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Jerzemowska G, Podlacha M, Orzeł-Gryglewska J. Amphetamine Injection into the Nucleus Accumbens and Electrical Stimulation of the Ventral Tegmental Area in Rats After Novelty Test-Behavioral and Neurochemical Correlates. Int J Mol Sci 2024; 26:182. [PMID: 39796042 PMCID: PMC11720036 DOI: 10.3390/ijms26010182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/16/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Amphetamine abuse is a global health epidemic that is difficult to treat due to individual differences in response to environmental factors, including stress reactivity and anxiety levels, as well as individual neuronal differences, which may result in increased/decreased vulnerability to addiction. In the present study, we investigated whether the Wistar rats behavioral traits of high (HR) and low (LR) locomotor activity to novelty influence motivational behavior (induced feeding model; iFR by electrical stimulation of the ventral tegmental area; Es-VTA) supported by amphetamine injection into the nucleus accumbens shell (AcbSh) (HRAmph, n = 5; LRAmph, n = 5). A correlation was found between the novelty test's locomotor activity score and the frequency threshold percentage change (p < 0.001, Rs = -0.867). In HRAmph, there was a shortening (-24.16%), while in LRAmph, there was a lengthening (+51.84%) of iFR latency. Immunofluorescence studies showed differential neuronal density (activity of tyrosine hydroxylase, choline acetyltransferase, and cFos protein) in the selected brain structures in HRAmph and LRAmph animals as well as in comparison to a control group (HRACSF, n = 5; LRACSF, n = 5). These results contribute to expanding the state of knowledge of the behavioral and neuronal propensity to take drug abuse.
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Affiliation(s)
- Grażyna Jerzemowska
- Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, 59 Wita Stwosza Str., 80-308 Gdansk, Poland;
| | - Magdalena Podlacha
- Department of Molecular Biology, Faculty of Biology, University of Gdansk, 59 Wita Stwosza Str., 80-308 Gdansk, Poland;
| | - Jolanta Orzeł-Gryglewska
- Department of Animal and Human Physiology, Faculty of Biology, University of Gdansk, 59 Wita Stwosza Str., 80-308 Gdansk, Poland;
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2
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Vijayashankar U, Ramashetty R, Rajeshekara M, Vishwanath N, Yadav AK, Prashant A, Lokeshwaraiah R. Leptin and ghrelin dynamics: unraveling their influence on food intake, energy balance, and the pathophysiology of type 2 diabetes mellitus. J Diabetes Metab Disord 2024; 23:427-440. [PMID: 38932792 PMCID: PMC11196531 DOI: 10.1007/s40200-024-01418-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/12/2024] [Indexed: 06/28/2024]
Abstract
Purpose Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by insulin resistance and impaired glucose homeostasis. In recent years, there has been growing interest in the role of hunger and satiety hormones such as ghrelin and leptin in the development and progression of T2DM. In this context, the present literature review aims to provide a comprehensive overview of the current understanding of how ghrelin and leptin influences food intake and maintain energy balance and its implications in the pathophysiology of T2DM. Methods A thorough literature search was performed using PubMed and Google Scholar to choose the studies that associated leptin and ghrelin with T2DM. Original articles and reviews were included, letters to editors and case reports were excluded. Results This narrative review article provides a comprehensive summary on mechanism of action of leptin and ghrelin, its association with obesity and T2DM, how they regulate energy and glucose homeostasis and potential therapeutic implications of leptin and ghrelin in managing T2DM. Conclusion Ghrelin, known for its appetite-stimulating effects, and leptin, a hormone involved in the regulation of energy balance, have been implicated in insulin resistance and glucose metabolism. Understanding the complexities of ghrelin and leptin interactions in the context of T2DM may offer insights into novel therapeutic strategies for this prevalent metabolic disorder. Further research is warranted to elucidate the molecular mechanisms underlying these hormone actions and to explore their clinical implications for T2DM prevention and management.
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Affiliation(s)
- Uma Vijayashankar
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
| | - Rajalakshmi Ramashetty
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
| | - Mahesh Rajeshekara
- Department of Surgical Gastroenterology, Bangalore Medical College and Research Institute, Bangalore, 560002 India
| | - Nagashree Vishwanath
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
| | - Anshu Kumar Yadav
- Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru-15, Mysuru, 570015 India
| | - Akila Prashant
- Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru-15, Mysuru, 570015 India
| | - Rajeshwari Lokeshwaraiah
- Department of Physiology, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru, 570015 India
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Hill TG, Hill DJ. The Importance of Intra-Islet Communication in the Function and Plasticity of the Islets of Langerhans during Health and Diabetes. Int J Mol Sci 2024; 25:4070. [PMID: 38612880 PMCID: PMC11012451 DOI: 10.3390/ijms25074070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/27/2024] [Accepted: 03/27/2024] [Indexed: 04/14/2024] Open
Abstract
Islets of Langerhans are anatomically dispersed within the pancreas and exhibit regulatory coordination between islets in response to nutritional and inflammatory stimuli. However, within individual islets, there is also multi-faceted coordination of function between individual beta-cells, and between beta-cells and other endocrine and vascular cell types. This is mediated partly through circulatory feedback of the major secreted hormones, insulin and glucagon, but also by autocrine and paracrine actions within the islet by a range of other secreted products, including somatostatin, urocortin 3, serotonin, glucagon-like peptide-1, acetylcholine, and ghrelin. Their availability can be modulated within the islet by pericyte-mediated regulation of microvascular blood flow. Within the islet, both endocrine progenitor cells and the ability of endocrine cells to trans-differentiate between phenotypes can alter endocrine cell mass to adapt to changed metabolic circumstances, regulated by the within-islet trophic environment. Optimal islet function is precariously balanced due to the high metabolic rate required by beta-cells to synthesize and secrete insulin, and they are susceptible to oxidative and endoplasmic reticular stress in the face of high metabolic demand. Resulting changes in paracrine dynamics within the islets can contribute to the emergence of Types 1, 2 and gestational diabetes.
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Affiliation(s)
- Thomas G. Hill
- Oxford Centre for Diabetes, Endocrinology, and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - David J. Hill
- Lawson Health Research Institute, St. Joseph’s Health Care, London, ON N6A 4V2, Canada;
- Departments of Medicine, Physiology and Pharmacology, Western University, London, ON N6A 3K7, Canada
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Liu S, Zhu H, Ren Y, Fan W, Wu H, Wu H, Huang Z, Zhu W. A hydrolyzed casein diet promotes Ngn3 controlling enteroendocrine cell differentiation to increase gastrointestinal motility in mice. Food Funct 2024; 15:1237-1249. [PMID: 38227487 DOI: 10.1039/d3fo04152b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2024]
Abstract
Gut hormones are produced by enteroendocrine cells (EECs) found along the intestinal epithelium, and these cells play a crucial role in regulating intestinal function, nutrient absorption and food intake. A hydrolyzed casein diet has been reported to promote the secretion of gut hormones through the regulation of EEC development, but the underlying mechanism remains unclear. Therefore, this study was conducted to investigate whether the hydrolyzed casein diet can regulate EEC differentiation by employing mouse and organoid models. Mice were fed diets containing either casein (casein group) or hydrolyzed casein (hydrolyzed casein group) as the sole protein source. The hydrolyzed casein diet upregulated the expression of transcription factors, induced EEC differentiation, increased fasting serum ghrelin concentrations and promoted gastrointestinal (GI) motility in the duodenum compared to the casein diet. Interestingly, these differences could be abolished when there is addition of antibiotics to the drinking water, suggesting a significant role of gut microbiota in the hydrolyzed casein-mediated EEC function. Further investigation showed that the hydrolyzed casein diet led to reduced microbial diversity, especially the abundance of Akkermansia muciniphila (A. muciniphila) on the duodenal mucosa. In contrast, gavage with A. muciniphila impaired EEC differentiation through attenuated neurog3 transcription factor (Ngn3) expression, mediated through the promotion of Notch signaling. Moreover, pasteurized A. muciniphila showed similar effects to enter organoids in vitro. Overall, we found that a hydrolyzed casein diet reduced the abundance of A. muciniphila and promoted Ngn3 controlling EEC differentiation and this pathway is associated with increased GI motility in mice. The findings provide new insights into the role of hydrolyzed casein in gut transit and guidelines for using hydrolyzed casein in safe formula milk.
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Affiliation(s)
- Siqiang Liu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Haining Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Yuting Ren
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Wenlu Fan
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Haiqin Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Huipeng Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Zan Huang
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China.
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural, University, Nanjing, Jiangsu 210095, China
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Kosiukhno S, Usenko O, Todurov I, Plehutsa О. CHANGE OF GHRELIN CONCENTRATION IN TYPE 2 DIABETES MELLITUS ASSOCIATED WITH OBESITY IN THE EARLY AND DELAYED PERIOD AFTER LAPAROSCOPIC SLEEVE GASTRECTOMY. FIZIOLOHICHNYĬ ZHURNAL 2023; 69:50-59. [DOI: 10.15407/fz69.03.050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Laparoscopic sleeve gastrectomy (LSG) is an effective method of treating obesity complicated by type 2 diabetes mellitus (T2DM). The performance of this metabolic surgical intervention involves removal fundus of the stomach, which in turn leads to an effect on the eating behavior of patients in the form of a decrease in appetite and loss of excess body weight with a parallel effect on the compensation of T2DM in the postoperative period, regardless of the loss of body weight. At present, mechanisms of T2DM compensation after LSG have not yet been clearly defined. The aim of our study was to study the effect of LSG on the dynamics of changes in the blood plasma ghrelin levels in patients with T2DM associated with obesity. The plasma ghrelin levels were assessed in the fasted state, 15, 30, 60, and 90 min after a standard breakfast carbohydrate preload, which included 125 ml of Nutricia Nutridrink, a balanced high-energy protein. The examination was carried out before the operation, on the 4th postoperative day and 3 months after the operation. 7 patients were diagnosed with T2DM for the first time, 3 had a history of diabetes for 2 years, one patient had a history of 3.5 years, and another had a history of 10 years. The average content of glycated hemoglobin before the operation was 7.7%, 3 months after LSG - 5.9%. The fasting ghrelin concentration before LSG performing was 6.8 ng/ml, on the 4th postoperative day – 4.6 ng/ml, and 3 months after the operation – 4.4 ng/ml (P = 0.001) in comparison with preoperative indicators). The peak insulin concentration was noted 30 min after the carbohydrate preload 3 months after the operation and was 175.1 μU/ml, and its fasting levels in the postoperative period reached a statistically significant difference compared to the preoperative values (30 μU/ml before surgery and 25.3 μU/ml 3 months after LSG). Thus, LSG leads to an early and significant suppression of fasting ghrelin secretion in patients with obesity-associated T2DM and likely to restore insulin secretion and/or reduce insulin resistance. Rapid postoperative improvement of carbohydrate metabolism components indicates the importance of the early reduction of ghrelin secretion in combination with the incretin effect of LSG in the implementation of the mechanisms of early compensation of T2DM and explains the metabolic activity of this operation and the significant role of the stomach in the regulation of glucose metabolism.
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Role of the Ghrelin System in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23105380. [PMID: 35628187 PMCID: PMC9141034 DOI: 10.3390/ijms23105380] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Revised: 05/06/2022] [Accepted: 05/10/2022] [Indexed: 02/06/2023] Open
Abstract
The ghrelin system contains several components (e.g., ghrelin with growing number of alternative peptides, growth hormone secretagogue receptors (GHS-Rs), and ghrelin-O-acyl-transferase (GOAT) and participates in regulation of a number of key processes of gastrointestinal (GI) tract cancer progression, including cell proliferation, migration, invasion, apoptosis, inflammation, and angiogenesis. However, its exact role in promoting or inhibiting cancer progression is still unclear. Colorectal cancer (CRC) is one of the most common human malignancies worldwide. Molecular studies suggest an autocrine/paracrine mechanism for the secretion of ghrelin in colorectal carcinogenesis and its contribution to its initial stages. However, the signalling pathways of CRC development involving the ghrelin system are poorly understood. Potential mechanisms of colon carcinogenesis involving components of the ghrelin system were previously described in an animal model and in in vitro studies. However, the diagnostic–prognostic role of serum ghrelin concentrations, tissue expression, or genetic changes of this system in various stages of CRC progression remains an open case. Thus, the aim of this study is to discuss the role of the ghrelin system in colon carcinogenesis, diagnostics and CRC prognostics, as well as the results of studies on the use of ghrelin and its analogues in the therapy of CRC-related syndromes (e.g., cachexia and sarcopenia).
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Sato T, Ida T, Shiimura Y, Matsui K, Oishi K, Kojima M. Insights Into the Regulation of Offspring Growth by Maternally Derived Ghrelin. Front Endocrinol (Lausanne) 2022; 13:852636. [PMID: 35250893 PMCID: PMC8894672 DOI: 10.3389/fendo.2022.852636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
The regulation of fetal development by bioactive substances such as hormones and neuropeptides derived from the gestational mother is considered to be essential for the development of the fetus. On the other hand, it has been suggested that changes in the physiological state of the pregnant mother due to various factors may alter the secretion of these bioactive substances and induce metabolic changes in the offspring, such as obesity, overeating, and inflammation, thereby affecting postnatal growth and health. However, our knowledge of how gestational maternal bioactive substances modulate offspring physiology remains fragmented and lacks a systematic understanding. In this mini-review, we focus on ghrelin, which regulates growth and energy metabolism, to advance our understanding of the mechanisms by which maternally derived ghrelin regulates the growth and health of the offspring. Understanding the regulation of offspring growth by maternally-derived ghrelin is expected to clarify the fetal onset of metabolic abnormalities and lead to a better understanding of lifelong health in the next generation of offspring.
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Affiliation(s)
- Takahiro Sato
- Division of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
- *Correspondence: Takahiro Sato, ; Masayasu Kojima,
| | - Takanori Ida
- Division for Identification and Analysis of Bioactive Peptides, Department of Bioactive Peptides, Frontier Science Research Center, University of Miyazaki, Miyazaki, Japan
| | - Yuki Shiimura
- Division of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
- Department of Cell Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, United States
| | - Kazuma Matsui
- Division of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
| | - Kanae Oishi
- Division of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
| | - Masayasu Kojima
- Division of Molecular Genetics, Institute of Life Science, Kurume University, Kurume, Japan
- *Correspondence: Takahiro Sato, ; Masayasu Kojima,
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Arne A, Ilgaza A, Kalnina LA. Ghrelin Immunoreactive Cell Amounts in the Abomasum in 4-Month-Old Calves by Feeding Different Amounts of Prebiotics and New Synbiotics. Vet Med Int 2021; 2021:5542372. [PMID: 34594486 PMCID: PMC8478566 DOI: 10.1155/2021/5542372] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 11/22/2022] Open
Abstract
The study aim was to determine prebiotic (inulin) and new synbiotic (inulin and Enterococcus faecium) varied dosage effects, during food breakdown-abomasum immunoreactive (IR) cell amount and cold carcass weight. Ghrelin is synthesized in the fundus region of the stomach. In the gastrointestinal system, ghrelin affects multiple functions, including secretion of gastric acid, gastric motility, and pancreatic protein output. The study consisted of 49 Holstein male calves (23 ± 5 days old, 50 ± 5 kg). Control and experimental groups were differentiated only with the additive amount added to the morning food source. Three prebiotic groups were fed Jerusalem artichoke flour (inulin content increased by 50%) in three amounts: 6 g (lowest) PreG6, 12 g (medium) PreG12, and 24 g (highest) PreG24. Three synbiotic groups were added 0.25 g of prebiotic Enterococcus faecium (2 ∗ 109 CFU/g) to the respective prebiotic, obtaining a new synbiotic (SynG6, SynG12, and SynG24). Calves were slaughtered after 56 days to obtain abomasum samples for ghrelin IR cell examination, and carcass weight was determined. It shows that ghrelin IR cell count in the abomasum was (p < 0.05) reduced in 6g and 12g inulin dosage, but carcass weight was significantly (p < 0.05) higher for PreG12 and PreG24 (p < 0.05) and then for CoG (CoG 42.6 kg; PreG12 51.4 kg; and PreG24 54.0 kg) and (p < 0.05) for SynG12 and SynG24 (SynG12 52.3 kg and SynG24 49.6 kg), which indicates longer satiety and more wholesome breakdown of the food uptake. It was concluded that ghrelin IR cells in 12-week-old calves are more abundant in the fundus region. Medium- and high-dosage prebiotic inulin feeding to the calves improves overall food digestion, allowing for longer satiety and higher cold carcass weight without increasing food amount. Adding synbiotic 0.25 g Enterococcus faecium (2 ∗ 109 CFU/g (Protexin, UK)) to inulin (produced in Latvia LTD "Herbe") does not improve the results of this prebiotic.
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Affiliation(s)
- Astra Arne
- Latvia University of Life Sciences and Technologies, Faculty of Veterinary Medicine, K. Helmaņa Street 8, Jelgava 3004, Latvia
| | - Aija Ilgaza
- Latvia University of Life Sciences and Technologies, Faculty of Veterinary Medicine, K. Helmaņa Street 8, Jelgava 3004, Latvia
| | - Liga Astra Kalnina
- St. John Fisher College, Biology Department, 3690 East Ave, Rochester, New York 14618, USA
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Micioni Di Bonaventura E, Botticelli L, Del Bello F, Giorgioni G, Piergentili A, Quaglia W, Cifani C, Micioni Di Bonaventura MV. Assessing the role of ghrelin and the enzyme ghrelin O-acyltransferase (GOAT) system in food reward, food motivation, and binge eating behavior. Pharmacol Res 2021; 172:105847. [PMID: 34438062 DOI: 10.1016/j.phrs.2021.105847] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 02/06/2023]
Abstract
The peripheral peptide hormone ghrelin is a powerful stimulator of food intake, which leads to body weight gain and adiposity in both rodents and humans. The hormone, thus, increases the vulnerability to obesity and binge eating behavior. Several studies have revealed that ghrelin's functions are due to its interaction with the growth hormone secretagogue receptor type 1a (GHSR1a) in the hypothalamic area; besides, ghrelin also promotes the reinforcing properties of hedonic food, acting at extra-hypothalamic sites and interacting with dopaminergic, cannabinoid, opioid, and orexin signaling. The hormone is primarily present in two forms in the plasma and the enzyme ghrelin O-acyltransferase (GOAT) allows the acylation reaction which causes the transformation of des-acyl-ghrelin (DAG) to the active form acyl-ghrelin (AG). DAG has been demonstrated to show antagonist properties; it is metabolically active, and counteracts the effects of AG on glucose metabolism and lipolysis, and reduces food consumption, body weight, and hedonic feeding response. Both peptides seem to influence the hypothalamic-pituitary-adrenal (HPA) axis and the corticosterone/cortisol level that drive the urge to eat under stressful conditions. These findings suggest that DAG and inhibition of GOAT may be targets for obesity and bingeing-related eating disorders and that AG/DAG ratio may be an important potential biomarker to assess the risk of developing maladaptive eating behaviors.
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Affiliation(s)
| | - Luca Botticelli
- School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 9, 62032 Camerino, Italy
| | - Fabio Del Bello
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, 62032 Camerino, Italy
| | - Gianfabio Giorgioni
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, 62032 Camerino, Italy
| | - Alessandro Piergentili
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, 62032 Camerino, Italy
| | - Wilma Quaglia
- School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino, 1, 62032 Camerino, Italy
| | - Carlo Cifani
- School of Pharmacy, Pharmacology Unit, University of Camerino, via Madonna delle Carceri, 9, 62032 Camerino, Italy.
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Nunez‐Salces M, Li H, Feinle‐Bisset C, Young RL, Page AJ. The regulation of gastric ghrelin secretion. Acta Physiol (Oxf) 2021; 231:e13588. [PMID: 33249751 DOI: 10.1111/apha.13588] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 11/19/2020] [Accepted: 11/23/2020] [Indexed: 12/13/2022]
Abstract
Ghrelin is a gastric hormone with multiple physiological functions, including the stimulation of food intake and adiposity. It is well established that circulating ghrelin levels are closely associated with feeding patterns, rising strongly before a meal and lowering upon food intake. However, the mechanisms underlying the modulation of ghrelin secretion are not fully understood. The purpose of this review is to discuss current knowledge on the circadian oscillation of circulating ghrelin levels, the neural mechanisms stimulating fasting ghrelin levels and peripheral mechanisms modulating postprandial ghrelin levels. Furthermore, the therapeutic potential of targeting the ghrelin pathway is discussed in the context of the treatment of various metabolic disorders, including obesity, type 2 diabetes, diabetic gastroparesis and Prader-Willi syndrome. Moreover, eating disorders including anorexia nervosa, bulimia nervosa and binge-eating disorder are also discussed.
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Affiliation(s)
- Maria Nunez‐Salces
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
| | - Hui Li
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
| | - Christine Feinle‐Bisset
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
| | - Richard L. Young
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
- Intestinal Nutrient Sensing Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
| | - Amanda J. Page
- Vagal Afferent Research Group Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Centre of Research Excellence in Translating Nutritional Science to Good Health Adelaide Medical School The University of Adelaide Adelaide SA Australia
- Nutrition, Diabetes & Gut Health, Lifelong Health Theme South Australian Health & Medical Research Institute (SAHMRI) Adelaide SA Australia
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Gulubova MV, Tolekova AN, Ivanova K, Hamza S, Hadzhi M, Chonov D, Ananiev J. Fructose-induced metabolic disturbances in rats and its impact on stomach endocrine cell number and smooth muscle contractility. Arch Physiol Biochem 2020; 126:440-448. [PMID: 30633582 DOI: 10.1080/13813455.2018.1555601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Context: Gastric ghrelin-positive endocrine cells (GHR + EC) were most dense in the oxyntic mucosa.Objective: We evaluated ECs and contractile activity in rat stomach with metabolic disorders.Materials and methods: Male Wistar rats were divided into two groups: Control (n = 9) received tap water and Fructose (n = 9) drank 15% fructose solution for 12 weeks. Streptozotocin was applied in a dose of 20 mg/kg b.w. two weeks after the beginning of the experiment on Fructose group. Smooth-muscle strips from the stomach were influenced by Angiotensin II for analysis of parameters of contractions. Stomach samples were elaborated with immunohistochemistry for ghrelin, somatostatin, gastrin antibodies and with double immunofluorescence.Results: In treated animals, GHR + EC were significantly increased in the corpus where somatostatin-positive cells were decreased. Contractile activity was decreased.Conclusions: The increase number of GHR + EC was discussed in the context of Somatostatin and Gastrin-positive ECs variations and correlated with the decrease of smooth muscle contraction.
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Affiliation(s)
- Maya V Gulubova
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Anna N Tolekova
- Department of Physiology, Pathophysiology and Pharmacology, Trakia University, Stara Zagora, Bulgaria
| | - Koni Ivanova
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Sevinch Hamza
- Department of Anatomy, Trakia University, Stara Zagora, Bulgaria
| | - Mehmed Hadzhi
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Dimitar Chonov
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
| | - Julian Ananiev
- Department of General and Clinical Pathology, Trakia University, Stara Zagora, Bulgaria
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12
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Pena-Leon V, Perez-Lois R, Seoane LM. mTOR Pathway is Involved in Energy Homeostasis Regulation as a Part of the Gut-Brain Axis. Int J Mol Sci 2020; 21:ijms21165715. [PMID: 32784967 PMCID: PMC7460813 DOI: 10.3390/ijms21165715] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 08/06/2020] [Accepted: 08/07/2020] [Indexed: 12/12/2022] Open
Abstract
Mammalian, or mechanic, target of rapamycin (mTOR) signaling is a crucial factor in the regulation of the energy balance that functions as an energy sensor in the body. The present review explores how the mTOR/S6k intracellular pathway is involved in modulating the production of different signals such as ghrelin and nesfatin-1 in the gastrointestinal tract to regulate food intake and body weight. The role of gastric mTOR signaling in different physiological processes was studied in depth through different genetic models that allow the modulation of mTOR signaling in the stomach and specifically in gastric X/A type cells. It has been described that mTOR signaling in X/A-like gastric cells has a relevant role in the regulation of glucose and lipid homeostasis due to its interaction with different organs such as liver and adipose tissue. These findings highlight possible therapeutic strategies, with the gut–brain axis being one of the most promising targets in the treatment of obesity.
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Affiliation(s)
- Veronica Pena-Leon
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Instituto de Investigación Sanitaria, Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (V.P.-L.); (R.P.-L.)
- Centro de Investigacion Biomedica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Raquel Perez-Lois
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Instituto de Investigación Sanitaria, Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (V.P.-L.); (R.P.-L.)
- Centro de Investigacion Biomedica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Luisa Maria Seoane
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Instituto de Investigación Sanitaria, Santiago de Compostela, Travesía da Choupana s/n, 15706 Santiago de Compostela, Spain; (V.P.-L.); (R.P.-L.)
- Centro de Investigacion Biomedica en Red Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
- Correspondence:
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13
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Lindqvist A, Shcherbina L, Prasad RB, Miskelly MG, Abels M, Martínez-Lopéz JA, Fred RG, Nergård BJ, Hedenbro J, Groop L, Hjerling-Leffler J, Wierup N. Ghrelin suppresses insulin secretion in human islets and type 2 diabetes patients have diminished islet ghrelin cell number and lower plasma ghrelin levels. Mol Cell Endocrinol 2020; 511:110835. [PMID: 32371087 DOI: 10.1016/j.mce.2020.110835] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 04/07/2020] [Accepted: 04/21/2020] [Indexed: 01/22/2023]
Abstract
It is not known how ghrelin affects insulin secretion in human islets from patients with type 2 diabetes (T2D) or whether islet ghrelin expression or circulating ghrelin levels are altered in T2D. Here we sought out to identify the effect of ghrelin on insulin secretion in human islets and the impact of T2D on circulating ghrelin levels and on islet ghrelin cells. The effect of ghrelin on insulin secretion was assessed in human T2D and non-T2D islets. Ghrelin expression was assessed with RNA-sequencing (n = 191) and immunohistochemistry (n = 21). Plasma ghrelin was measured with ELISA in 40 T2D and 40 non-T2D subjects. Ghrelin exerted a glucose-dependent insulin-suppressing effect in islets from both T2D and non-T2D donors. Compared with non-T2D donors, T2D donors had reduced ghrelin mRNA expression and 75% less islet ghrelin cells, and ghrelin mRNA expression correlated negatively with HbA1c. T2D subjects had 25% lower fasting plasma ghrelin levels than matched controls. Thus, ghrelin has direct insulin-suppressing effects in human islets and T2D patients have lower fasting ghrelin levels, likely as a result of reduced number of islet ghrelin cells. These findings support inhibition of ghrelin signaling as a potential therapeutic avenue for stimulation of insulin secretion in T2D patients.
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Affiliation(s)
- A Lindqvist
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - L Shcherbina
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - R B Prasad
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - M G Miskelly
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - M Abels
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | - J A Martínez-Lopéz
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - R G Fred
- Lund University Diabetes Centre, Lund University, Malmö, Sweden
| | | | - J Hedenbro
- Lund University Diabetes Centre, Lund University, Malmö, Sweden; Aleris Obesitas, Lund, Sweden
| | - L Groop
- Lund University Diabetes Centre, Lund University, Malmö, Sweden; Finnish Institute of Molecular Medicine, Helsinki, Finland
| | - J Hjerling-Leffler
- Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden
| | - N Wierup
- Lund University Diabetes Centre, Lund University, Malmö, Sweden.
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14
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Abstract
Gastric acid secretion (i) facilitates digestion of protein as well as absorption of micronutrients and certain medications, (ii) kills ingested microorganisms, including Helicobacter pylori, and (iii) prevents bacterial overgrowth and enteric infection. The principal regulators of acid secretion are the gastric peptides gastrin and somatostatin. Gastrin, the major hormonal stimulant for acid secretion, is synthesized in pyloric mucosal G cells as a 101-amino acid precursor (preprogastrin) that is processed to yield biologically active amidated gastrin-17 and gastrin-34. The C-terminal active site of gastrin (Trp-Met-Asp-Phe-NH2 ) binds to gastrin/CCK2 receptors on parietal and, more importantly, histamine-containing enterochromaffin-like (ECL) cells, located in oxyntic mucosa, to induce acid secretion. Histamine diffuses to the neighboring parietal cells where it binds to histamine H2 -receptors coupled to hydrochloric acid secretion. Gastrin is also a trophic hormone that maintains the integrity of gastric mucosa, induces proliferation of parietal and ECL cells, and is thought to play a role in carcinogenesis. Somatostatin, present in D cells of the gastric pyloric and oxyntic mucosa, is the main inhibitor of acid secretion, particularly during the interdigestive period. Somatostatin exerts a tonic paracrine restraint on gastrin secretion from G cells, histamine secretion from ECL cells, and acid secretion from parietal cells. Removal of this restraint, for example by activation of cholinergic neurons during ingestion of food, initiates and maximizes acid secretion. Knowledge regarding the structure and function of gastrin, somatostatin, and their respective receptors is providing novel avenues to better diagnose and manage acid-peptic disorders and certain cancers. Published 2020. Compr Physiol 10:197-228, 2020.
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Affiliation(s)
- Mitchell L Schubert
- Division of Gastroenterology, Department of Medicine, Virginia Commonwealth University Health System, Richmond, Virginia, USA.,Hunter Holmes McGuire Veterans Affairs Medical Center, Richmond, Virginia, USA
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
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15
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Fothergill LJ, Galiazzo G, Hunne B, Stebbing MJ, Fakhry J, Weissenborn F, Fazio Coles TE, Furness JB. Distribution and co-expression patterns of specific cell markers of enteroendocrine cells in pig gastric epithelium. Cell Tissue Res 2019; 378:457-469. [PMID: 31309318 DOI: 10.1007/s00441-019-03065-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/01/2019] [Indexed: 12/19/2022]
Abstract
Although the pig is an accepted model species for human digestive physiology, no previous study of the pig gastric mucosa and gastric enteroendocrine cells has investigated the parallels between pig and human. In this study, we have investigated markers for each of the classes of gastric endocrine cells, gastrin, ghrelin, somatostatin, 5-hydroxytryptamine, histidine decarboxylase, and PYY cells in pig stomach. The lining of the proximal stomach consisted of a collar of stratified squamous epithelium surrounded by gastric cardiac glands in the fundus. This differs considerably from human that has only a narrow band of cardiac glands at its entrance, surrounded by a fundic mucosa consisting of oxyntic glands. However, the linings of the corpus and antrum are similar in pig and human. Likewise, the endocrine cell types are similar and similarly distributed in the two species. As in human, gastrin cells were almost exclusively in the antrum, ghrelin cells were most abundant in the oxyntic mucosa and PYY cells were rare. In the pig, 70% of enterochromaffin-like (ECL) cells in the antrum and 95% in the fundus contained 5-hydroxytryptamine (5-HT), higher proportions than in human. Unlike the enteroendocrine of the small intestine, most gastric enteroendocrine cells (EEC) did not contain colocalised hormones. This is similar to human and other species. We conclude that the pig stomach has substantial similarity to human, except that the pig has a protective lining at its entrance that may reflect the difference between a pig diet with hard abrasive components and the soft foods consumed by humans.
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Affiliation(s)
- Linda J Fothergill
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3010, Australia
| | - Giorgia Galiazzo
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Billie Hunne
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Martin J Stebbing
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3010, Australia
| | - Josiane Fakhry
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Frank Weissenborn
- Department of Agriculture and Food, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Therese E Fazio Coles
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - John B Furness
- Department of Anatomy & Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia. .,Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3010, Australia. .,Department of Agriculture and Food, University of Melbourne, Parkville, Victoria, 3010, Australia.
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16
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Hunne B, Stebbing MJ, McQuade RM, Furness JB. Distributions and relationships of chemically defined enteroendocrine cells in the rat gastric mucosa. Cell Tissue Res 2019; 378:33-48. [PMID: 31049687 DOI: 10.1007/s00441-019-03029-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 04/04/2019] [Indexed: 12/12/2022]
Abstract
This paper provides quantitative data on the distributions of enteroendocrine cells (EEC), defined by the hormones they contain, patterns of colocalisation between hormones and EEC relations to nerve fibres in the rat gastric mucosa. The rat stomach has three mucosal types: non-glandular stratified squamous epithelium of the fundus and esophageal groove, a region of oxyntic glands in the corpus, and pyloric glands of the antrum and pylorus. Ghrelin and histamine were both contained in closed cells, not contacting the lumen, and were most numerous in the corpus. Gastrin cells were confined to the antrum, and 5-hydroxytryptamine (5-HT) and somatostatin cells were more frequent in the antrum than the corpus. Most somatostatin cells had basal processes that in the antrum commonly contacted gastrin cells. Peptide YY (PYY) cells were rare and mainly in the antrum. The only numerous colocalisations were 5-HT and histamine, PYY and gastrin and gastrin and histamine in the antrum, but each of these populations was small. Peptide-containing nerve fibres were found in the mucosa. One of the most common types was vasoactive intestinal peptide (VIP) fibres. High-resolution analysis showed that ghrelin cells were closely and selectively approached by VIP fibres. In contrast, gastrin cells were not selectively innervated by VIP or CGRP fibres. The study indicates that there are distinct populations of gastric EEC and selective innervation of ghrelin cells. It also shows that, in contrast to EEC of the small intestine, the majority of EEC within the stomach contained only a single hormone.
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Affiliation(s)
- Billie Hunne
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
| | - Martin J Stebbing
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3010, Australia
| | - Rachel M McQuade
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3010, Australia
| | - John B Furness
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, Victoria, 3010, Australia.
- Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, 3010, Australia.
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17
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Suarez AN, Noble EE, Kanoski SE. Regulation of Memory Function by Feeding-Relevant Biological Systems: Following the Breadcrumbs to the Hippocampus. Front Mol Neurosci 2019; 12:101. [PMID: 31057368 PMCID: PMC6482164 DOI: 10.3389/fnmol.2019.00101] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Accepted: 04/03/2019] [Indexed: 12/15/2022] Open
Abstract
The hippocampus (HPC) controls fundamental learning and memory processes, including memory for visuospatial navigation (spatial memory) and flexible memory for facts and autobiographical events (declarative memory). Emerging evidence reveals that hippocampal-dependent memory function is regulated by various peripheral biological systems that are traditionally known for their roles in appetite and body weight regulation. Here, we argue that these effects are consistent with a framework that it is evolutionarily advantageous to encode and recall critical features surrounding feeding behavior, including the spatial location of a food source, social factors, post-absorptive processing, and other episodic elements of a meal. We review evidence that gut-to-brain communication from the vagus nerve and from feeding-relevant endocrine systems, including ghrelin, insulin, leptin, and glucagon-like peptide-1 (GLP-1), promote hippocampal-dependent spatial and declarative memory via neurotrophic and neurogenic mechanisms. The collective literature reviewed herein supports a model in which various stages of feeding behavior and hippocampal-dependent memory function are closely linked.
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Affiliation(s)
| | | | - Scott E. Kanoski
- Human and Evolutionary Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, United States
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18
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Sakata N, Yoshimatsu G, Kodama S. Development and Characteristics of Pancreatic Epsilon Cells. Int J Mol Sci 2019; 20:ijms20081867. [PMID: 31014006 PMCID: PMC6514973 DOI: 10.3390/ijms20081867] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Revised: 04/11/2019] [Accepted: 04/12/2019] [Indexed: 12/19/2022] Open
Abstract
Pancreatic endocrine cells expressing the ghrelin gene and producing the ghrelin hormone were first identified in 2002. These cells, named ε cells, were recognized as the fifth type of endocrine cells. Differentiation of ε cells is induced by various transcription factors, including Nk2 homeobox 2, paired box proteins Pax-4 and Pax6, and the aristaless-related homeobox. Ghrelin is generally considered to be a "hunger hormone" that stimulates the appetite and is produced mainly by the stomach. Although the population of ε cells is small in adults, they play important roles in regulating other endocrine cells, especially β cells, by releasing ghrelin. However, the roles of ghrelin in β cells are complex. Ghrelin contributes to increased blood glucose levels by suppressing insulin release from β cells and is also involved in the growth and proliferation of β cells and the prevention of β cell apoptosis. Despite increasing evidence and clarification of the mechanisms of ε cells over the last 20 years, many questions remain to be answered. In this review, we present the current evidence for the participation of ε cells in differentiation and clarify their characteristics by focusing on the roles of ghrelin.
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Affiliation(s)
- Naoaki Sakata
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
| | - Gumpei Yoshimatsu
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
| | - Shohta Kodama
- Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University, Fukuoka 814-0180, Japan.
- Center for Regenerative Medicine, Fukuoka University Hospital, Fukuoka 814-0180, Japan.
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19
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Germain N, Cuenco J, Ling Y, Minnion JS, Bageacu S, Grouselle D, Estour B, Galusca B. Ghrelin acylation by ghrelin- O-acyltransferase can occur in healthy part of oncological liver in humans. Am J Physiol Gastrointest Liver Physiol 2019; 316:G366-G371. [PMID: 30576216 DOI: 10.1152/ajpgi.00143.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Activation of ghrelin is controlled by the enzyme ghrelin- O-acyl transferase (GOAT). In humans, localization of this acylation is poorly understood. The aim of this study is to explore GOAT localization and activation in the human liver by evaluating both bioactive and non-bioactive ghrelin in the bloodstream entering and leaving the liver and to simultaneously evaluate GOAT mRNA expression in the liver. A healthy part of oncologic hepatic tissue collected from nine patients undergoing hepatectomy was used to evaluate GOAT mRNA expression by quantitative real-time polymerase chain reaction (RT-qPCR). Simultaneously, blood from the portal vein, the suprahepatic vein, the subclavicular vein, and the radial artery was also sampled to assay total and acylated ghrelin. Acylated ghrelin level was significantly increased in the suprahepatic vein compared with the portal vein level (385 ± 42 ng/ml vs. 268 ± 24 ng/ml, P = 0.04). Suprahepatic-to-portal vein ratio for acylated ghrelin (acylation ratio) is 1.4 ± 0.1. Mean expression of GOAT mRNA in the liver, expressed as 2-∆Ct·µg total RNA-1·1 µl of liver tissue-1 was at 0.042 ± 0.021 arbitrary units. GOAT mRNA expression in the liver was correlated with acylated-to-total ghrelin ratio in the suprahepatic vein ( P = 0.016, R = 0.75) and with the acylation liver ratio ( P = 0.05, R = 0.61). Blood concentration of acylated ghrelin was found significantly increased after its passage through the liver, suggesting that acylation can occur in the liver. RT-qPCR data confirmed the presence of GOAT in the liver, with a positive correlation between GOAT expression and acylated ghrelin liver ratio. This study strongly suggests that the liver is a site of ghrelin acylation in humans. NEW & NOTEWORTHY Although the activation of ghrelin by the enzyme ghrelin- O-acyl transferase (GOAT) is yet well demonstrated, its localization, especially in humans, remains poorly understood. We explored GOAT localization and activation in the human liver by simultaneously evaluating both bioactive and non-bioactive ghrelin in the bloodstream entering and leaving the liver and also GOAT mRNA expression in the liver. We therefore showed for the first time, to our knowledge, that GOAT localized in the liver is active and takes part in ghrelin activation.
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Affiliation(s)
- Natacha Germain
- Division of Endocrinology, CHU Saint-Etienne, Saint-Etienne , France.,EA 7423, Eating Disorders, Addictions & Extreme Bodyweight Research Group , Saint-Etienne , France
| | - Joyceline Cuenco
- Division of Diabetes, Endocrinology, and Metabolism, Imperial College , London , United Kingdom
| | - Yiin Ling
- EA 7423, Eating Disorders, Addictions & Extreme Bodyweight Research Group , Saint-Etienne , France
| | - James S Minnion
- Division of Diabetes, Endocrinology, and Metabolism, Imperial College , London , United Kingdom
| | - Serban Bageacu
- Division of Gut Surgery, CHU Saint-Etienne, Saint-Etienne , France
| | - Dominique Grouselle
- UMR 894 INSERM Psychiatry and Neurosciences Center, Paris Descartes University , Paris , France
| | - Bruno Estour
- Division of Endocrinology, CHU Saint-Etienne, Saint-Etienne , France.,EA 7423, Eating Disorders, Addictions & Extreme Bodyweight Research Group , Saint-Etienne , France
| | - Bogdan Galusca
- Division of Endocrinology, CHU Saint-Etienne, Saint-Etienne , France.,EA 7423, Eating Disorders, Addictions & Extreme Bodyweight Research Group , Saint-Etienne , France
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20
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Dominguez Gutierrez G, Kim J, Lee AH, Tong J, Niu J, Gray SM, Wei Y, Ding Y, Ni M, Adler C, Murphy AJ, Gromada J, Xin Y. Gene Signature of the Human Pancreatic ε Cell. Endocrinology 2018; 159:4023-4032. [PMID: 30380031 PMCID: PMC6963699 DOI: 10.1210/en.2018-00833] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 10/17/2018] [Indexed: 12/31/2022]
Abstract
The ghrelin-producing ε cell represents the fifth endocrine cell type in human pancreatic islets. The abundance of ε cells in adult pancreas is extremely low, which has hampered the investigation on the molecular pathways regulating the development and the function of this cell type. In this study, we explored the molecular features defining the function of pancreatic ε cells isolated from adult nondiabetic donors using single-cell RNA sequencing technology. We focus on transcription factors, cell surface receptors, and genes involved in metabolic pathways that contribute to regulation of cellular function. Furthermore, the genes that separate ε cells from the other islet endocrine cell types are presented. This study expands prior knowledge about the genes important for ε cell functioning during development and provides a resource to interrogate the transcriptome of this rare human islet cell type.
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Affiliation(s)
| | - Jinrang Kim
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Ann-Hwee Lee
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Jenny Tong
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - JingJing Niu
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Sarah M Gray
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Yi Wei
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Yueming Ding
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Min Ni
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | | | | | | | - Yurong Xin
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
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21
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Fakhry J, Stebbing MJ, Hunne B, Bayguinov Y, Ward SM, Sasse KC, Callaghan B, McQuade RM, Furness JB. Relationships of endocrine cells to each other and to other cell types in the human gastric fundus and corpus. Cell Tissue Res 2018; 376:37-49. [PMID: 30467709 DOI: 10.1007/s00441-018-2957-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 11/01/2018] [Indexed: 02/07/2023]
Abstract
Gastric endocrine cell hormones contribute to the control of the stomach and to signalling to the brain. In other gut regions, enteroendocrine cells (EECs) exhibit extensive patterns of colocalisation of hormones. In the current study, we characterise EECs in the human gastric fundus and corpus. We utilise immunohistochemistry to investigate EECs with antibodies to ghrelin, serotonin (5-HT), somatostatin, peptide YY (PYY), glucagon-like peptide 1, calbindin, gastrin and pancreastatin, the latter as a marker of enterochromaffin-like (ECL) cells. EECs were mainly located in regions of the gastric glands populated by parietal cells. Gastrin cells were absent and PYY cells were very rare. Except for about 25% of 5-HT cells being a subpopulation of ECL cells marked by pancreastatin, colocalisation of hormones in gastric EECs was infrequent. Ghrelin cells were distributed throughout the fundus and corpus; most were basally located in the glands, often very close to parietal cells and were closed cells i.e., not in contact with the lumen. A small proportion had long processes located close to the base of the mucosal epithelium. The 5-HT cells were of at least three types: small, round, closed cells; cells with multiple, often very long, processes; and a subgroup of ECL cells. Processes were in contact with their surrounding cells, including parietal cells. Mast cells had very weak or no 5-HT immunoreactivity. Somatostatin cells were a closed type with long processes. In conclusion, four major chemically defined EEC types occurred in the human oxyntic mucosa. Within each group were cells with distinct morphologies and relationships to other mucosal cells.
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Affiliation(s)
- Josiane Fakhry
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Martin J Stebbing
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia
| | - Billie Hunne
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Yulia Bayguinov
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, 89557, USA
| | - Sean M Ward
- Department of Physiology and Cell Biology, Reno School of Medicine, University of Nevada, Reno, NV, 89557, USA
| | - Kent C Sasse
- School of Medicine, Universiity of Nevada, Reno, NV, 89557, USA.,Renown Regional Medical Center, Reno, NV, 89502, USA
| | - Brid Callaghan
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia
| | - Rachel M McQuade
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia.,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia
| | - John B Furness
- Department of Anatomy and Neuroscience, University of Melbourne, Parkville, VIC, 3010, Australia. .,Florey Institute of Neuroscience and Mental Health, Parkville, VIC, 3010, Australia.
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22
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Ding Y, Zhang N, Li J, Jin Y, Shao B. Molecular cloning and expression of ghrelin in the hypothalamus-pituitary-gastrointestinal tract axis of the Yak (Bos grunniens) in the Qinghai-Tibetan Plateau. Anat Histol Embryol 2018; 47:583-590. [PMID: 30178622 DOI: 10.1111/ahe.12400] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 06/25/2018] [Accepted: 07/30/2018] [Indexed: 01/28/2023]
Abstract
Ghrelin is a very important brain-gut peptide that modulates appetite and energy metabolism in mammals. The yak is the only large mammal that can adapt to the cold temperatures and hypoxia conditions present in the Qinghai-Tibet Plateau. However, there are no reports on ghrelin molecular characterization and expression in the hypothalamus-pituitary-digestive tract axis of the yak to date. In this study, the coding region sequence of the yak ghrelin, containing a complete ORF (351) encoding for 117 amino acids, was cloned. Immunohistochemistry analysis of the yak samples showed that ghrelin-immunoreactive cells were expressed at the arcuate nucleus (ARC), the ventromedial nucleus (VMN), the dorsomedial nucleus (DMN) of the hypothalamus and also at the anterior pituitary. Ghrelin-positive cells were also present in approximately two thirds of the submucosa of the abomasum fundic gland and mucous layer of the duodenum intestinal gland. Ghrelin's mRNA highest expression occurred in the abomasum sample, followed by the duodenum, hypothalamus and lowest at the pituitary gland. The level of ghrelin mRNA measured in yak was higher than in cattle for all the tissues that were compared. The ghrelin protein and mRNA expression profiles were similar. These data imply that the high expression of ghrelin in the hypothalamus-pituitary-digestive tract axis of yak could aid adaptation to the extreme environment better than cattle, by improving appetite and fat accumulation, regulating body temperature and reducing energy consumption via regulating energy metabolism.
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Affiliation(s)
- Yanping Ding
- School of Life science, Northwest Normal University, Lanzhou, China
| | - Na Zhang
- School of Life Science, Lanzhou University, Lanzhou, China
| | - Jialong Li
- School of Life Science, Lanzhou University, Lanzhou, China
| | - Yiran Jin
- School of Life science, Northwest Normal University, Lanzhou, China
| | - Baoping Shao
- School of Life Science, Lanzhou University, Lanzhou, China
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23
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Abstract
Ghrelin, a gastric-derived acylated peptide, regulates energy homeostasis by transmitting information about peripheral nutritional status to the brain, and is essential for protecting organisms against famine. Ghrelin operates brain circuits to regulate homeostatic and hedonic feeding. Recent research advances have shed new light on ghrelin's multifaceted roles in cellular homeostasis, which could maintain the internal environment and overcome metaflammation in metabolic organs. Here, we highlight our current understanding of the regulatory mechanisms of the ghrelin system in energy metabolism and cellular homeostasis and its clinical trials. Future studies of ghrelin will further elucidate how the stomach regulates systemic homeostasis.
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Affiliation(s)
- Shigehisa Yanagi
- Divisions of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan
| | - Takahiro Sato
- Molecular Genetics, Institute of Life Science, Kurume University, Kurume 839-0864, Japan
| | - Kenji Kangawa
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Masamitsu Nakazato
- Divisions of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
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24
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Abstract
Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.
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Affiliation(s)
- Gabriela Da Silva Xavier
- Section of Functional Genomics and Cell Biology, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston B15 2TT, UK.
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25
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Folgueira C, Barja-Fernandez S, Prado L, Al-Massadi O, Castelao C, Pena-Leon V, Gonzalez-Saenz P, Baltar J, Baamonde I, Leis R, Dieguez C, Pagotto U, Casanueva FF, Tovar SA, Nogueiras R, Seoane LM. Pharmacological inhibition of cannabinoid receptor 1 stimulates gastric release of nesfatin-1 via the mTOR pathway. World J Gastroenterol 2017; 23:6403-6411. [PMID: 29085189 PMCID: PMC5643265 DOI: 10.3748/wjg.v23.i35.6403] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 07/31/2017] [Accepted: 08/25/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether Nucb2/nesfatin1 production is regulated by the cannabinoid system through the intracellular mTOR pathway in the stomach.
METHODS Sprague Dawley rats were treated with vehicle, rimonabant, rapamycin or rapamycin+rimonabant. Gastric tissue obtained from the animals was used for biochemical assays: Nucb2 mRNA measurement by real time PCR, gastric Nucb2/nesfatin protein content by western blot, and gastric explants to obtain gastric secretomes. Nucb2/nesfatin levels were measured in gastric secretomes and plasma using enzyme-linked immunosorbent assay.
RESULTS The inhibition of cannabinoid receptor 1 (CB1) by the peripheral injection of an inverse agonist, namely rimonabant, decreases food intake and increases the gastric secretion and circulating levels of Nucb2/nesfatin-1. In addition, rimonabant treatment activates mTOR pathway in the stomach as showed by the increase in pmTOR/mTOR expression in gastric tissue obtained from rimonabant treated animals. These effects were confirmed by the use of a CB1 antagonist, AM281. When the intracellular pathway mTOR/S6k was inactivated by chronic treatment with rapamycin, rimonabant treatment was no longer able to stimulate the gastric secretion of Nucb2/nesfatin-1.
CONCLUSION The peripheral cannabinoid system regulates food intake through a mechanism that implies gastric production and release of Nucb2/Nesfatin-1, which is mediated by the mTOR/S6k pathway.
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Affiliation(s)
- Cintia Folgueira
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases, 15782 Santiago de Compostela, Spain
| | - Silvia Barja-Fernandez
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Department of Pediatric, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Laura Prado
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Omar Al-Massadi
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases, 15782 Santiago de Compostela, Spain
| | - Cecilia Castelao
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
| | - Veronica Pena-Leon
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
| | - Patricia Gonzalez-Saenz
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
| | - Javier Baltar
- Servicio de Cirugía General, Complexo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
| | - Ivan Baamonde
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
- Servicio de Cirugía General, Complexo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
| | - Rosaura Leis
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Department of Pediatric, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
| | - Carlos Dieguez
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases, 15782 Santiago de Compostela, Spain
| | - Uberto Pagotto
- Endocrinology Unit and Center for Applied Biomedical Research, Department of Medical and Surgical Sciences, Hospital S. Orsola-Malpighi, Alma Mater University of Bologna, 40126 Bologna, Italy
| | - Felipe F Casanueva
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Laboratorio de Endocrinología Molecular y Celular. Universidad de Santiago de Compostela, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago, 15706 Santiago de Compostela, Spain
| | - Sulay A Tovar
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases, 15782 Santiago de Compostela, Spain
| | - Ruben Nogueiras
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
- Department of Physiology, Research Centre of Molecular Medicine and Chronic Diseases, 15782 Santiago de Compostela, Spain
| | - Luisa M Seoane
- Grupo Fisiopatología Endocrina, Instituto de Investigación Sanitaria de Santiago de Compostela, 15706 Santiago de Compostela, Spain
- CIBER Fisiopatología Obesidad y Nutrición, Instituto de Salud Carlos III, 15782 Santiago de compostela, Spain
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Chen SR, Chen H, Zhou JJ, Pradhan G, Sun Y, Pan HL, Li DP. Ghrelin receptors mediate ghrelin-induced excitation of agouti-related protein/neuropeptide Y but not pro-opiomelanocortin neurons. J Neurochem 2017; 142:512-520. [DOI: 10.1111/jnc.14080] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/19/2017] [Accepted: 05/22/2017] [Indexed: 12/21/2022]
Affiliation(s)
- Shao-Rui Chen
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - Hong Chen
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - Jing-Jing Zhou
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - Geetali Pradhan
- Department of Pediatrics; USDA/ARS Children's Nutrition Research Center; Baylor College of Medicine; Houston Texas USA
| | - Yuxiang Sun
- Department of Pediatrics; USDA/ARS Children's Nutrition Research Center; Baylor College of Medicine; Houston Texas USA
- Department of Nutrition and Food Science (NFSC); Texas A&M University; College Station Texas USA
| | - Hui-Lin Pan
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
| | - De-Pei Li
- Department of Anesthesiology and Perioperative Medicine; Center for Neuroscience and Pain Research; The University of Texas MD Anderson Cancer Center; Houston Texas USA
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27
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Ge T, Yang W, Fan J, Li B. Preclinical evidence of ghrelin as a therapeutic target in epilepsy. Oncotarget 2017; 8:59929-59939. [PMID: 28938694 PMCID: PMC5601790 DOI: 10.18632/oncotarget.18349] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Accepted: 05/22/2017] [Indexed: 12/17/2022] Open
Abstract
Ghrelin, an orexigenic peptide synthesized by endocrine cells of the gastric mucosa, plays a major role in inhibiting seizures. However, the underlying mechanism of ghrelin's anticonvulsant action is still unclear. Nowadays, there are considerable evidences showing that ghrelin is implicated in various neurophysiological processes, including learning and memory, neuroprotection, neurogenesis, and inflammatory effects. In this review, we will summarize the effects of ghrelin on epilepsy. It may provide a comprehensive picture of the role of ghrelin in epilepsy.
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Affiliation(s)
- Tongtong Ge
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Wei Yang
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Jie Fan
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, PR China
| | - Bingjin Li
- Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, PR China
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28
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Stefanov IS, Ananiev JR, Ivanova KV, Tolekova AN, Vodenicharov AP, Gulubova MV. Distribution of ghrelin-positive mast cells in rat stomach. BIOTECHNOL BIOTEC EQ 2017. [DOI: 10.1080/13102818.2017.1326013] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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29
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Clarifying the Ghrelin System's Ability to Regulate Feeding Behaviours Despite Enigmatic Spatial Separation of the GHSR and Its Endogenous Ligand. Int J Mol Sci 2017; 18:ijms18040859. [PMID: 28422060 PMCID: PMC5412441 DOI: 10.3390/ijms18040859] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/04/2017] [Accepted: 04/11/2017] [Indexed: 12/23/2022] Open
Abstract
Ghrelin is a hormone predominantly produced in and secreted from the stomach. Ghrelin is involved in many physiological processes including feeding, the stress response, and in modulating learning, memory and motivational processes. Ghrelin does this by binding to its receptor, the growth hormone secretagogue receptor (GHSR), a receptor found in relatively high concentrations in hypothalamic and mesolimbic brain regions. While the feeding and metabolic effects of ghrelin can be explained by the effects of this hormone on regions of the brain that have a more permeable blood brain barrier (BBB), ghrelin produced within the periphery demonstrates a limited ability to reach extrahypothalamic regions where GHSRs are expressed. Therefore, one of the most pressing unanswered questions plaguing ghrelin research is how GHSRs, distributed in brain regions protected by the BBB, are activated despite ghrelin’s predominant peripheral production and poor ability to transverse the BBB. This manuscript will describe how peripheral ghrelin activates central GHSRs to encourage feeding, and how central ghrelin synthesis and ghrelin independent activation of GHSRs may also contribute to the modulation of feeding behaviours.
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30
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Jiao Q, Du X, Li Y, Gong B, Shi L, Tang T, Jiang H. The neurological effects of ghrelin in brain diseases: Beyond metabolic functions. Neurosci Biobehav Rev 2016; 73:98-111. [PMID: 27993602 DOI: 10.1016/j.neubiorev.2016.12.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 12/01/2016] [Accepted: 12/10/2016] [Indexed: 02/08/2023]
Abstract
Ghrelin, a peptide released by the stomach that plays a major role in regulating energy metabolism, has recently been shown to have effects on neurobiological behaviors. Ghrelin enhances neuronal survival by reducing apoptosis, alleviating inflammation and oxidative stress, and accordingly improving mitochondrial function. Ghrelin also stimulates the proliferation, differentiation and migration of neural stem/progenitor cells (NS/PCs). Additionally, the ghrelin is benefit for the recovery of memory, mood and cognitive dysfunction after stroke or traumatic brain injury. Because of its neuroprotective and neurogenic roles, ghrelin may be used as a therapeutic agent in the brain to combat neurodegenerative disease. In this review, we highlight the pre-clinical evidence and the proposed mechanisms underlying the role of ghrelin in physiological and pathological brain function.
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Affiliation(s)
- Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, China.
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, China.
| | - Yong Li
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, China.
| | - Bing Gong
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China.
| | - Limin Shi
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, China.
| | - Tingting Tang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, China.
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, Medical College of Qingdao University, Qingdao, China; Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Qingdao University, Qingdao, China.
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31
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Serrano J, Casanova-Martí À, Depoortere I, Blay MT, Terra X, Pinent M, Ardévol A. Subchronic treatment with grape-seed phenolics inhibits ghrelin production despite a short-term stimulation of ghrelin secretion produced by bitter-sensing flavanols. Mol Nutr Food Res 2016; 60:2554-2564. [PMID: 27417519 DOI: 10.1002/mnfr.201600242] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 06/06/2016] [Accepted: 07/06/2016] [Indexed: 12/26/2022]
Abstract
SCOPE Grape-seed phenolic compounds have recently been described as satiating agents in rats when administered as a whole phenolic extract (GSPE). This satiating effect may involve the release of satiating gut hormones such as GLP-1, although a short-term increase in the orexigenic hormone ghrelin was also reported. In this study, we investigated the short- and long-term effects of GSPE in rats, focusing on the role of the main grape-seed phenolics in ghrelin secretion. METHODS AND RESULTS GSPE produced a short-term increase in plasma ghrelin in rats after an acute treatment. A mouse ghrelinoma cell line was used to test the effects of the main pure grape-seed phenolic compounds on ghrelin release. Monomeric flavanols stimulated ghrelin secretion by activating bitter taste receptors. In contrast, gallic acid (GA) and oligomeric flavanols inhibited ghrelin release. The ghrelin-inhibiting effects of GA were confirmed in rats and in rat duodenal segments. One day after the last dose of a subchronic treatment, GSPE decreased plasma ghrelin in rats, ghrelin secretion in intestinal segments, and ghrelin mRNA expression in stomach. CONCLUSION The sustained satiating effects of GSPE are related to a long-term decrease in ghrelin expression. GA and oligomeric flavanols play a ghrelin-inhibiting role in this process.
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Affiliation(s)
- Joan Serrano
- MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain
| | - Àngela Casanova-Martí
- MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain
| | - Inge Depoortere
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders, KU Leuven, Leuven, Belgium
| | - Maria Teresa Blay
- MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain
| | - Ximena Terra
- MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain
| | - Montserrat Pinent
- MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain
| | - Anna Ardévol
- MoBioFood Research Group, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Tarragona, Spain
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Rats with a truncated ghrelin receptor (GHSR) do not respond to ghrelin, and show reduced intake of palatable, high-calorie food. Physiol Behav 2016; 163:88-96. [DOI: 10.1016/j.physbeh.2016.04.048] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 03/29/2016] [Accepted: 04/25/2016] [Indexed: 11/19/2022]
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Mani BK, Osborne-Lawrence S, Vijayaraghavan P, Hepler C, Zigman JM. β1-Adrenergic receptor deficiency in ghrelin-expressing cells causes hypoglycemia in susceptible individuals. J Clin Invest 2016; 126:3467-78. [PMID: 27548523 DOI: 10.1172/jci86270] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 07/07/2016] [Indexed: 01/06/2023] Open
Abstract
Ghrelin is an orexigenic gastric peptide hormone secreted when caloric intake is limited. Ghrelin also regulates blood glucose, as emphasized by the hypoglycemia that is induced by caloric restriction in mouse models of deficient ghrelin signaling. Here, we hypothesized that activation of β1-adrenergic receptors (β1ARs) localized to ghrelin cells is required for caloric restriction-associated ghrelin release and the ensuing protective glucoregulatory response. In mice lacking the β1AR specifically in ghrelin-expressing cells, ghrelin secretion was markedly blunted, resulting in profound hypoglycemia and prevalent mortality upon severe caloric restriction. Replacement of ghrelin blocked the effects of caloric restriction in β1AR-deficient mice. We also determined that treating calorically restricted juvenile WT mice with beta blockers led to reduced plasma ghrelin and hypoglycemia, the latter of which is similar to the life-threatening, fasting-induced hypoglycemia observed in infants treated with beta blockers. These findings highlight the critical functions of ghrelin in preventing hypoglycemia and promoting survival during severe caloric restriction and the requirement for ghrelin cell-expressed β1ARs in these processes. Moreover, these results indicate a potential role for ghrelin in mediating beta blocker-associated hypoglycemia in susceptible individuals, such as young children.
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34
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Edwards A, Abizaid A. Driving the need to feed: Insight into the collaborative interaction between ghrelin and endocannabinoid systems in modulating brain reward systems. Neurosci Biobehav Rev 2016; 66:33-53. [PMID: 27136126 DOI: 10.1016/j.neubiorev.2016.03.032] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2015] [Revised: 03/08/2016] [Accepted: 03/31/2016] [Indexed: 01/29/2023]
Abstract
Independent stimulation of either the ghrelin or endocannabinoid system promotes food intake and increases adiposity. Given the similar distribution of their receptors in feeding associated brain regions and organs involved in metabolism, it is not surprising that evidence of their interaction and its importance in modulating energy balance has emerged. This review documents the relationship between ghrelin and endocannabinoid systems within the periphery and hypothalamus (HYP) before presenting evidence suggesting that these two systems likewise work collaboratively within the ventral tegmental area (VTA) to modulate non-homeostatic feeding. Mechanisms, consistent with current evidence and local infrastructure within the VTA, will be proposed.
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Affiliation(s)
- Alexander Edwards
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
| | - Alfonso Abizaid
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, ON K1S 5B6, Canada.
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Barja-Fernandez S, Folgueira C, Castelao C, Leis R, Crujeiras AB, Casanueva FF, Seoane LM. Regulation of Growth Hormone by the Splanchnic Area. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 138:41-60. [DOI: 10.1016/bs.pmbts.2015.10.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Goshadrou F, Kazerouni F, Mehranfard N, Sadeghi B. Chronic administration of ghrelin regulates plasma glucose and normalizes insulin levels following fasting hyperglycemia and hyperinsulinemia. Gen Comp Endocrinol 2015; 224:113-20. [PMID: 26159083 DOI: 10.1016/j.ygcen.2015.07.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2015] [Revised: 06/15/2015] [Accepted: 07/05/2015] [Indexed: 12/15/2022]
Abstract
Ghrelin is an endogenous ligand for the growth hormone secretagogue receptor. The majority of the previous studies have shown that the short-term ghrelin treatment induces hyperglycemia and hypoinsulinemia in healthy humans and rodents. However, the results obtained from long-term treatment with ghrelin are not clear enough. In this study, we assessed acute (1 day) and chronic (21 days) effects of intraperitoneally administered ghrelin (at different doses of 1, 10 and 20 μg/kg) during a 12-h fasting period in rats using glucose oxidase method and direct sandwich ELISA (the Enzyme-Linked Immunosorbent Assay) and then compared the effects of exogenous ghrelin on blood glucose and insulin levels on day 21 with those on day 1. The results showed that acute ghrelin administration markedly increased fasting plasma glucose at doses of 1 and 10 μg/kg as well as insulin levels at 1 μg/kg in comparison to control values. Ghrelin (at 1 μg/kg) altered plasma glucose but not insulin levels on the 21st day compared to control values. In addition, the comparison of the influence of ghrelin administration on plasma glucose and insulin levels on day 21 with those on the first day revealed that the chronic administration of ghrelin notably decreased plasma glucose and insulin levels relative to the acute ghrelin treatment. These findings indicate that hyperglycemia and hyperinsulinemia caused by the exogenous ghrelin during acute treatment are temporary and prolonged treatment with ghrelin regulates plasma glucose and restores insulin to normal levels, suggesting a possible role for ghrelin in improving insulin resistance.
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Affiliation(s)
- Fatemeh Goshadrou
- Department of Physiology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Faranak Kazerouni
- Department of Laboratory Medicine, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Nasrin Mehranfard
- Department of Physiology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Bahman Sadeghi
- Department of Physiology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Neuroscience Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Laermans J, Vancleef L, Tack J, Depoortere I. Role of the clock gene Bmal1 and the gastric ghrelin-secreting cell in the circadian regulation of the ghrelin-GOAT system. Sci Rep 2015; 5:16748. [PMID: 26576661 PMCID: PMC4649743 DOI: 10.1038/srep16748] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Accepted: 10/19/2015] [Indexed: 11/09/2022] Open
Abstract
As adequate food intake is crucial to survival, organisms have evolved endogenous circadian clocks to generate optimal temporal patterns of food-related behavior and physiology. The gastric ghrelin-secreting cell is thought to be part of this network of peripheral food-entrainable oscillators (FEOs), regulating the circadian release of this orexigenic peptide. This study aimed to determine the role of the core clock gene Bmal1 and the gastric ghrelin-secreting cell as an FEO in the circadian rhythmicity of ghrelin expression and secretion in vivo and in vitro. Bmal1-deficient mice not only lacked circadian rhythmicity in plasma ghrelin levels and food intake, but also showed decreased gastric mRNA expression of ghrelin and ghrelin O-acyltransferase (GOAT), the ghrelin activating enzyme. Furthermore, in the absence of the hypothalamic master clock, food-related stimuli entrained the molecular clock of gastric ghrelinoma cells to regulate the rhythmic release of ghrelin. Divergent responses in octanoyl and total ghrelin release towards different food cues were observed, suggesting that the FEO also regulates the circadian rhythmicity of GOAT. Collectively, these findings indicate that circadian rhythmicity of ghrelin signaling requires Bmal1 and is driven by a food-responsive clock in the gastric ghrelin-secreting cell that not only regulates ghrelin, but also GOAT activity.
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Affiliation(s)
- J Laermans
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - L Vancleef
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - J Tack
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - I Depoortere
- Gut Peptide Research Lab, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
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Ali SS, Hamed EA, Ayuob NN, Shaker Ali A, Suliman MI. Effects of different routes of nicotine administration on gastric morphology and hormonal secretion in rats. Exp Physiol 2015; 100:881-895. [PMID: 26079093 DOI: 10.1113/ep085015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 05/06/2015] [Indexed: 01/02/2025]
Abstract
What is the central question of this study? Does chronic administration of nicotine by different routes affect gastric hormonal secretions and morphology in rats? What is the main finding and its importance? Chronic nicotine administration increased levels of gastrin, ghrelin and histamine but decreased prostaglandin E2 . Nicotine administered orally and by inhalation had a marked negative impact on the histological structure of the gastric mucosa compared with intraperitoneal administration. The negative impact of nicotine administration on gastric structure was associated with an increased concentration of gastrin and decreased prostaglandin E2 , which might be the cause of gastric/peptic ulcers in heavy smokers. The increase in ghrelin concentration and its effect following chronic nicotine administration needs further investigation. The aim was to assess the effects of different routes of chronic nicotine administration on gastric morphology and hormonal secretion; mainly gastrin, ghrelin, histamine and prostaglandin E2 (PGE2 ). Forty adult male albino rats were randomly assigned into four groups (10 rats per group), treated for 21 days as follows: control group (given standard rat pellets and water only); oral nicotine-treated group [50 μg (ml drinking water)(-1) ]; intraperitoneal nicotine-treated group [0.5 mg (kg body weight)(-1) ]; and inhaled nicotine-treated group [0.5 mg (kg body weight)(-1) ]. Concentrations of gastrin, ghrelin, PGE2 and histamine in serum and gastric tissue homogenates were assessed using ELISA kits. Stomach fundus was processed for histopathology and immunohistochemistry using light and electron microscopy. Different routes of chronic nicotine administration resulted in a significant increase in serum and gastric homogenate gastrin and ghrelin concentrations and a significant decrease in serum and homogenate PGE2 concentrations compared with the control group. Moreover, nicotine administration via oral and inhalation routes caused gastric erosion, transformation of peptic cells into the mucous variety, a significant increase in parietal cell numbers and an increase in expression of gastrin. In conclusion, the negative impact of nicotine administration on gastric structure that is associated with an increased concentration of gastrin and decreased concentration PGE2 might be the leading cause of gastric/peptic ulcers in heavy smokers. The increased ghrelin concentration and its effect following nicotine chronic administration needs further investigation. Based on these findings, we suggest that the alteration in gastric structure following chronic administration of nicotine can be prevented by reducing gastrin secretion and/or targeting its receptors.
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Affiliation(s)
- Soad Shaker Ali
- Anatomy Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Enas Ahmed Hamed
- Physiology Department, Faculty of Medicine, Assuit University, Asyut, Egypt
| | - Nasra Naeim Ayuob
- Anatomy Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
- Histology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Ahmed Shaker Ali
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mansour Ibrahem Suliman
- Pharmacology Department, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
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Perello M, Dickson SL. Ghrelin signalling on food reward: a salient link between the gut and the mesolimbic system. J Neuroendocrinol 2015; 27:424-34. [PMID: 25377898 PMCID: PMC5033008 DOI: 10.1111/jne.12236] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 10/29/2014] [Accepted: 11/02/2014] [Indexed: 12/12/2022]
Abstract
'Hunger is the best spice' is an old and wise saying that acknowledges the fact that almost any food tastes better when we are hungry. The neurobiological underpinnings of this lore include activation of the brain's reward system and the stimulation of this system by the hunger-promoting hormone ghrelin. Ghrelin is produced largely from the stomach and levels are higher preprandially. The ghrelin receptor is expressed in many brain areas important for feeding control, including not only the hypothalamic nuclei involved in energy balance regulation, but also reward-linked areas such as the ventral tegmental area. By targeting the mesoaccumbal dopamine neurones of the ventral tegmental area, ghrelin recruits pathways important for food reward-related behaviours that show overlap with but are also distinct from those important for food intake. We review a variety of studies that support the notion that ghrelin signalling at the level of the mesolimbic system is one of the key molecular substrates that provides a physiological signal connecting gut and reward pathways.
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Affiliation(s)
- M. Perello
- Laboratory of Neurophysiology, Multidisciplinary Institute of Cell Biology [Argentine Research Council (CONICET) and Scientific Research CommissionProvince of Buenos Aires (CIC‐PBA)]La PlataBuenos AiresArgentina
| | - S. L. Dickson
- Department of Physiology/EndocrinologyThe Sahlgrenska Academy at the University of GothenburgGothenburgSweden
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Lin TC, Liu YP, Chan YC, Su CY, Lin YF, Hsu SL, Yang CS, Hsiao M. Ghrelin promotes renal cell carcinoma metastasis via Snail activation and is associated with poor prognosis. J Pathol 2015; 237:50-61. [PMID: 25925728 DOI: 10.1002/path.4552] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2014] [Revised: 04/09/2015] [Accepted: 04/23/2015] [Indexed: 01/04/2023]
Abstract
Ghrelin is an appetite-regulating molecule that promotes growth hormone (GH) release and food intake through growth hormone secretagogue receptor (GHS-R). Recently, high ghrelin levels have been detected in various types of human cancer. Ghrelin expression is observed in proximal and distal renal tubules, where renal cell carcinoma (RCC) arises. However, whether ghrelin is up-regulated and promotes renal cell carcinogenesis remains obscure. In this study, we observed that ghrelin was highly expressed in renal tumours, especially in metastatic RCC. In addition, high ghrelin levels correlated with poor outcome, lymph node and distant metastasis. The addition of ghrelin promoted the migration ability of RCC cell lines 786-0, ACHN and A-498. Furthermore, knockdown of ghrelin expression reduced in vitro migration and in vivo metastasis, suggesting a requirement for ghrelin accumulation in the microenvironment for RCC metastasis. Analysis of microarray signatures using Ingenuity Pathway Analysis (IPA) and MetaCore pointed to the potential regulation by ghrelin of Snail, a transcriptional repressor of E-cadherin. We further observed that Ghrelin increased the expression, nuclear translocation and promoter-binding activity of Snail. Snail silencing blocked the ghrelin-mediated effects on E-cadherin repression and cell migration. Snail-E-cadherin regulation was mediated by GHS-R-triggered Akt phosphorylation at Ser473 and Thr308. Pretreatment with PI3K inhibitors, LY294002 and wortmannin, as well as Akt siRNA, decreased ghrelin-induced Akt phosphorylation, Snail promoter binding activity and migration. Taken together, our findings indicate that ghrelin can activate Snail function via the GHS-R-PI3K-Akt axis, which may contribute to RCC metastasis. The microarray raw data were retrieved from the Cancer Genome Atlas (TCGA) [KIRC gene expression (IlluminaHiSeq) dataset].
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Affiliation(s)
| | - Yu-Peng Liu
- Department of Genome Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Chia-Yi Su
- Genomics Research Centre, Academia Sinica, Taipei, Taiwan
| | - Yuan-Feng Lin
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Shih-Lan Hsu
- Department of Medical Research, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Chung-Shi Yang
- Institute of Biomedical Engineering and Nanomedicine, National Health Research Institutes, Miaoli, Taiwan
| | - Michael Hsiao
- Genomics Research Centre, Academia Sinica, Taipei, Taiwan
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Iwakura H, Kangawa K, Nakao K. The regulation of circulating ghrelin - with recent updates from cell-based assays. Endocr J 2015; 62:107-22. [PMID: 25273611 DOI: 10.1507/endocrj.ej14-0419] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Ghrelin is a stomach-derived orexigenic hormone with a wide range of physiological functions. Elucidation of the regulation of the circulating ghrelin level would lead to a better understanding of appetite control in body energy homeostasis. Earlier studies revealed that circulating ghrelin levels are under the control of both acute and chronic energy status: at the acute scale, ghrelin levels are increased by fasting and decreased by feeding, whereas at the chronic scale, they are high in obese subjects and low in lean subjects. Subsequent studies revealed that nutrients, hormones, or neural activities can influence circulating ghrelin levels in vivo. Recently developed in vitro assay systems for ghrelin secretion can assess whether and how individual factors affect ghrelin secretion from cells. In this review, on the basis of numerous human, animal, and cell-based studies, we summarize current knowledge on the regulation of circulating ghrelin levels and enumerate the factors that influence ghrelin levels.
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Affiliation(s)
- Hiroshi Iwakura
- Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan
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Zhao CM, Kodama Y, Flatberg A, Beisvag V, Kulseng B, Sandvik AK, Rehfeld JF, Chen D. Gene expression profiling of gastric mucosa in mice lacking CCK and gastrin receptors. ACTA ACUST UNITED AC 2014; 192-193:35-44. [PMID: 25160855 DOI: 10.1016/j.regpep.2014.08.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 08/07/2014] [Accepted: 08/12/2014] [Indexed: 01/04/2023]
Abstract
The stomach produces acid, which may play an important role in the regulation of bone homeostasis. The aim of this study was to reveal signaling pathways in the gastric mucosa that involve the acid secretion and possibly the bone metabolism in CCK1 and/or CCK2 receptor knockout (KO) mice. Gastric acid secretion was impaired and the ECL cell signaling pathway was inhibited in CCK2 receptor KO mice but not in CCK1 receptor KO mice. However, in CCK1+2 receptor double KO mice the acid secretion in response to pylorus ligation-induced vagal stimulation and the ECL cell pathway were partially normalized, which was associated with an up-regulated pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1). The basal part of the gastric mucosa expressed parathyroid hormone-like hormone (PTHLH) in a subpopulation of likely ECL cells (and possibly other cells) and vitamin D3 1α hydroxylase probably in trefoil peptide2-immunoreactive cells. In conclusion, mice lacking CCK receptors exhibited a functional shift from the gastrin-CCK pathways to the neuronal pathway in control of the ECL cells and eventually the acid secretion. Taking the present data together with previous findings, we suggest a possible link between gastric PTHLH and vitamin D and bone metabolism.
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Affiliation(s)
- Chun-Mei Zhao
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway.
| | - Yosuke Kodama
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway
| | - Arnar Flatberg
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway
| | - Vidar Beisvag
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway
| | - Bård Kulseng
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway
| | - Arne K Sandvik
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway; Department of Gastrointestinal and Liver Diseases, St. Olav's University Hospital, 7006 Trondheim, Norway
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 2100 København Ø, Denmark
| | - Duan Chen
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, 7006 Trondheim, Norway
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Li W, Baraboi ED, Cluny NL, Roy MC, Samson P, Biertho L, Sharkey KA, Richard D. Malabsorption plays a major role in the effects of the biliopancreatic diversion with duodenal switch on energy metabolism in rats. Surg Obes Relat Dis 2014; 11:356-66. [PMID: 25553888 DOI: 10.1016/j.soard.2014.07.020] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Revised: 07/03/2014] [Accepted: 07/25/2014] [Indexed: 12/25/2022]
Abstract
BACKGROUND The mechanisms underlying the metabolic benefits of the biliopancreatic diversion with duodenal switch (BPD/DS) have not been clarified. The objective of this study was to investigate the metabolic roles of sleeve gastrectomy (SG) and duodenal switch (DS) as main surgical components of BPD/DS. METHODS BPD/DS, SG, and DS surgeries were performed on chow-fed nonobese Wistar rats. Weight and energy intake were recorded during 8 postsurgical weeks. Glucagon-like peptide 1 (GLP-1), peptide tyrosine-tyrosine (PYY), glucose-dependent insulinotropic peptide, and ghrelin were measured pre- and postprandially at weeks 3 and 8, after surgery. Body composition, muscle, liver, and adipose tissue weights were measured. Gut morphometry and the presence and distribution of GLP-1 and PYY (L-cells) in the gut were determined using histochemical techniques. RESULTS Compared with sham, BPD/DS and DS led to significant reductions in weight gain, percentage of fat, and adipose tissue weight. These effects were accompanied by a reduction in digestible energy intake associated with fecal energy loss due to DS. BPD/DS and DS produced intestinal hypertrophy, as well as higher plasma GLP-1 and PYY in both fasted and refed states. It is noteworthy that none of those alterations were observed after SG, which nonetheless led to transient postoperative reduction in gross energy intake and weight. Similar to BPD/DS, SG alone produced a reduced meal size and an enhanced postprandial depression of plasma ghrelin. CONCLUSION BPD/DS results in metabolic benefits, which appear largely caused by food malabsorption due to DS. The elevation of anorectic GLP-1 and PYY are additional consequences of DS, which, together with malabsorption, could promote the metabolic benefits of BPD/DS.
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Affiliation(s)
- Wei Li
- Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Elena-Dana Baraboi
- Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Nina L Cluny
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Marie-Claude Roy
- Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Pierre Samson
- Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Laurent Biertho
- Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada
| | - Keith A Sharkey
- Department of Physiology and Pharmacology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada
| | - Denis Richard
- Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada.
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Abstract
The islets of Langerhans are key regulators of glucose homeostasis and have been known as a structure for almost one and a half centuries. During the twentieth century several different cell types were described in the islets of different species and at different developmental stages. Six cell types with identified hormonal product have been described so far by the use of histochemical staining methods, transmission electron microscopy, and immunohistochemistry. Thus, glucagon-producing α-cells, insulin-producing β-cells, somatostatin-producing δ-cells, pancreatic polypeptide-producing PP-cells, serotonin-producing enterochromaffin-cells, and gastrin-producing G-cells have all been found in the mammalian pancreas at least at some developmental stage. Species differences are at hand and age-related differences are also to be considered. Eleven years ago a novel cell type, the ghrelin cell, was discovered in the human islets. Subsequent studies have shown the presence of islet ghrelin cells in several animals, including mouse, rat, gerbils, and fish. The developmental regulation of ghrelin cells in the islets of mice has gained a lot of interest and several studies have added important pieces to the puzzle of molecular mechanisms and the genetic regulation that lead to differentiation into mature ghrelin cells. A body of evidence has shown that ghrelin is an insulinostatic hormone, and the potential for blockade of ghrelin signalling as a therapeutic avenue for type 2 diabetes is intriguing. Furthermore, ghrelin-expressing pancreatic tumours have been reported and ghrelin needs to be taken into account when diagnosing pancreatic tumours. In this review article, we summarise the knowledge about islet ghrelin cells obtained so far.
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Affiliation(s)
- Nils Wierup
- Unit of Neuroendocrine Cell Biology, Department of Clinical Sciences in Malmö, Lund University Diabetes Centre, Clinical Research Centre, Scania University Hospital, Jan Waldenströms gata 35, SE 205 02 Malmö, Sweden Imaging Team, Novo Nordisk A/S, Novo Nordisk Park, DK2760 Måløv, Denmark
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Abstract
Ghrelin is a gut-derived peptide hormone, first isolated from the stomach. Ghrelin was initially characterized as a growth hormone (GH) secretagogue, but it plays a more important role as a potent orexigen and modulator of whole-body energy homeostasis. Ghrelin itself is closely regulated by metabolic status. Bone remodeling constantly renews the skeleton in a highly energy-dependent fashion. Accordingly, bone metabolism is tightly coupled to energy metabolism through the integration of peripheral and central mechanisms, involving the sympathetic nervous system and factors such as leptin. Ghrelin has been shown to modulate osteoblast differentiation and function, both directly and perhaps also through regulation of the GH-insulin-like growth factor axis. However, recently it has also been shown that ghrelin interacts with leptin in modulating bone structure, constituting a new mechanism that couples bone metabolism with energy homeostasis. In this review, we discuss the role that ghrelin plays modulating bone cell function, and its integrative role in coupling bone metabolism with energy metabolism.
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Naot D, Cornish J. Cytokines and Hormones That Contribute to the Positive Association between Fat and Bone. Front Endocrinol (Lausanne) 2014; 5:70. [PMID: 24847313 PMCID: PMC4023068 DOI: 10.3389/fendo.2014.00070] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 04/27/2014] [Indexed: 01/20/2023] Open
Abstract
The positive association between body weight and bone density has been established in numerous laboratory and clinical studies. Apart from the direct effect of soft tissue mass on bone through skeletal loading, a number of cytokines and hormones contribute to the positive association between adipose and bone tissue, acting either locally in sites where cells of the two tissues are adjacent to each other or systemically through the circulation. The current review describes the effects of such local and systemic factors on bone physiology. One class of factors are the adipocyte-secreted peptides (adipokines), which affect bone turnover through a combination of direct effects in bone cells and indirect mechanisms mediated by the central nervous system. Another source of hormones that contribute to the coupling between fat and bone tissue are beta cells of the pancreas. Insulin, amylin, and preptin are co-secreted from pancreatic beta cells in response to increased glucose levels after feeding, and are also found in high circulating levels in obesity. A number of peptide hormones secreted from the gastrointestinal tract in response to feeding affect both fat and bone cells and thus can also act as mediators of the association between the two tissues. The current review focuses on results of laboratory studies investigating possible mechanism involved in the positive association between fat mass and bone mass.
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Affiliation(s)
- Dorit Naot
- Department of Medicine, University of Auckland, Auckland, New Zealand
- *Correspondence: Dorit Naot, Department of Medicine, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand e-mail:
| | - Jillian Cornish
- Department of Medicine, University of Auckland, Auckland, New Zealand
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Haddad H, Mroueh M, Faour WH, Daher C. Growth hormone treatment modulates active ghrelin levels in rats. Endocr Res 2014; 39:39-43. [PMID: 23772680 DOI: 10.3109/07435800.2013.799484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
INTRODUCTION Impairments in neuroendocrine regulation of food intake and postprandial satiety are leading causes to obesity. Ghrelin peptide is a GI hormone known to increase food intake partly through induction of growth hormone. The regulation of ghrelin production is still unknown. OBJECTIVE The aim of the current study is to investigate the influence of growth hormone (Genotropin) treatment on active ghrelin levels in plasma, stomach, pancreas and kidney in rats. MATERIAL/METHODS Male Sprague-Dawley rats, randomly allocated into control and three treatment groups, received daily subcutaneous injections of Genotropin at 2, 20 and 100 µg/rat/day for 5 consecutive days. Active ghrelin levels were quantified per tissue mass or tissue protein. RESULTS In control groups, the highest active ghrelin concentration in pmol/g tissue was found in the stomach (15.5 ± 0.21) followed by the pancreas (1.96 ± 0.066) and the kidney (1.36 ± 0.037). Genotropin treatment caused a dose dependent decrease in active ghrelin concentration in stomach, kidney and pancreas with a concomitant increase in plasma, and reaching significance at 20 and 100 µg/rat/day doses. However, the treatment caused variable effect on total protein concentrations, with a decrease in pancreas and an increase in stomach and kidney supernatants. Consequently, under such treatment, determination of active ghrelin concentration per tissue mass rather than per tissue protein is favored. CONCLUSIONS The present study suggests a direct correlation between Genotropin treatment and active ghrelin secretion into the rat plasma via modulating its stores in stomach, kidney and pancreas.
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Affiliation(s)
- Haytham Haddad
- School of Arts and Sciences, Natural Sciences Department and
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Solomon A, De Fanti BA, Martínez JA. Peripheral Ghrelin participates in glucostatic feeding mechanisms and in the anorexigenic signalling mediated by CART and CRF neurons. Nutr Neurosci 2013; 8:287-95. [PMID: 16669599 DOI: 10.1080/10284150500502546] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Ghrelin is upregulated under negative energy balance conditions, including starvation and hypoglycemia, while it is downregulated under situations of positive energy balance, such as feeding, hyperglycemia and obesity. The aims of this study were to assess potential ghrelin interactions with glucose levels in appetite control and to identify potential mechanisms involving orexigenic and anorexigenic ghrelin mediated signals by using a specific anti-ghrelin antibody. Our results confirm that peripheral ghrelin is an important signal in meal initiation and food intake stimulation. C-fos positive neurons in the PVN increased after insulin or 2-deoxyglucose administration. Moreover, we also demonstrate that peripheral ghrelin blockade with a specific anti-ghrelin antibody reduces, in part, the orexigenic signal induced by insulin and 2-DG administration. Furthermore, when we blocked peripheral ghrelin, c-fos positive CRF neurons and CART expression increased in the PVN, both under hypoglycemia or cytoglycopenia conditions, suggesting a neuronal activation (anorexigenic signalling) in this hypothalamic region. In summary, our findings imply that peripheral ghrelin plays an important role in regulatory "glucostatic" feeding mechanisms due to its role as a "hunger" signal affecting the PVN area, which may contribute to energy homeostasis through both orexigenic/anorexigenic pathways.
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Affiliation(s)
- Andrew Solomon
- Department of Physiology and Nutrition, University of Navarra, 31008 Pamplona, Spain
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Delporte C. Structure and physiological actions of ghrelin. SCIENTIFICA 2013; 2013:518909. [PMID: 24381790 PMCID: PMC3863518 DOI: 10.1155/2013/518909] [Citation(s) in RCA: 102] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/08/2013] [Accepted: 11/10/2013] [Indexed: 05/30/2023]
Abstract
Ghrelin is a gastric peptide hormone, discovered as being the endogenous ligand of growth hormone secretagogue receptor. Ghrelin is a 28 amino acid peptide presenting a unique n-octanoylation modification on its serine in position 3, catalyzed by ghrelin O-acyl transferase. Ghrelin is mainly produced by a subset of stomach cells and also by the hypothalamus, the pituitary, and other tissues. Transcriptional, translational, and posttranslational processes generate ghrelin and ghrelin-related peptides. Homo- and heterodimers of growth hormone secretagogue receptor, and as yet unidentified receptors, are assumed to mediate the biological effects of acyl ghrelin and desacyl ghrelin, respectively. Ghrelin exerts wide physiological actions throughout the body, including growth hormone secretion, appetite and food intake, gastric secretion and gastrointestinal motility, glucose homeostasis, cardiovascular functions, anti-inflammatory functions, reproductive functions, and bone formation. This review focuses on presenting the current understanding of ghrelin and growth hormone secretagogue receptor biology, as well as the main physiological effects of ghrelin.
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Affiliation(s)
- Christine Delporte
- Laboratory of Pathophysiological and Nutritional Biochemistry, Université Libre de Bruxelles, 808 Route de Lennik, Bat G/E-CP611, 1070 Brussels, Belgium
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