affiliation(s)
- Ziru Li
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109-0346, USA
| | - Michael Mulholland
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109-0346, USA.
| | - Weizhen Zhang
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109-0346, USA. .,Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191, China.
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28
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Reichelt AC, Westbrook RF, Morris MJ. Integration of reward signalling and appetite regulating peptide systems in the control of food-cue responses. Br J Pharmacol 2015; 172:5225-38. [PMID: 26403657 DOI: 10.1111/bph.13321] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2015] [Revised: 07/28/2015] [Accepted: 08/27/2015] [Indexed: 12/24/2022] Open
Abstract
Understanding the neurobiological substrates that encode learning about food-associated cues and how those signals are modulated is of great clinical importance especially in light of the worldwide obesity problem. Inappropriate or maladaptive responses to food-associated cues can promote over-consumption, leading to excessive energy intake and weight gain. Chronic exposure to foods rich in fat and sugar alters the reinforcing value of foods and weakens inhibitory neural control, triggering learned, but maladaptive, associations between environmental cues and food rewards. Thus, responses to food-associated cues can promote cravings and food-seeking by activating mesocorticolimbic dopamine neurocircuitry, and exert physiological effects including salivation. These responses may be analogous to the cravings experienced by abstaining drug addicts that can trigger relapse into drug self-administration. Preventing cue-triggered eating may therefore reduce the over-consumption seen in obesity and binge-eating disorder. In this review we discuss recent research examining how cues associated with palatable foods can promote reward-based feeding behaviours and the potential involvement of appetite-regulating peptides including leptin, ghrelin, orexin and melanin concentrating hormone. These peptide signals interface with mesolimbic dopaminergic regions including the ventral tegmental area to modulate reactivity to cues associated with palatable foods. Thus, a novel target for anti-obesity therapeutics is to reduce non-homeostatic, reward driven eating behaviour, which can be triggered by environmental cues associated with highly palatable, fat and sugar rich foods.
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Affiliation(s)
- A C Reichelt
- School of Psychology, UNSW Sydney, Sydney, UNSW, Australia.,School of Medical Sciences, UNSW Sydney, Sydney, UNSW, Australia
| | - R F Westbrook
- School of Psychology, UNSW Sydney, Sydney, UNSW, Australia
| | - M J Morris
- School of Medical Sciences, UNSW Sydney, Sydney, UNSW, Australia
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Hunt RH, Camilleri M, Crowe SE, El-Omar EM, Fox JG, Kuipers EJ, Malfertheiner P, McColl KEL, Pritchard DM, Rugge M, Sonnenberg A, Sugano K, Tack J. The stomach in health and disease. Gut 2015; 64:1650-68. [PMID: 26342014 PMCID: PMC4835810 DOI: 10.1136/gutjnl-2014-307595] [Citation(s) in RCA: 241] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2015] [Accepted: 07/14/2015] [Indexed: 12/12/2022]
Abstract
The stomach is traditionally regarded as a hollow muscular sac that initiates the second phase of digestion. Yet this simple view ignores the fact that it is the most sophisticated endocrine organ with unique physiology, biochemistry, immunology and microbiology. All ingested materials, including our nutrition, have to negotiate this organ first, and as such, the stomach is arguably the most important segment within the GI tract. The unique biological function of gastric acid secretion not only initiates the digestive process but also acts as a first line of defence against food-borne microbes. Normal gastric physiology and morphology may be disrupted by Helicobacter pylori infection, the most common chronic bacterial infection in the world and the aetiological agent for most peptic ulcers and gastric cancer. In this state-of-the-art review, the most relevant new aspects of the stomach in health and disease are addressed. Topics include gastric physiology and the role of gastric dysmotility in dyspepsia and gastroparesis; the stomach in appetite control and obesity; there is an update on the immunology of the stomach and the emerging field of the gastric microbiome. H. pylori-induced gastritis and its associated diseases including peptic ulcers and gastric cancer are addressed together with advances in diagnosis. The conclusions provide a future approach to gastric diseases underpinned by the concept that a healthy stomach is the gateway to a healthy and balanced host. This philosophy should reinforce any public health efforts designed to eradicate major gastric diseases, including stomach cancer.
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Affiliation(s)
- R H Hunt
- Division of Gastroenterology, Farncombe Family Digestive Health Research Institute, McMaster University Health Science Centre, Hamilton, Ontario, Canada
| | - M Camilleri
- Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - S E Crowe
- Division of Gastroenterology, Department of Medicine, University of California, San Diego, La Jolla, California, USA
| | - E M El-Omar
- Division of Applied Medicine, Aberdeen University, Institute of Medical Sciences, Foresterhill, Aberdeen, UK
| | - J G Fox
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
| | - E J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - P Malfertheiner
- Klinik für Gastroenterologie, Hepatologie und Infektiologi Universitätsklinikum Magdeburg A.ö.R.Leipziger Str. 44, Magdeburg, Germany
| | - K E L McColl
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - D M Pritchard
- Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK
| | - M Rugge
- Department of Medicine DIMED, Pathology & Cytopathology Unit, University of Padova, Padova, Italy
| | - A Sonnenberg
- Department of Gastroenterology, Oregon Health Science University, Portland, Oregon, USA
| | - K Sugano
- Department of Internal Medicine, Jichi Medical School, Shimotsuke, Japan
| | - J Tack
- Translational Research in GastroIntestinal Disorders, Leuven, Belgium
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Weiss N, Zamponi GW. All roads lead to presynaptic calcium channel inhibition by the ghrelin receptor: Separate agonist-dependent and -independent signaling pathways. ACTA ACUST UNITED AC 2015; 146:201-4. [PMID: 26283201 PMCID: PMC4555476 DOI: 10.1085/jgp.201511462] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- Norbert Weiss
- Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, v.v.i., 199 00 Prague 9, Czech Republic
| | - Gerald W Zamponi
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada
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Schellekens H, De Francesco PN, Kandil D, Theeuwes WF, McCarthy T, van Oeffelen WEPA, Perelló M, Giblin L, Dinan TG, Cryan JF. Ghrelin's Orexigenic Effect Is Modulated via a Serotonin 2C Receptor Interaction. ACS Chem Neurosci 2015; 6:1186-97. [PMID: 25727097 DOI: 10.1021/cn500318q] [Citation(s) in RCA: 82] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Understanding the intricate pathways that modulate appetite and subsequent food intake is of particular importance considering the rise in the incidence of obesity across the globe. The serotonergic system, specifically the 5-HT2C receptor, has been shown to be of critical importance in the regulation of appetite and satiety. The GHS-R1a receptor is another key receptor that is well-known for its role in the homeostatic control of food intake and energy balance. We recently showed compelling evidence for an interaction between the GHS-R1a receptor and the 5-HT2C receptor in an in vitro cell line system heterologously expressing both receptors. Here, we investigated this interaction further. First, we show that the GHS-R1a/5-HT2C dimer-induced attenuation of calcium signaling is not due to coupling to GαS, as no increase in cAMP signaling is observed. Next, flow cytometry fluorescence resonance energy transfer (fcFRET) is used to further demonstrate the direct interaction between the GHS-R1a receptor and 5-HT2C receptor. In addition, we demonstrate colocalized expression of the 5-HT2C and GHS-R1a receptor in cultured primary hypothalamic and hippocampal rat neurons, supporting the biological relevance of a physiological interaction. Furthermore, we demonstrate that when 5-HT2C receptor signaling is blocked ghrelin's orexigenic effect is potentiated in vivo. In contrast, the specific 5-HT2C receptor agonist lorcaserin, recently approved for the treatment of obesity, attenuates ghrelin-induced food intake. This underscores the biological significance of our in vitro findings of 5-HT2C receptor-mediated attenuation of GHS-R1a receptor activity. Together, this study demonstrates, for the first time, that the GHS-R1a/5-HT2C receptor interaction translates into a biologically significant modulation of ghrelin's orexigenic effect. This data highlights the potential development of a combined GHS-R1a and 5-HT2C receptor treatment strategy in weight management.
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Affiliation(s)
| | - Pablo N. De Francesco
- Laboratory
of Neurophysiology, Multidisciplinary Institute of Cell Biology, National Scientific and Technical Research Council, La Plata, Argentina
| | | | | | | | | | - Mario Perelló
- Laboratory
of Neurophysiology, Multidisciplinary Institute of Cell Biology, National Scientific and Technical Research Council, La Plata, Argentina
| | - Linda Giblin
- Teagasc Food Research Centre, Moorepark, Fermoy, Co. Cork, Ireland
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Altabas V, Zjačić-Rotkvić V. Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacotherapy. Immunotargets Ther 2015; 4:123-30. [PMID: 27471718 PMCID: PMC4918252 DOI: 10.2147/itt.s60398] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Obesity is a medical condition caused by accumulated excess body fat with negative impact on patients’ health, including decreased life expectancy. It has become a major health problem in most developed and developing countries, since the worldwide prevalence of obesity nearly doubled during the last 30 years. Consequently, novel treatments focusing on obesity are being investigated. Potential targets include several pathophysiological mechanisms involved in appetite control affecting multiple organ systems, like adipose tissue; some cell types in the stomach and gut; pancreas; thyroid gland; several hypothalamic areas; and centers located in the brainstem. One of the most important orexigenic neuropeptides is ghrelin, which is produced and secreted primarily by ghrelin cells located in the stomach and duodenum. In humans, plasma ghrelin levels rise when the stomach is empty and fall shortly after meal ingestion. In fat tissue, ghrelin increases fat storage. In the brain, it exerts its orexigenic action through activation of NPY/AgRP neurons in the arcuate nucleus. From the pharmacological point of view, it seems that opposing ghrelin activity could be used as a therapeutic principle in treating obesity. The principal idea of antiobesity drugs is to augment anorexigenic and lipolytic signaling, or to block orexigenic and lipogenic mediators. Recent studies have shown that therapeutic vaccines could be a new approach in the development of antiobesity medications. A vaccine should provoke an immune response to a specific causal factor for a particular disease. Several types of anti-ghrelin vaccines have been developed so far, with significant immune response in terms of rising anti-ghrelin antibodies. However, in the only clinical trial performed yet, the results were disappointing, showing no additional weight loss in the study group. Until now, several studies have demonstrated the “proof of concept”, but more studies are required to develop prophylactic and therapeutic vaccines to prevent and/or cure obesity.
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Affiliation(s)
- Velimir Altabas
- Department of Endocrinology, Diabetes and Metabolic Diseases, "Mladen Sekso", Clinic for Internal Medicine, University Hospital Center "Sestre milosrdnice", Zagreb, Croatia
| | - Vanja Zjačić-Rotkvić
- Department of Endocrinology, Diabetes and Metabolic Diseases, "Mladen Sekso", Clinic for Internal Medicine, University Hospital Center "Sestre milosrdnice", Zagreb, Croatia
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33
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Schumacher D. Pharmacological Management of the Obese Patient. Am J Lifestyle Med 2015. [DOI: 10.1177/1559827613504733] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Being obese goes beyond moral failure or a character flaw. Obesity has the defining characteristics of a chronic disease for which there is no cure. Treatment may require lifelong treatment which may include pharmacotherapy. Experience with long term use of obesity drugs is limited but evidence suggests that pharmacotherapy can improve patient outcomes and patient outlook. With current obesity drugs, weight loss is usually modest but clinically significant satisfying the FDA threshold for drug effectiveness. This weight loss is associated with clinically significant improvements in many obesity co morbidities and risk factors and could eliminate some risk factors with continued use. When used in conjunction with a comprehensive program for weight management, obesity drugs can reduce appetite or hunger, increase satiety, provide improved control over aberrant eating behaviors and modify food seeking behaviors. Pharmacotherapy can enhance weight loss and compliance during the periods of weight loss and in maintaining that weight loss, increasing physical activity and may enhance a focus on making life long changes. This article will discuss mechanisms of action of obesity drugs, theories of altered body defense of body weight, Food and Drug Administration (FDA) approved obesity drugs, and off-label use of FDA approved drugs. The value of over-the counter (OTC) medications and diet supplements, as well as fat substitutes in the treatment of obesity drugs will be explored. Obesity drugs awaiting FDA approval and compounds under development will be reviewed. The section on approaches to drug management will include clinical considerations for; who should receive pharmacotherapy and when, length of treatment and drug discontinuation, weight regain and the role of pharmacotherapy.
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Scott RV, Tan TM, Bloom SR. Can Bayliss and Starling gut hormones cure a worldwide pandemic? J Physiol 2014; 592:5153-67. [PMID: 25217372 PMCID: PMC4262331 DOI: 10.1113/jphysiol.2014.272955] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Accepted: 09/04/2014] [Indexed: 12/17/2022] Open
Abstract
Bayliss and Starling first coined the term 'hormone' with reference to secretin, a substance they found that was produced by the gut, but released into the blood stream to act at a distance. The intestine is now known as the largest endocrine organ in the body, and it produces numerous hormones with a wide range of functions. These include controlling appetite and energy homeostasis. Obesity is one of the greatest health threats facing the world today. At present, the only successful treatment is surgery. Bariatric procedures such as the Roux-en-Y bypass work by elevating gut hormones that induce satiety. Significant research has gone into producing versions of these hormones that can be delivered therapeutically to treat obesity. This review looks at the role of gut hormones in obesity, and the development of gut hormone-derived obesity treatments.
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Affiliation(s)
- R V Scott
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - T M Tan
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
| | - S R Bloom
- Division of Diabetes, Endocrinology and Metabolism, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK
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Najib K, Moghtaderi M, Farjadian S, Falahzadeh E. Low postprandial circulating inactive ghrelin: role of early satiety in undernourished children. Indian J Pediatr 2014; 81:1147-50. [PMID: 24659412 DOI: 10.1007/s12098-014-1355-1] [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: 05/21/2013] [Accepted: 01/13/2014] [Indexed: 11/30/2022]
Abstract
OBJECTIVE To determine difference in the levels of circulating inactive ghrelin between undernourished and healthy children. METHODS The present cross-sectional study was conducted in undernourished children from southwestern Iran, from July 2011 through July 2012. Postprandial inactive ghrelin levels were measured in 40 undernourished children and sex- and age-matched healthy controls by enzyme immunoassay. RESULTS The levels of postprandial inactive ghrelin were considerably lower in undernourished compared to the healthy children (6.4 vs. 12.9, P < 0.001). Among the undernourished children, the level of inactive ghrelin was significantly lower in girls than in boys (5.8 vs. 7.1, P = 0.032). CONCLUSIONS Thus, the levels of inactive ghrelin was found to be low in undernourished children compared to healthy children. Early loss of appetite might be a result of low circulating inactive ghrelin levels in the postprandial state in undernourished children.
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Affiliation(s)
- Khadijehsadat Najib
- Allergy Research Center, Shiraz University of Medical Sciences, Zand St, 71348-45794, Shiraz, Iran
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Borer KT. Counterregulation of insulin by leptin as key component of autonomic regulation of body weight. World J Diabetes 2014; 5:606-629. [PMID: 25317239 PMCID: PMC4138585 DOI: 10.4239/wjd.v5.i5.606] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2013] [Revised: 05/15/2014] [Accepted: 06/03/2014] [Indexed: 02/05/2023] Open
Abstract
A re-examination of the mechanism controlling eating, locomotion, and metabolism prompts formulation of a new explanatory model containing five features: a coordinating joint role of the (1) autonomic nervous system (ANS); (2) the suprachiasmatic (SCN) master clock in counterbalancing parasympathetic digestive and absorptive functions and feeding with sympathetic locomotor and thermogenic energy expenditure within a circadian framework; (3) interaction of the ANS/SCN command with brain substrates of reward encompassing dopaminergic projections to ventral striatum and limbic and cortical forebrain. These drive the nonhomeostatic feeding and locomotor motivated behaviors in interaction with circulating ghrelin and lateral hypothalamic neurons signaling through melanin concentrating hormone and orexin-hypocretin peptides; (4) counterregulation of insulin by leptin of both gastric and adipose tissue origin through: potentiation by leptin of cholecystokinin-mediated satiation, inhibition of insulin secretion, suppression of insulin lipogenesis by leptin lipolysis, and modulation of peripheral tissue and brain sensitivity to insulin action. Thus weight-loss induced hypoleptimia raises insulin sensitivity and promotes its parasympathetic anabolic actions while obesity-induced hyperleptinemia supresses insulin lipogenic action; and (5) inhibition by leptin of bone mineral accrual suggesting that leptin may contribute to the maintenance of stability of skeletal, lean-body, as well as adipose tissue masses.
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Torres-Fuentes C, Theeuwes WF, McMullen MK, McMullen AK, Dinan TG, Cryan JF, Schellekens H. Devil's Claw to suppress appetite--ghrelin receptor modulation potential of a Harpagophytum procumbens root extract. PLoS One 2014; 9:e103118. [PMID: 25068823 PMCID: PMC4113378 DOI: 10.1371/journal.pone.0103118] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2014] [Accepted: 06/25/2014] [Indexed: 11/29/2022] Open
Abstract
Ghrelin is a stomach-derived peptide that has been identified as the only circulating hunger hormone that exerts a potent orexigenic effect via activation of its receptor, the growth hormone secretagogue receptor (GHS-R1a). Hence, the ghrelinergic system represents a promising target to treat obesity and obesity-related diseases. In this study we analysed the GHS-R1a receptor activating potential of Harpagophytum procumbens, popularly known as Devil's Claw, and its effect on food intake in vivo. H. procumbens is an important traditional medicinal plant from Southern Africa with potent anti-inflammatory and analgesic effects. This plant has been also used as an appetite modulator but most evidences are anecdotal and to our knowledge, no clear scientific studies relating to appetite modulation have been done to this date. The ghrelin receptor activation potential of an extract derived from the dried tuberous roots of H. procumbens was analysed by calcium mobilization and receptor internalization assays in human embryonic kidney cells (Hek) stably expressing the GHS-R1a receptor. Food intake was investigated in male C57BL/6 mice following intraperitoneal administration of H. procumbens root extract in ad libitum and food restricted conditions. Exposure to H. procumbens extract demonstrated a significant increased cellular calcium influx but did not induce subsequent GHS-R1a receptor internalization, which is a characteristic for full receptor activation. A significant anorexigenic effect was observed in male C57BL/6 mice following peripheral administration of H. procumbens extract. We conclude that H. procumbens root extract is a potential novel source for potent anti-obesity bioactives. These results reinforce the promising potential of natural bioactives to be developed into functional foods with weight-loss and weight maintenance benefits.
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Affiliation(s)
| | - Wessel F. Theeuwes
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Michael K. McMullen
- Life Force Research, Ljungskile, Sweden
- School of Biosciences, University of Westminster, London, United Kingdom
| | | | - Timothy G. Dinan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Dept of Psychiatry, University College Cork, Cork, Ireland
| | - John F. Cryan
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
| | - Harriët Schellekens
- Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
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Abstract
Although the stomach is often perceived as a crude, food-grinding, muscular bag, scientific breakthroughs have shown us that in the case of the stomach there is more than meets the eye. The endocrine function of the stomach is mainly exerted through the actions of ghrelin, an acylated peptide hormone that is the first known and so far most extensively studied endogenous orexigenic substance. The satiety-hunger balance is kept in check by many anorexigenic gut hormones among which is the deacylated form of ghrelin--desacyl ghrelin. The interplay of gut hormones affects the brain directly, as most gut hormones cross the blood-brain barrier and bind to their respective receptors in the central nervous system. Other hormones like obestatin and nesfatin are secreted from the stomach along with ghrelin, yet their physiological function is to be elucidated. The importance of the satiety-hunger balance can be seen in its most typical derangement--obesity. Some studies imply that ghrelin, along with other gut hormones, plays an important part in the pathophysiology of obesity. More importantly, it seems that the mechanisms by which bariatric surgery procedures induce weight loss are primarily based on changing the gut hormone levels, including ghrelin. If proven, ghrelin antagonists could be the renaissance of pharmacological obesity treatment.
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Affiliation(s)
- Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
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Li E, Kim Y, Kim S, Sato T, Kojima M, Park S. Ghrelin stimulates proliferation, migration and differentiation of neural progenitors from the subventricular zone in the adult mice. Exp Neurol 2014; 252:75-84. [DOI: 10.1016/j.expneurol.2013.11.021] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2013] [Revised: 11/21/2013] [Accepted: 11/22/2013] [Indexed: 12/29/2022]
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40
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Abstract
In the developed world, the hazards associated with obesity have largely outstripped the risk of starvation. Obesity remains a difficult public health issue to address, due in large part to the many disciplines involved. A full understanding requires knowledge in the fields of genetics, endocrinology, psychology, sociology, economics, and public policy - among others. In this short review, which serves as an introduction to the Frontiers in Endocrinology research topic, we address one cross-disciplinary relationship: the interaction between the hunger/satiation neural circuitry, an individual's perceived locus of control, and the risk for obesity. Mammals have evolved a complex system for modulating energy intake. Overlaid on this, in humans, there exists a wide variation in "perceived locus of control" - that is, the extent to which an individual believes to be in charge of the events that affect them. Whether one has primarily an internal or external locus of control itself affects, and is affected by, external and physiological factors and has been correlated with the risk for obesity. Thus, the path from hunger and satiation to an individual's actual behavior may often be moderated by psychological factors, included among which is locus of control.
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Affiliation(s)
- Florence Neymotin
- Nova Southeastern University, Fort Lauderdale, FL, USA
- *Correspondence: Florence Neymotin, Nova Southeastern University, 3301 College Avenue, Fort Lauderdale, FL 33314, USA e-mail:
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Fang P, Shi M, Yu M, Guo L, Bo P, Zhang Z. Endogenous peptides as risk markers to assess the development of insulin resistance. Peptides 2014; 51:9-14. [PMID: 24184593 DOI: 10.1016/j.peptides.2013.10.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 10/19/2013] [Accepted: 10/21/2013] [Indexed: 01/15/2023]
Abstract
Insulin resistance, the reciprocal of insulin sensitivity, is known to be a characteristic of type 2 diabetes mellitus, and is regarded as an important mechanism in the pathogenesis. The hallmark of insulin resistance is a gradual break-down of insulin-regulative glucose uptake by muscle and adipose tissues in subjects. Insulin resistance is increasingly estimated in various disease conditions to examine and assess their etiology, pathogenesis and consequences. Although our understanding of insulin resistance has tremendously been improved in recent years, certain aspects of its estimation and etiology still remain elusive to clinicians and researchers. There are numerous factors involved in pathogenesis and mechanisms of insulin resistance. Recent studies have provided compelling clues about some peptides and proteins, including galanin, galanin-like peptide, ghrelin, adiponectin, retinol binding protein 4 (RBP4) and CRP, which may be used to simplify and to improve the determination of insulin resistance. And alterations of these peptide levels may be recognized as risk markers of developing insulin resistance and type 2 diabetes mellitus. This review examines the updated information for these peptides, highlighting the relations between these peptide levels and insulin resistance. The plasma high ghrelin, RBP4 and CRP as well as low galanin, GALP and adiponectin levels may be taken as the markers of deteriorating insulin resistance. An increase in the knowledge of these marker proteins and peptides will help us correctly diagnose and alleviate insulin resistance in clinic and study.
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Affiliation(s)
- Penghua Fang
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China; Department of Physiology, Nanjing University of Chinese Medicine Hanlin College, Taizhou, Jiangsu 225300, China
| | - Mingyi Shi
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Mei Yu
- Taizhou Hospital of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Taizhou, Jiangsu 225300, China
| | - Lili Guo
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Ping Bo
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China
| | - Zhenwen Zhang
- Research Institution of Combining Chinese Traditional and Western Medicine, Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China; Department of Endocrinology, Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu 225001, China.
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Schellekens H, Dinan TG, Cryan JF. Taking two to tango: a role for ghrelin receptor heterodimerization in stress and reward. Front Neurosci 2013; 7:148. [PMID: 24009547 PMCID: PMC3757321 DOI: 10.3389/fnins.2013.00148] [Citation(s) in RCA: 63] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Accepted: 08/01/2013] [Indexed: 12/25/2022] Open
Abstract
The gut hormone, ghrelin, is the only known peripherally derived orexigenic signal. It activates its centrally expressed receptor, the growth hormone secretagogue receptor (GHS-R1a), to stimulate food intake. The ghrelin signaling system has recently been suggested to play a key role at the interface of homeostatic control of appetite and the hedonic aspects of food intake, as a critical role for ghrelin in dopaminergic mesolimbic circuits involved in reward signaling has emerged. Moreover, enhanced plasma ghrelin levels are associated with conditions of physiological stress, which may underline the drive to eat calorie-dense "comfort-foods" and signifies a role for ghrelin in stress-induced food reward behaviors. These complex and diverse functionalities of the ghrelinergic system are not yet fully elucidated and likely involve crosstalk with additional signaling systems. Interestingly, accumulating data over the last few years has shown the GHS-R1a receptor to dimerize with several additional G-protein coupled receptors (GPCRs) involved in appetite signaling and reward, including the GHS-R1b receptor, the melanocortin 3 receptor (MC3), dopamine receptors (D1 and D2), and more recently, the serotonin 2C receptor (5-HT2C). GHS-R1a dimerization was shown to affect downstream signaling and receptor trafficking suggesting a potential novel mechanism for fine-tuning GHS-R1a receptor mediated activity. This review summarizes ghrelin's role in food reward and stress and outlines the GHS-R1a dimer pairs identified to date. In addition, the downstream signaling and potential functional consequences of dimerization of the GHS-R1a receptor in appetite and stress-induced food reward behavior are discussed. The existence of multiple GHS-R1a heterodimers has important consequences for future pharmacotherapies as it significantly increases the pharmacological diversity of the GHS-R1a receptor and has the potential to enhance specificity of novel ghrelin-targeted drugs.
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Sofer S, Eliraz A, Kaplan S, Voet H, Fink G, Kima T, Madar Z. Changes in daily leptin, ghrelin and adiponectin profiles following a diet with carbohydrates eaten at dinner in obese subjects. Nutr Metab Cardiovasc Dis 2013; 23:744-750. [PMID: 22901843 DOI: 10.1016/j.numecd.2012.04.008] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2011] [Revised: 04/05/2012] [Accepted: 04/19/2012] [Indexed: 01/03/2023]
Abstract
BACKGROUND AND AIMS Our recently published randomised clinical trial evaluated the effect of a low-calorie diet with carbohydrates eaten at dinner. This dietary pattern led to lower hunger scores, and better anthropometric, biochemical and inflammatory outcomes compared to a standard low-calorie diet. In the same study, changes in diurnal secretion patterns of leptin, ghrelin and adiponectin were investigated. METHODS AND RESULTS Seventy-eight police officers (body mass index (BMI) > 30) were randomly allocated to experimental (carbohydrates at dinner) or control weight loss diets for 6 months. Sixty-three subjects finished the programme. On days 0, 7, 90 and 180 blood samples and hunger scores were collected every 4 h from 8:00 to 20:00. Hormonal profiles were available for 39. The dietary manipulation led to changes in daylight hormonal profiles in the experimental group. Leptin's secretion curve became convex, with a nadir later in the day (significant difference compared to baseline at morning and evening, p = 0.023, p = 0.021, respectively). Ghrelin's secretion curve became concave, peaking only in the evening hours. Adiponectin's curve was elevated only after the experimental diet (significant difference compared to baseline at afternoon, p = 0.044). CONCLUSIONS We propose that a low-calorie diet with carbohydrates eaten at dinner can modulate daytime hormonal profiles. Taken together with our earlier results, we believe this diet regime may prevent mid-day hunger, better support weight loss and improve metabolic outcomes compared to conventional weight loss diets. The trial is registered at controlled-trials.com, ISRCTN37829376, December 2009.
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Affiliation(s)
- S Sofer
- The Robert H Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry and Food Science, The Hebrew University of Jerusalem, PO Box 12, Rehovot 76100, Israel
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Effect of Ghrelin on Hepatic IGF-Binding Protein-1 Production. ISRN OBESITY 2013; 2013:751401. [PMID: 24555152 PMCID: PMC3901966 DOI: 10.1155/2013/751401] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Accepted: 01/01/2013] [Indexed: 11/18/2022]
Abstract
Ghrelin plays key roles in energy homeostasis by central and peripheral actions that include effects on insulin signalling pathways in liver. Insulin is an important inhibitor of production by hepatocytes of insulin-like growth factor-binding protein-1 (IGFBP-1) which has an endocrine role to inhibit IGF availability. The effects of ghrelin, insulin, an AMPK activator, and an AMPK inhibitor on IGFBP-1 secretion were studied in H4-II-E rat liver cells. Ghrelin (100 nM) blocked the inhibitory effect of a maximally effective concentration of insulin (10 ng/mL) on IGFBP-1 secretion during a 5 h incubation period (P < 0.001) in the absence and presence of an AMPK inhibitor. Ghrelin, alone, had no effect on IGFBP-1 production, but enhanced secretion independently of insulin under conditions of AMPK activation (P < 0.001). In conclusion, IGFBP-1 is identified as a novel target of ghrelin action in liver that may contribute to its metabolic effects in obesity.
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Dong CX, Brubaker PL. Ghrelin, the proglucagon-derived peptides and peptide YY in nutrient homeostasis. Nat Rev Gastroenterol Hepatol 2012; 9:705-15. [PMID: 23026903 DOI: 10.1038/nrgastro.2012.185] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Dysregulation of nutrient homeostasis is implicated in the current epidemics of obesity and type 2 diabetes mellitus. The maintenance of homeostasis in the setting of repeated cycles of feeding and fasting occurs through complex interactions between metabolic, hormonal and neural factors. Although pancreatic islets, the liver, muscle, adipocytes and the central nervous system are all key players in this network, the gastrointestinal tract is the first tissue exposed to ingested nutrients and thus has an important role. This Review focuses on several of the endocrine hormones released by the gastrointestinal tract prior to or during nutrient ingestion that have key roles in maintaining energy balance. These hormones include the gastric orexigenic hormone, ghrelin, and the distal L cell anorexigenic and metabolic hormones, glucagon-like peptide (GLP)-1, GLP-2, oxyntomodulin and peptide YY. Each of these hormones exerts a distinct set of biological actions to maintain nutrient homeostasis, the properties of which are currently, or might soon be, exploited in the clinic for the treatment of obesity and type 2 diabetes mellitus.
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Affiliation(s)
- Charlotte X Dong
- Department of Physiology, Medical Sciences Building, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada
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Ellis AC, Chandler-Laney P, Casazza K, Goree LL, Gower BA. Effects of habitual diet on ethnic differences in serum total ghrelin. Endocrine 2012; 42:359-65. [PMID: 22481313 PMCID: PMC3646388 DOI: 10.1007/s12020-012-9667-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2012] [Accepted: 03/22/2012] [Indexed: 11/30/2022]
Abstract
Ghrelin, an orexigenic hormone, may be involved in the etiology of obesity. African Americans (AA) experience higher obesity rates than European Americans (EA), but it is unclear whether ghrelin differs with ethnicity. This study was designed to compare ghrelin concentrations between overweight AA and EA adults in a post absorptive state, in response to a standard meal, and after 8-week habituation to diets of differing macronutrient profiles. Sixty-one overweight men and women (31 EA and 30 AA) were assigned to either a higher-carbohydrate/lower-fat diet (55% CHO, 18% PRO, 27% FAT) or a lower-carbohydrate/higher-fat diet (43% CHO, 18% PRO, 39% FAT) for 8 weeks. At baseline and week 8, participants ingested a standard liquid mixed meal. Blood was sampled before the meal and serially after ingestion to measure total ghrelin and insulin. Hunger was assessed with a visual analog scale. Composite scores for ghrelin, insulin, and hunger were calculated as area under the curve (AUC), and ghrelin suppression was calculated as the change from fasting concentration. Fasting ghrelin and ghrelin AUC were higher among EA at baseline and week 8 (p < 0.001), and these differences were not affected by diet habituation. Despite greater postprandial ghrelin suppression, EA displayed greater hunger immediately following the test meal (p < 0.05). Overweight EA displayed higher circulating ghrelin and greater ghrelin suppression compared to AA. Further study is warranted to explore the physiological basis for these ethnic differences and to determine whether they may relate to higher obesity rates among AA.
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Affiliation(s)
- Amy C Ellis
- Department of Nutrition Sciences, University of Alabama at Birmingham, 427 Webb Building, 1675 University Boulevard, Birmingham, AL 35294-3360, USA.
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Schellekens H, Finger BC, Dinan TG, Cryan JF. Ghrelin signalling and obesity: at the interface of stress, mood and food reward. Pharmacol Ther 2012; 135:316-26. [PMID: 22749794 DOI: 10.1016/j.pharmthera.2012.06.004] [Citation(s) in RCA: 154] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Accepted: 06/07/2012] [Indexed: 12/14/2022]
Abstract
The neuronal circuitry underlying the complex relationship between stress, mood and food intake are slowly being unravelled and several studies suggest a key role herein for the peripherally derived hormone, ghrelin. Evidence is accumulating linking obesity as an environmental risk factor to psychiatric disorders such as stress, anxiety and depression. Ghrelin is the only known orexigenic hormone from the periphery to stimulate food intake. Plasma ghrelin levels are enhanced under conditions of physiological stress and ghrelin has recently been suggested to play an important role in stress-induced food reward behaviour. In addition, chronic stress or atypical depression has often demonstrated to correlate with an increase in ingestion of caloric dense 'comfort foods' and have been implicated as one of the major contributor to the increased prevalence of obesity. Recent evidence suggests ghrelin as a critical factor at the interface of homeostatic control of appetite and reward circuitries, modulating the hedonic aspects of food intake. Therefore, the reward-related feeding of ghrelin may reveal itself as an important factor in the development of addiction to certain foods, similar to its involvement in the dependence to drugs of abuse, including alcohol. This review will highlight the accumulating evidence demonstrating the close interaction between food, mood and stress and the development of obesity. We consider the ghrelinergic system as an effective target for the development of successful anti-obesity pharmacotherapies, which not only affects appetite but also selectively modulates the rewarding properties of food and impact on psychological well-being in conditions of stress, anxiety and depression.
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Hussain SS, Bloom SR. The regulation of food intake by the gut-brain axis: implications for obesity. Int J Obes (Lond) 2012; 37:625-33. [PMID: 22710925 DOI: 10.1038/ijo.2012.93] [Citation(s) in RCA: 124] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Our understanding of the regulation of appetite has improved considerably over the last few decades. Recent work, stimulated by efforts aimed at curbing the current obesity epidemic, has unravelled some of the complex pathways regulating energy homeostasis. Key factors to this progress have been the discovery of leptin and the neuronal circuitry involved in mediating its effects, as well as the identification of gut hormones that have important physiological roles relating to energy homeostasis. Despite these advances in research, there are currently no effective treatments for the growing problem of obesity. In this article, we summarise the regulatory pathways controlling appetite with a special focus on gut hormones. We detail how recent findings have contributed to our knowledge regarding the pathogenesis and treatment of common obesity. A number of barriers still need to be overcome to develop safe and effective anti-obesity treatments. We outline problems highlighted by historical failures and discuss the potential of augmenting natural satiety signals, such as gut hormones, to treat obesity.
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Affiliation(s)
- S S Hussain
- Department of Diabetes, Endocrinology and Metabolism, Hammersmith Hospital, Imperial College London, London, UK
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Ellis AC, Casazza K, Chandler-Laney P, Gower BA. Higher postprandial serum ghrelin among African-American girls before puberty. J Pediatr Endocrinol Metab 2012; 25:691-6. [PMID: 23155695 PMCID: PMC3652648 DOI: 10.1515/jpem-2012-0081] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE Recent reports suggest that ghrelin regulation may differ by ethnicity and age. This study was designed to examine circulating ghrelin among overweight female African Americans across different age groups. METHODS Eleven overweight peripubertal girls, 17 overweight pubertal girls, and a control group of 18 overweight African-American premenopausal women ingested a standard liquid meal after an overnight fast. Blood samples were obtained before the meal and for 4 h postchallenge. Participants rated appetite by a visual analog scale. RESULTS Peripubertal girls demonstrated higher postprandial ghrelin and lesser ghrelin suppression compared with adults (p < 0.05), corresponding with greater desire to eat across the test period (p = 0.017). Fasting ghrelin tended to be inversely related to fasting estradiol (r = -0.264, p = 0.076). CONCLUSION Compared with overweight African-American women, peripubertal girls had higher ghrelin as well as greater appetite after a standard meal. These results may suggest a dysregulation in ghrelin reflective of demands of growth.
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Affiliation(s)
- Amy C Ellis
- Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-3360, USA.
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