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Ma Y, Yan Q, Wang P, Guo W, Yu L. Therapeutic potential of ghrelin/GOAT/GHSR system in gastrointestinal disorders. Front Nutr 2024; 11:1422431. [PMID: 39246401 PMCID: PMC11380557 DOI: 10.3389/fnut.2024.1422431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 08/08/2024] [Indexed: 09/10/2024] Open
Abstract
Ghrelin, a peptide primarily secreted in the stomach, acts via the growth hormone secretagogue receptor (GHSR). It regulates several physiological processes, such as feeding behavior, energy homeostasis, glucose and lipid metabolism, cardiovascular function, bone formation, stress response, and learning. GHSR exhibits significant expression within the central nervous system. However, numerous murine studies indicate that ghrelin is limited in its ability to enter the brain from the bloodstream and is primarily confined to specific regions, such as arcuate nucleus (ARC) and median eminence (ME). Nevertheless, the central ghrelin system plays an essential role in regulating feeding behavior. Furthermore, the role of vagal afferent fibers in regulating the functions of ghrelin remains a major topic of discussion among researchers. In recent times, numerous studies have elucidated the substantial therapeutic potential of ghrelin in most gastrointestinal (GI) diseases. This has led to the development of numerous pharmaceutical agents that target the ghrelin system, some of which are currently under examination in clinical trials. Furthermore, ghrelin is speculated to serve as a promising biomarker for GI tumors, which indicates its potential use in tumor grade and stage evaluation. This review presents a summary of recent findings in research conducted on both animals and humans, highlighting the therapeutic properties of ghrelin system in GI disorders.
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Affiliation(s)
- Yunxiao Ma
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Qihui Yan
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Ping Wang
- Department of Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, Jilin University, Changchun, China
| | - Weiying Guo
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
| | - Lu Yu
- Department of Endocrinology and Metabolism of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, China
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Yamano H, Horike H, Taguchi Y, Inabu Y, Sugino T, Suzuki N, Etoh T, Shiotsuka Y, Fujino R, Takahashi H. Effect of Ca-octanoate supplementation on concentrations of ghrelin and ghrelin-related hormones in plasma and milk of beef cattle. Heliyon 2023; 9:e16795. [PMID: 37313147 PMCID: PMC10258411 DOI: 10.1016/j.heliyon.2023.e16795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 04/20/2023] [Accepted: 05/29/2023] [Indexed: 06/15/2023] Open
Abstract
We aimed to evaluate the effect of dietary calcium (Ca)-octanoate supplementation on concentrations of ghrelin, growth hormone (GH), insulin-like growth factor-1 (IGF-1), and insulin in plasma and milk of beef cattle during late gestation and early postpartum. Twelve Japanese Black cattle were offered concentrate without (CON, n = 6) or with Ca-octanoate supplementation at 1.5% of dietary dry matter (OCT, n = 6). Blood samples were collected at -60, -30, and -7 d relative to the expected parturition date and daily from d 0 to 3 after parturition. Milk samples were collected daily postpartum. Compared to the CON group, concentrations of acylated ghrelin increased in plasma as parturition approached in the OCT group (P = 0.02). However, concentrations of GH, IGF-1, and insulin in plasma and milk were not affected by treatment groups throughout the study. Additionally, we showed for the first time that bovine colostrum and transition milk contain acylated ghrelin at a significantly higher concentration than plasma (P = 0.01). Interestingly, concentrations of acylated ghrelin in milk were negatively correlated with those in plasma postpartum (r = -0.50, P < 0.01). Feeding Ca-octanoate increased concentrations of total cholesterol (T-cho) in plasma and milk (P < 0.05), tended to increase those of glucose in plasma at postpartum and milk (P < 0.1). We conclude that feeding Ca-octanoate in late gestation and early postpartum may contribute to increased concentrations of glucose and T-cho in plasma and milk without affecting concentrations of ghrelin, GH, IGF-1, and insulin in plasma and milk.
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Affiliation(s)
- Haruki Yamano
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
| | - Hiroshi Horike
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
| | - Yutaka Taguchi
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
| | - Yudai Inabu
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
| | - Toshihisa Sugino
- The Research Center for Animal Science, Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima 739-8528, Japan
| | - Nonomi Suzuki
- Feed and Livestock Sector, Kanematsu Agritech Co., Ltd., Saitama, 343-0845, Japan
| | - Tetsuji Etoh
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
| | - Yuji Shiotsuka
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
| | - Ryoichi Fujino
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
| | - Hideyuki Takahashi
- Kuju Agricultural Research Center, Graduate School of Agriculture, Kyushu University, Oita, 878-0201, Japan
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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: 23] [Impact Index Per Article: 5.8] [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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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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Khaleel EF, Abdel-Aleem GA. Obestatin protects and reverses nonalcoholic fatty liver disease and its associated insulin resistance in rats via inhibition of food intake, enhancing hepatic adiponectin signaling, and blocking ghrelin acylation. Arch Physiol Biochem 2019; 125:64-78. [PMID: 29429367 DOI: 10.1080/13813455.2018.1437638] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
This study investigated the ameliorative and protective effects of long-term obestatin administration (80 nmol/kg/ intraperitoneal injection (i.p.)) on the pathogenesis of high-fat diet (HFD) induced nonalcoholic fatty liver disease (NAFLD) in rats. Rats (n = 8/group) were divided as control, NAFLD, NAFLD + Simvastatin, NAFLD + obestatin, NAFLD then obestatin, and obestatin then NAFLD. Obestatin co -or post-therapy significantly reduced hepatomegaly and reversed hyperlipidemia, hepatic lipid accumulation, and insulin resistance (IR). Mechanistically obestatin treatments in these rats significantly prevented the increases in final body weights and food intake. Concomitantly, it enhanced circulatory adiponectin levels and hepatic signaling as evident by elevated hepatic protein levels of adiponectin receptors (adipoRII), carnitine palmitoyltransferase-1 (CPT-1), peroxisome proliferator-activated receptor- α (PPAR-α), and phosphor-AMPK (p-AMPK). In addition, obestatin enhanced total circulatory ghrelin levels and significantly increased deacylated ghrelin to acylated ghrelin (DAG/AG) ratio. These data suggest that obestatin reverses and protects against development or progression of NAFLD directly by modulating ghrelin and adiponectin signaling or indirectly by lowering food intake.
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Affiliation(s)
- Eman F Khaleel
- a Department of Medical Physiology, College of Medicine , King Khalid University , Abha , Saudi Arabia
- b Department of Medical Physiology, Faculty of Medicine , Cairo University , Cairo , Egypt
| | - Ghada A Abdel-Aleem
- c Department of Medical Biochemistry, College of Medicine , King Khalid University , Abha , Saudi Arabia
- d Department of Medical Biochemistry, Faculty of Medicine , Tanta University , Tanta , Egypt
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Lemarié F, Beauchamp E, Drouin G, Legrand P, Rioux V. Dietary caprylic acid and ghrelin O-acyltransferase activity to modulate octanoylated ghrelin functions: What is new in this nutritional field? Prostaglandins Leukot Essent Fatty Acids 2018; 135:121-127. [PMID: 30103923 DOI: 10.1016/j.plefa.2018.07.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Revised: 07/15/2018] [Accepted: 07/16/2018] [Indexed: 12/15/2022]
Abstract
Caprylic acid (octanoic acid, C8:0) belongs to the class of medium-chain saturated fatty acids (MCFAs). Dairy products and specific oils such as coconut oil are natural sources of dietary caprylic acid. MCFAs display distinct chemico-physical and metabolic properties from those of long-chain saturated fatty acids (LCFAs ≥ 12 carbons) and potential beneficial physiological effects of dietary C8:0 have been studied for many years. More recently, caprylic acid was shown to octanoylate ghrelin, the only known peptide hormone with an orexigenic effect. Through its covalent binding to the ghrelin peptide, caprylic acid exhibits an emerging and specific role in modulating physiological functions themselves regulated by octanoylated ghrelin. Dietary caprylic acid is therefore now suspected to provide the ghrelin O-acyltransferase (GOAT) enzyme with octanoyl-CoA co-substrates necessary for the acyl modification of ghrelin. Recent studies suggest that decreasing the circulating octanoylated ghrelin level through the inhibition of GOAT activity, or simply by modulating the availability of its C8:0 substrate, might constitute a therapeutic strategy against obesity. Both dietary caprylic acid availability and GOAT activity may indeed be important to modulate octanoylated ghrelin concentration and functions. This review highlights recent findings in the field of nutrition.
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Affiliation(s)
- Fanny Lemarié
- Laboratoire de Biochimie-Nutrition Humaine, Agrocampus Ouest, Rennes, France; Centre for Molecular Medicine and Therapeutics (CMMT), The University of British Columbia, BC Children's Hospital Research Institute, Vancouver, Canada
| | - Erwan Beauchamp
- Laboratoire de Biochimie-Nutrition Humaine, Agrocampus Ouest, Rennes, France
| | - Gaëtan Drouin
- Laboratoire de Biochimie-Nutrition Humaine, Agrocampus Ouest, Rennes, France
| | - Philippe Legrand
- Laboratoire de Biochimie-Nutrition Humaine, Agrocampus Ouest, Rennes, France
| | - Vincent Rioux
- Laboratoire de Biochimie-Nutrition Humaine, Agrocampus Ouest, Rennes, France.
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The Role of Ghrelin in Anorexia Nervosa. Int J Mol Sci 2018; 19:ijms19072117. [PMID: 30037011 PMCID: PMC6073411 DOI: 10.3390/ijms19072117] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Revised: 07/11/2018] [Accepted: 07/17/2018] [Indexed: 12/26/2022] Open
Abstract
Ghrelin, a 28-amino acid peptide hormone expressed in X/A-like endocrine cells of the stomach, is the only known peripherally produced and centrally acting peptide that stimulates food intake and therefore attracted a lot of attention with one major focus on the treatment of conditions where an increased energy intake or body weight gain is desired. Anorexia nervosa is an eating disorder characterized by a pronounced reduction of body weight, a disturbed body image and hormonal alterations. Ghrelin signaling has been thoroughly investigated under conditions of anorexia nervosa. The present review will highlight these alterations of ghrelin in anorexia and discuss possible treatment strategies targeting ghrelin signaling. Lastly, gaps in knowledge will be mentioned to foster future research.
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Murtuza MI, Isokawa M. Endogenous ghrelin-O-acyltransferase (GOAT) acylates local ghrelin in the hippocampus. J Neurochem 2017; 144:58-67. [PMID: 29063591 DOI: 10.1111/jnc.14244] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 10/11/2017] [Accepted: 10/13/2017] [Indexed: 12/22/2022]
Abstract
Ghrelin is an appetite-stimulating peptide. Serine 3 on ghrelin must be acylated by octanoate via the enzyme ghrelin-O-acyltransferase (GOAT) for the peptide to bind and activate the cognate receptor, growth hormone secretagogue receptor type 1a (GHSR1a). Interest in GHSR1a increased dramatically when GHSR1a mRNA was demonstrated to be widespread in the brain, including the cortex and hippocampus, indicating that it has multifaceted functions beyond the regulation of metabolism. However, the source of octanoylated ghrelin for GHSR1a in the brain, outside of the hypothalamus, is not well understood. Here, we report the presence of GOAT and its ability to acylate non-octanoylated ghrelin in the hippocampus. GOAT immunoreactivity is aggregated at the base of the dentate granule cell layer in the rat and wild-type mouse. This immunoreactivity was not affected by the pharmacological inhibition of GHSR1a or the metabolic state-dependent fluctuation of systemic ghrelin levels. However, it was absent in the GHSR1a knockout mouse hippocampus, pointing the possibility that the expression of GHSR1a may be a prerequisite for the production of GOAT. Application of fluorescein isothiocyanate (FITC)-conjugated non-octanoylated ghrelin in live hippocampal slice culture (but not in fixed culture or in the presence of GOAT inhibitors) mimicked the binding profile of FITC-conjugated octanoylated ghrelin, suggesting that extracellularly applied non-octanoylated ghrelin was acylated by endogenous GOAT in the live hippocampus while GOAT being mobilized out of neurons. Our results will advance the understanding for the role of endogenous GOAT in the hippocampus and facilitate the search for the source of ghrelin that is intrinsic to the brain.
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Affiliation(s)
- Mohammad I Murtuza
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, Texas, USA
| | - Masako Isokawa
- Department of Health and Biomedical Sciences, University of Texas Rio Grande Valley, Brownsville, Texas, USA
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Wang Q, Tang W, Rao WS, Song X, Shan CX, Zhang W. Changes of Ghrelin/GOAT axis and mTOR pathway in the hypothalamus after sleeve gastrectomy in obese type-2 diabetes rats. World J Gastroenterol 2017; 23:6231-6241. [PMID: 28974889 PMCID: PMC5603489 DOI: 10.3748/wjg.v23.i34.6231] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2017] [Revised: 05/02/2017] [Accepted: 06/01/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To examine the changes of the ghrelin/ghrelin O-acyltransferase (GOAT) axis and the mammalian target of rapamycin (mTOR) pathway in the hypothalamus after sleeve gastrectomy. METHODS A total of 30 obese type-2 diabetes Sprague-Dawley (SD) rats, 6 wk of age, fed with high-sugar and high-fat fodder for 2 mo plus intraperitoneal injection of streptozotocin were randomly divided into three groups: non-operation group (S0 group, n = 10), sham operation group (Sh group, n = 10) and sleeve gastrectomy group (SG group, n = 10). Data of body mass, food intake, oral glucose tolerance test (OGTT), acylated ghrelin (AG) and total ghrelin (TG) were collected and measured at the first day (when the rats were 6 wk old), preoperative day 3 and postoperative week 8. The mRNA expression of preproghrelin, GOAT and neuropeptide Y (NPY), and protein expression of ghrelin, GOAT, GHSR and the mTOR pathway (p-Akt, p-mTOR and p-S6) were measured in the hypothalamus. RESULTS SG can significantly improve metabolic symptoms by reducing body mass and food intake. The obese rats showed lower serum TG levels and no change in AG, but the ratio of AG/TG was increased. When compared with the S0 and Sh groups, the SG group showed decreased TG (1482.03 ± 26.55, 1481.49 ± 23.30 and 1206.63 ± 52.02 ng/L, respectively, P < 0.05), but unchanged AG (153.06 ± 13.74, 155.37 ± 19.30 and 144.44 ± 16.689 ng/L, respectively, P > 0.05). As a result, the ratio of AG/TG further increased in the SG group (0.103 ± 0.009, 0.105 ± 0.013 and 0.12 ± 0.016, respectively, P < 0.05). When compared with the S0 group, SG suppressed mRNA and protein levels of preproghrelin (0.63 ± 0.12 vs 0.5 ± 0.11, P < 0.05) and GOAT (0.96 ± 0.09 vs 0.87 ± 0.08, P < 0.05), but did not change NPY mRNA expression (0.61 ± 0.04 vs 0.65 ± 0.07, P > 0.05) in the hypothalamus. The protein levels of p-Akt, p-mTOR and p-S6 were higher in the SG group, which indicated that the hypothalamic mTOR pathway was activated after SG at the postoperative week 8. CONCLUSION The reduction of ghrelin expression and activation of the mTOR pathway might have opposite effects on food intake, as SG improves obesity and T2DM.
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MESH Headings
- Acylation
- Acyltransferases/metabolism
- Animals
- Diabetes Mellitus, Experimental/blood
- Diabetes Mellitus, Experimental/chemically induced
- Diabetes Mellitus, Experimental/metabolism
- Diabetes Mellitus, Experimental/surgery
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/chemically induced
- Diabetes Mellitus, Type 2/metabolism
- Diabetes Mellitus, Type 2/surgery
- Eating
- Gastrectomy/methods
- Gastroplasty/methods
- Ghrelin/metabolism
- Glucose Tolerance Test
- Humans
- Hypothalamus/metabolism
- Male
- Obesity/blood
- Obesity/complications
- Obesity/metabolism
- Obesity/surgery
- RNA, Messenger/metabolism
- Rats
- Rats, Sprague-Dawley
- Signal Transduction
- TOR Serine-Threonine Kinases/metabolism
- Weight Loss
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Affiliation(s)
- Qiang Wang
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Wei Tang
- Department of Surgery, University of Tokyo Hospital, Tokyo 113-8655, Japan
| | - Wen-Sheng Rao
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Xin Song
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Cheng-Xiang Shan
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Wei Zhang
- Department of General Surgery, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China
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Abstract
Obesity, a major risk factor for the development of diabetes mellitus, cardiovascular diseases and certain types of cancer, arises from a chronic positive energy balance that is often due to unlimited access to food and an increasingly sedentary lifestyle on the background of a genetic and epigenetic vulnerability. Our understanding of the humoral and neuronal systems that mediate the control of energy homeostasis has improved dramatically in the past few decades. However, our ability to develop effective strategies to slow the current epidemic of obesity has been hampered, largely owing to the limited knowledge of the mechanisms underlying resistance to the action of metabolic hormones such as leptin and ghrelin. The development of resistance to leptin and ghrelin, hormones that are crucial for the neuroendocrine control of energy homeostasis, is a hallmark of obesity. Intensive research over the past several years has yielded tremendous progress in our understanding of the cellular pathways that disrupt the action of leptin and ghrelin. In this Review, we discuss the molecular mechanisms underpinning resistance to leptin and ghrelin and how they can be exploited as targets for pharmacological management of obesity.
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Affiliation(s)
- Huxing Cui
- Department of Pharmacology, University of Iowa, Iowa City, Iowa 52246, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA
| | - Miguel López
- Department of Physiology, Center for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela 15782, Spain
- Centro de Investigación Biomédica en Red-Fisiopatología de la Obesidad y Nutrición (CIBERobn), Santiago de Compostela 15706, Spain
| | - Kamal Rahmouni
- Department of Pharmacology, University of Iowa, Iowa City, Iowa 52246, USA
- Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa 52242, USA
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Cho YH, Lee SY, Jeong DW, Cho AR, Jeon JS, Kim YJ, Lee JG, Yi YH, Tak YJ, Hwang HR, Lee SH, Lee SM. Metabolic Syndrome is Associated with Lower Plasma Levels of Desacyl Ghrelin and Total Ghrelin in Asymptomatic Middle-aged Korean Men. J Obes Metab Syndr 2017; 26:114-121. [PMID: 31089505 PMCID: PMC6484903 DOI: 10.7570/jomes.2017.26.2.114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2016] [Revised: 10/27/2016] [Accepted: 12/12/2016] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Desacyl ghrelin is acylated by ghrelin O-acyltransferase (GOAT) and converted to acyl ghrelin. To date, little is known about the relationship among the levels of these two forms of ghrelin, GOAT level, and insulin resistance in Asian individuals. The purpose of this study was to determine the relationship between insulin resistance and the levels of plasma acyl ghrelin, desacyl ghrelin, and GOAT in asymptomatic middle-aged Korean men. METHODS This cross-sectional study evaluated 78 asymptomatic middle-aged Korean men with metabolic syndrome (MS). We examined the correlation between the plasma levels of acyl ghrelin, desacyl ghrelin, and GOAT and sociodemographic, dietary, anthropometric, and metabolic parameters, as well as the association between insulin resistance and plasma levels of acyl ghrelin, desacyl ghrelin, and GOAT. RESULTS The levels of desacyl ghrelin and total ghrelin were significantly lower in the MS group than in the non-MS group (P<0.017, P=0.01, respectively). HOMA-IR values showed a significant negative correlation with desacyl ghrelin (r=-0.271, P=0.017) and total ghrelin (r=-0.271, P=0.016) levels. Acyl ghrelin and GOAT were not significantly correlated with HOMA-IR, and no correlation was found between the plasma levels of the two ghrelin types and GOAT. CONCLUSION The plasma levels of desacyl ghrelin and total ghrelin in middle-aged Korean men with MS were lower than in those without MS. A significant negative correlation was observed between desacyl ghrelin level and HOMA-IR; however, no correlation was found between plasma levels of acyl ghrelin and GOAT and HOMA-IR.
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Affiliation(s)
- Young Hye Cho
- Family Medicine Clinic, Obesity, Metabolism and Nutrition Center and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan,
Korea
| | - Sang Yeoup Lee
- Family Medicine Clinic, Obesity, Metabolism and Nutrition Center and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan,
Korea
- Medical Education Unit, Pusan National University, School of Medicine, Yangsan,
Korea
| | - Dong Wook Jeong
- Family Medicine Clinic, Obesity, Metabolism and Nutrition Center and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan,
Korea
| | - A Ra Cho
- Family Medicine Clinic, Obesity, Metabolism and Nutrition Center and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan,
Korea
| | - Jeong Suk Jeon
- Family Medicine Clinic, Obesity, Metabolism and Nutrition Center and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan,
Korea
| | - Yun Jin Kim
- Department of Family Medicine, Pusan National University Hospital, Busan,
Korea
| | - Jeong Gyu Lee
- Department of Family Medicine, Pusan National University Hospital, Busan,
Korea
| | - Yu Hyeon Yi
- Department of Family Medicine, Pusan National University Hospital, Busan,
Korea
| | - Young Jin Tak
- Department of Family Medicine, Pusan National University Hospital, Busan,
Korea
| | - Hye Rim Hwang
- Department of Family Medicine, Pusan National University Hospital, Busan,
Korea
| | - Seung-Hun Lee
- Department of Family Medicine, Pusan National University Hospital, Busan,
Korea
| | - Sun Min Lee
- Department of Laboratory Medicine and Molecular Genetics and Research Institute of Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan,
Korea
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12
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Molecular Ghrelin System in the Pancreatic Acinar Cells: The Role of the Polypeptide, Caerulein and Sensory Nerves. Int J Mol Sci 2017; 18:ijms18050929. [PMID: 28468316 PMCID: PMC5454842 DOI: 10.3390/ijms18050929] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 04/09/2017] [Accepted: 04/19/2017] [Indexed: 12/25/2022] Open
Abstract
Ghrelin (GHRL) is an endogenous ligand for the growth hormone secretagogue receptor (GHS-R). Experimental studies showed that GHRL protects the stomach and pancreas against acute damage, but the effect of GHRL on pancreatic acinar cells was still undetermined. Aim: To investigate the effect of GHRL and caerulein on the functional ghrelin system in pancreatic acinar cells taking into account the role of sensory nerves (SN). Methods: Experiments were carried out on isolated pancreatic acinar cells and AR42J cells. Before acinar cells isolation, GHRL was administered intraperitoneally at a dose of 50 µg/kg to rats with intact SN or with capsaicin deactivation of SN (CDSN). After isolation, pancreatic acinar cells were incubated in caerulein-free or caerulein containing solution. AR42J cells were incubated under basal conditions and stimulated with caerulein, GHRL or a combination of the above. Results: Incubation of isolated acinar cells with caerulein inhibited GHS-R and GHRL expression at the level of mRNA and protein in those cells. Either in rats with intact SN or with CDSN, administration of GHRL before isolation of acinar cells increased expression of GHRL and GHS-R in those cells and reversed the caerulein-induced reduction in expression of those parameters. Similar upregulation of GHS-R and GHRL was observed after administration of GHRL in AR42J cells. Conclusions: GHRL stimulates its own expression and expression of its receptor in isolated pancreatic acinar cells and AR42J cells on the positive feedback pathway. This mechanism seems to participate in the pancreatoprotective effect of GHRL in the course of acute pancreatitis.
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13
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Characterization of Ghrelin O-Acyltransferase (GOAT) in goldfish (Carassius auratus). PLoS One 2017; 12:e0171874. [PMID: 28178327 PMCID: PMC5298278 DOI: 10.1371/journal.pone.0171874] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 01/26/2017] [Indexed: 12/21/2022] Open
Abstract
Ghrelin is the only known hormone posttranslationally modified with an acylation. This modification is crucial for most of ghrelin’s physiological effects and is catalyzed by the polytopic enzyme ghrelin O-acyltransferase (GOAT). The aim of this study was to characterize GOAT in a teleost model, goldfish (Carassius auratus). First, the full-length cDNA sequence was obtained by RT-PCR and rapid amplification of cDNA ends methods. Two highly homologous cDNAs of 1491 and 1413 bp, respectively, named goat-V1 and goat-V2 were identified. Deduced protein sequences (393 and 367 amino acids, respectively) are predicted to present 11 and 9 transmembrane regions, respectively, and both contain two conserved key residues proposed to be involved in catalysis: asparagine 273 and histidine 304. RT-qPCR revealed that both forms of goat mRNAs show a similar widespread tissue distribution, with the highest expression in the gastrointestinal tract and gonads and less but considerable expression in brain, pituitary, liver and adipose tissue. Immunostaining of intestinal sections showed the presence of GOAT immunoreactive cells in the intestinal mucosa, some of which colocalize with ghrelin. Using an in vitro approach, we observed that acylated ghrelin downregulates GOAT gene and protein levels in cultured intestine in a time-dependent manner. Finally, we found a rhythmic oscillation of goat mRNA expression in the hypothalamus, pituitary and intestinal bulb of goldfish fed at midday, but not at midnight. Together, these findings report novel data characterizing GOAT, and offer new information about the ghrelinergic system in fish.
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14
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Villa-Osaba A, Gahete MD, Cordoba-Chacon J, de Lecea L, Castaño JP, Luque RM. Fasting modulates GH/IGF-I axis and its regulatory systems in the mammary gland of female mice: Influence of endogenous cortistatin. Mol Cell Endocrinol 2016; 434:14-24. [PMID: 27291340 DOI: 10.1016/j.mce.2016.06.014] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Revised: 05/27/2016] [Accepted: 06/08/2016] [Indexed: 11/19/2022]
Abstract
Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are essential factors in mammary-gland (MG) development and are altered during fasting. However, no studies have investigated the alterations in the expression of GH/IGF-I and its regulatory systems (somatostatin/cortistatin and ghrelin) in MG during fasting. Therefore, this study was aimed at characterizing the regulation of GH/IGF-I/somatostatin/cortistatin/ghrelin-systems expression in MG of fasted female-mice (compared to fed-controls) and the influence of endogenous-cortistatin (using cortistatin-knockouts). Fasting decreased IGF-I while increased IGF-I/Insulin-receptors expression in MGs. Fasting provoked an increase in GH expression that might be associated to enhanced ghrelin-variants/ghrelin-O-acyl-transferase enzyme expression, while an upregulation of somatostatin-receptors was observed. However, cortistatin-knockouts mice showed a decrease in GH and somatostatin receptor-subtypes expression. Altogether, we demonstrate that GH/IGF-I, somatostatin/cortistatin and ghrelin systems expression is altered in MG during fasting, suggesting a relevant role in coordinating its response to metabolic stress, wherein endogenous cortistatin might be essential for an appropriate response.
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Affiliation(s)
- Alicia Villa-Osaba
- Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Spain; Hospital Universitario Reina Sofía (HURS), Spain; CIBERobn, Córdoba, Spain; ceiA3, Córdoba, Spain
| | - Manuel D Gahete
- Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Spain; Hospital Universitario Reina Sofía (HURS), Spain; CIBERobn, Córdoba, Spain; ceiA3, Córdoba, Spain
| | - José Cordoba-Chacon
- Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Spain; Hospital Universitario Reina Sofía (HURS), Spain; CIBERobn, Córdoba, Spain; ceiA3, Córdoba, Spain
| | - Luis de Lecea
- Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA
| | - Justo P Castaño
- Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Spain; Hospital Universitario Reina Sofía (HURS), Spain; CIBERobn, Córdoba, Spain; ceiA3, Córdoba, Spain.
| | - Raúl M Luque
- Maimonides Institute of Biomedical Research of Cordoba (IMIBIC), Spain; Department of Cell Biology, Physiology and Immunology, University of Córdoba, Spain; Hospital Universitario Reina Sofía (HURS), Spain; CIBERobn, Córdoba, Spain; ceiA3, Córdoba, Spain.
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15
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Ritze Y, Schollenberger A, Hamze Sinno M, Bühler N, Böhle M, Bárdos G, Sauer H, Mack I, Enck P, Zipfel S, Meile T, Königsrainer A, Kramer M, Bischoff SC. Gastric ghrelin, GOAT, leptin, and leptinR expression as well as peripheral serotonin are dysregulated in humans with obesity. Neurogastroenterol Motil 2016; 28:806-15. [PMID: 26787056 DOI: 10.1111/nmo.12773] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Accepted: 12/19/2015] [Indexed: 01/01/2023]
Abstract
BACKGROUND Gastrointestinal hormone release and the regulation of appetite and body weight are thought to be dysbalanced in obesity. However, human data investigating the expression of gastrointestinal hormones in the obese are rare. We studied the expression of ghrelin, leptin, and the serotonergic system in stomach tissue and serum of obese and non-obese individuals. METHODS Gastric tissue and serum were collected from 29 adult obese (BMI 48.7 ± 10.6 kg/m(2) ; mean ± SD) who underwent laparoscopic sleeve gastrectomy. Gastric biopsies, surgery specimen or serum was obtained from 35 adult non-obese humans (BMI 22.7 ± 1.9 kg/m(2) ). Ghrelin, ghrelin O-acyl transferase (GOAT), leptin, leptin receptor, and tryptophan hydroxylase 1 (TPH1) mRNA expression were measured by qRT-PCR. Serotonin (5HT) and leptin protein concentration were quantified in tissue extracts and serum; GOAT and ghrelin-positive cells were immunohistologically quantified in tissue. Additionally, 21 blood immune markers were analyzed. KEY RESULTS In gastric tissue, GOAT-positive cells were reduced (p < 0.01), but ghrelin-positive cells and mRNA were increased (both p < 0.05) in obese compared with non-obese individuals. Gastric leptin (p < 0.001) and leptin receptor (p < 0.001) mRNA expression, as well as leptin concentrations in serum (p < 0.001), were increased in obese compared with non-obese individuals. Serum 5HT was reduced (p < 0.05), while tissue 5HT and TPH1 mRNA were reduced only by trend. Interleukin 1 receptor a (IL1Ra), IL-8, IL-12, and monocyte chemoattractant protein 1 (IL1Ra) were increased and IL1Ra correlated negatively with serum leptin. CONCLUSIONS & INFERENCES Our data indicate that obesity causes a dysregulation of gastrointestinal hormones at the tissue level and serum, including a negative correlation with an increased marker of subclinical inflammation.
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Affiliation(s)
- Y Ritze
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany.,Institute for Medical Psychology and Behavioral Neurobiology, University of Tübingen, Tübingen, Germany
| | - A Schollenberger
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - M Hamze Sinno
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - N Bühler
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - M Böhle
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - G Bárdos
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
| | - H Sauer
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - I Mack
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - P Enck
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - S Zipfel
- Department of Psychosomatic Medicine and Psychotherapy, University Hospital Tübingen, Tübingen, Germany
| | - T Meile
- Department of General and Transplant Surgery and Comprehensive Cancer Center, University of Tübingen, Tübingen, Germany
| | - A Königsrainer
- Department of General and Transplant Surgery and Comprehensive Cancer Center, University of Tübingen, Tübingen, Germany
| | - M Kramer
- Arabella Clinic, München, Germany
| | - S C Bischoff
- Department of Nutritional Medicine, University of Hohenheim, Stuttgart, Germany
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16
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Blanco AM, Sánchez-Bretaño A, Delgado MJ, Valenciano AI. Brain Mapping of Ghrelin O-Acyltransferase in Goldfish (Carassius Auratus): Novel Roles for the Ghrelinergic System in Fish? Anat Rec (Hoboken) 2016; 299:748-58. [PMID: 27064922 DOI: 10.1002/ar.23346] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 02/16/2016] [Accepted: 02/22/2016] [Indexed: 12/19/2022]
Abstract
Ghrelin O-acyltransferase (GOAT) is the enzyme responsible for acylation of ghrelin, a gut-brain hormone with important roles in many physiological functions in vertebrates. Many aspects of GOAT remain to be elucidated, especially in fish, and particularly its anatomical distribution within the different brain areas has never been reported to date. The present study aimed to characterize the brain mapping of GOAT using RT-qPCR and immunohistochemistry in a teleost, the goldfish (Carassius auratus). Results show that goat transcripts are expressed in different brain areas of the goldfish, with the highest levels in the vagal lobe. Using immunohistochemistry, we also report the presence of GOAT immunoreactive cells in different encephalic areas, including the telencephalon, some hypothalamic nuclei, pineal gland, optic tectum and cerebellum, although they are especially abundant in the hindbrain. Particularly, an important signal is observed in the vagal lobe and some fiber tracts of the brainstem, such as the medial longitudinal fasciculus, Mauthneri fasciculus, secondary gustatory tract and spinothalamic tract. Most of the forebrain areas where GOAT is detected, particularly the hypothalamic nuclei, also express the ghs-r1a ghrelin receptor and other appetite-regulating hormones (e.g., orexin and NPY), supporting the role of ghrelin as a modulator of food intake and energy balance in fish. Present results are the first report on the presence of GOAT in the brain using imaging techniques. The high presence of GOAT in the hindbrain is a novelty, and point to possible new functions for the ghrelinergic system in fish. Anat Rec, 299:748-758, 2016. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- Ayelén M Blanco
- Department of Animal Physiology II, Faculty of Biology, Complutense University, Madrid, 28040, Spain
| | - Aída Sánchez-Bretaño
- Department of Animal Physiology II, Faculty of Biology, Complutense University, Madrid, 28040, Spain
| | - María J Delgado
- Department of Animal Physiology II, Faculty of Biology, Complutense University, Madrid, 28040, Spain
| | - Ana I Valenciano
- Department of Animal Physiology II, Faculty of Biology, Complutense University, Madrid, 28040, Spain
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17
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Periprandial changes and effects of short- and long-term fasting on ghrelin, GOAT, and ghrelin receptors in goldfish (Carassius auratus). J Comp Physiol B 2016; 186:727-38. [DOI: 10.1007/s00360-016-0986-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Revised: 03/26/2016] [Accepted: 03/29/2016] [Indexed: 02/06/2023]
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18
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Li Z, Mulholland M, Zhang W. Ghrelin O-acyltransferase (GOAT) and energy metabolism. SCIENCE CHINA-LIFE SCIENCES 2016; 59:281-91. [PMID: 26732975 DOI: 10.1007/s11427-015-4973-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 10/09/2015] [Indexed: 12/16/2022]
Abstract
Ghrelin O-acyltransferase (GOAT), a member of MBOATs family, is essential for octanoylation of ghrelin, which is required for active ghrelin to bind with and activate its receptor. GOAT is expressed mainly in the stomach, pancreas and hypothalamus. Levels of GOAT are altered by energy status. GOAT contains 11 transmembrane helices and one reentrant loop. Its invariant residue His-338 and conserved Asn-307 are located in the endoplasmic reticulum lumen and cytosol respectively. GOAT contributes to the regulation of food intake and energy expenditure, as well as glucose and lipids homeostasis. Deletion of GOAT blocks the acylation of ghrelin leading to subsequent impairment in energy homeostasis and survival when mice are challenged with high energy diet or severe caloric restriction. GO-CoA-Tat, a peptide GOAT inhibitor, attenuates acyl-ghrelin production and prevents weight gain induced by a medium-chain triglycerides-rich high fat diet. Further, GO-CoA-Tat increases glucose- induced insulin secretion. Overall, inhibition of GOAT is a novel strategy for treatment of obesity and related metabolic disorders.
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Affiliation(s)
- Ziru Li
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109-0346, USA
| | - Michael Mulholland
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109-0346, USA.
| | - Weizhen Zhang
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, 48109-0346, USA. .,Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, 100191, China.
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19
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Wellman M, Abizaid A. Knockdown of central ghrelin O-acyltransferase by vivo-morpholino reduces body mass of rats fed a high-fat diet. Peptides 2015; 70:17-22. [PMID: 26028164 DOI: 10.1016/j.peptides.2015.05.007] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 05/19/2015] [Accepted: 05/20/2015] [Indexed: 10/23/2022]
Abstract
The enzyme ghrelin O-acyltransferase (GOAT) activates the orexigenic peptide ghrelin by transferring an acyl group from fatty acids to the serine-3 residue of the ghrelin molecule. This allows ghrelin to bind to its only known receptor, the growth hormone secretagogue receptor type 1a (GHSR1a). While studies have examined the hypothalamic transcriptional response of GOAT to metabolic challenge in mice, little has been examined in the rat hypothalamus. Furthermore, it has not been possible to identify the role of central GOAT separate from that of the periphery, since previous studies either knocked out GOAT system-wide or administered a GOAT inhibitor intraperitoneally. To determine if central GOAT expression is modulated by changes in energy state, we subjected rats to either forty-eight hours of food deprivation or three weeks of food restriction and found that GOAT mRNA increases significantly in both the hypothalamus and the stomach fundus in response to both metabolic challenges. We also found increases in hypothalamic ghrelin mRNA and stomach GHSR1a mRNA in response to food deprivation, as well as increases in hypothalamic GHSR1a mRNA in response to food restriction. We then conducted a second study where we continuously infused amorpholino antisense oligonucleotide into the lateral ventricles of rats to knock-down GOAT centrally while the animals were exposed to a high fat diet. Our results show that rats receiving the GOAT antisense gained less weight, and decreased their caloric efficiency when eating a high fat diet compared to control animals. These data suggest that central GOAT plays a role in modulating metabolism in rats.
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Affiliation(s)
- Martin Wellman
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
| | - Alfonso Abizaid
- Department of Neuroscience, Carleton University, 1125 Colonel By Drive, Ottawa, Ontario K1S 5B6, Canada.
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20
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Hatef A, Yufa R, Unniappan S. Ghrelin O-Acyl Transferase in Zebrafish Is an Evolutionarily Conserved Peptide Upregulated During Calorie Restriction. Zebrafish 2015; 12:327-38. [PMID: 26226634 DOI: 10.1089/zeb.2014.1062] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Ghrelin is a multifunctional orexigenic hormone with a unique acyl modification enabled by ghrelin O-acyl transferase (GOAT). Ghrelin is well-characterized in nonmammals, and GOAT sequences of several fishes are available in the GenBank. However, endogenous GOAT in non-mammals remains poorly understood. In this research, GOAT sequence comparison, tissue-specific GOAT expression, and its regulation by nutrient status and exogenous ghrelin were studied. It was found that the bioactive core of zebrafish GOAT amino acid sequence share high identity with that of mammals. GOAT mRNA was most abundant in the gut. GOAT-like immunoreactivity (i.r.) was found colocalized with ghrelin in the gastric mucosa. Food deprivation increased, and feeding decreased GOAT and preproghrelin mRNA expression in the brain and gut. GOAT and ghrelin peptides in the gut and brain showed corresponding decrease in food-deprived state. Intraperitoneal injection of acylated fish ghrelin caused a significant decrease in GOAT mRNA expression, suggesting a feedback mechanism regulating its abundance. Together, these results provide the first in-depth characterization of GOAT in a non-mammal. Our results demonstrate that endogenous GOAT expression is responsive to metabolic status and availability of acylated ghrelin, providing further evidences for GOAT in the regulation of feeding in teleosts.
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Affiliation(s)
- Azadeh Hatef
- 1 Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan , Saskatoon, Saskatchewan, Canada
| | - Roman Yufa
- 2 Department of Biology, York University , Toronto, Ontario, Canada
| | - Suraj Unniappan
- 1 Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan , Saskatoon, Saskatchewan, Canada
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21
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Méquinion M, Chauveau C, Viltart O. The use of animal models to decipher physiological and neurobiological alterations of anorexia nervosa patients. Front Endocrinol (Lausanne) 2015; 6:68. [PMID: 26042085 PMCID: PMC4436882 DOI: 10.3389/fendo.2015.00068] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Accepted: 04/15/2015] [Indexed: 12/18/2022] Open
Abstract
Extensive studies were performed to decipher the mechanisms regulating feeding due to the worldwide obesity pandemy and its complications. The data obtained might be adapted to another disorder related to alteration of food intake, the restrictive anorexia nervosa. This multifactorial disease with a complex and unknown etiology is considered as an awful eating disorder since the chronic refusal to eat leads to severe, and sometimes, irreversible complications for the whole organism, until death. There is an urgent need to better understand the different aspects of the disease to develop novel approaches complementary to the usual psychological therapies. For this purpose, the use of pertinent animal models becomes a necessity. We present here the various rodent models described in the literature that might be used to dissect central and peripheral mechanisms involved in the adaptation to deficient energy supplies and/or the maintenance of physiological alterations on the long term. Data obtained from the spontaneous or engineered genetic models permit to better apprehend the implication of one signaling system (hormone, neuropeptide, neurotransmitter) in the development of several symptoms observed in anorexia nervosa. As example, mutations in the ghrelin, serotonin, dopamine pathways lead to alterations that mimic the phenotype, but compensatory mechanisms often occur rendering necessary the use of more selective gene strategies. Until now, environmental animal models based on one or several inducing factors like diet restriction, stress, or physical activity mimicked more extensively central and peripheral alterations decribed in anorexia nervosa. They bring significant data on feeding behavior, energy expenditure, and central circuit alterations. Animal models are described and criticized on the basis of the criteria of validity for anorexia nervosa.
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Affiliation(s)
- Mathieu Méquinion
- INSERM UMR-S1172, Development and Plasticity of Postnatal Brain, Lille, France
| | - Christophe Chauveau
- Pathophysiology of Inflammatory Bone Diseases, EA 4490, University of the Littoral Opal Coast, Boulogne sur Mer, France
| | - Odile Viltart
- INSERM UMR-S1172, Early stages of Parkinson diseases, University Lille 1, Lille, France
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Gao H, Tanchico DT, Yallampalli U, Balakrishnan MP, Yallampalli C. Appetite regulation is independent of the changes in ghrelin levels in pregnant rats fed low-protein diet. Physiol Rep 2015; 3:3/4/e12368. [PMID: 25907788 PMCID: PMC4425973 DOI: 10.14814/phy2.12368] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Gestational protein restriction causes hypertension in the adult offspring. Very little is known about the food intake regulation and ghrelin signaling in pregnant dams fed a low-protein (LP) diet. We hypothesized that diet intake and ghrelin signaling are altered in pregnant rats fed the low-protein diet. Sprague–Dawley rats were fed a control (CT) or LP diet from Day 3 of pregnancy. Diet intake and body weight were monitored daily. Expression of ghrelin production-related genes in the stomach and appetite-related genes in the hypothalamus was analyzed by real-time PCR. Plasma levels of total and active ghrelin, growth hormone and leptin were measured by ELISA. Main results include: (1) Daily diet intake was greater in the LP group than in the CT group in early pregnancy, but substantially lower in late pregnancy; (2) Daily gain in body weight was substantially lower in the LP group in late pregnancy; (3) Expression of ghrelin production-related genes in the stomach and plasma total ghrelin levels were increased in LP group in late pregnancy; (4) Plasma active ghrelin levels were elevated in the LP group at mid-late pregnancy, but growth hormone and leptin levels were uncorrelated with active ghrelin in late pregnancy; and (5) Hypothalamic expression of ghrelin-stimulated genes in LP rats was unassociated with the changes in both plasma ghrelin levels and the diet intake. Taken together, the appetite in LP rats is greater in early pregnancy but reduced at late pregnancy, possibly due to ghrelin insensitivity in appetite regulation.
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Affiliation(s)
- Haijun Gao
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, Texas
| | - Daren T Tanchico
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, Texas
| | - Uma Yallampalli
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, Texas
| | - Meena P Balakrishnan
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, Texas
| | - Chandra Yallampalli
- Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas Texas Children's Hospital, Houston, Texas
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Zhang SR, Fan XM. Ghrelin-ghrelin O-acyltransferase system in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 2015; 21:3214-3222. [PMID: 25805927 PMCID: PMC4363750 DOI: 10.3748/wjg.v21.i11.3214] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2014] [Revised: 12/29/2014] [Accepted: 01/30/2015] [Indexed: 02/06/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is currently considered as the most common liver disease in Western countries, and is rapidly becoming a serious threat to public health worldwide. However, the underlying mechanisms leading to the development of NAFLD are still not fully understood. The ghrelin-ghrelin O-acyltransferase (GOAT) system has recently been found to play a crucial role in both the development of steatosis and its progression to nonalcoholic steatohepatitis. Ghrelin, the natural ligand of the growth hormone secretagogue receptor, is a 28-amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by GOAT. The ghrelin-GOAT system is involved in insulin resistance, lipid metabolism dysfunction, and inflammation, all of which play important roles in the pathogenesis of NAFLD. A better understanding of ghrelin-GOAT system biology led to the identification of its potential roles in NAFLD. Molecular targets modulating ghrelin-GOAT levels and the biologic effects are being studied, which provide a new insight into the pathogenesis of NAFLD. This review probes into the possible relationship between the ghrelin-GOAT system and NAFLD, and considers the potential mechanisms by which the ghrelin-GOAT system brings about insulin resistance and other aspects concerning NAFLD.
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Stark R, Reichenbach A, Lockie SH, Pracht C, Wu Q, Tups A, Andrews ZB. Acyl ghrelin acts in the brain to control liver function and peripheral glucose homeostasis in male mice. Endocrinology 2015; 156:858-68. [PMID: 25535832 DOI: 10.1210/en.2014-1733] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Recent evidence suggests that peripheral ghrelin regulates glucose metabolism. Here, we designed experiments to examine how central acyl ghrelin infusion affects peripheral glucose metabolism under pair-fed or ad libitum feeding conditions. Mice received intracerebroventricular (icv) infusion of artificial cerebrospinal fluid (aCSF), ghrelin, and allowed to eat ad libitum (icv ghrelin ad lib) or ghrelin and pair-fed to the aCSF group (icv ghrelin pf). Minipumps delivered acyl ghrelin at a dose of 0.25 μg/h at 0.5 μL/h for 7 days. There was no difference in daily blood glucose, insulin, glucagon, triglycerides, or nonesterified fatty acids. Body weight gain and food intake was significantly higher in icv ghrelin ad lib mice. However, both icv ghrelin ad lib and icv ghrelin pf groups exhibited heavier white adipose mass. Icv ghrelin pf mice exhibited better glucose tolerance than aCSF or icv ghrelin ad lib mice during a glucose tolerance test, although both icv ghrelin ad lib and icv ghrelin pf increased insulin release during the glucose tolerance test. Central acyl ghrelin infusion and pair feeding also increased breakdown of liver glycogen and triglyceride, and regulated genes involved in hepatic lipid and glucose metabolism. Icv ghrelin pf mice had an increase in plasma blood glucose during a pyruvate tolerance test relative to icv ghrelin ad lib or aCSF mice. Our results suggest that under conditions of negative energy (icv ghrelin pf), central acyl ghrelin engages a neural circuit that influences hepatic glucose function. Metabolic status affects the ability of central acyl ghrelin to regulate peripheral glucose homeostasis.
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Affiliation(s)
- Romana Stark
- Department of Physiology (R.S., A.R., S.H.L., Q.W., Z.B.A.), Monash University, Clayton, Victoria 3800, Australia; Traditional Chinese Medicine Department (Q.W.), Peking Union Medical College Hospital, Dongcheng District, Beijing 100730, China; Department of Animal Physiology (C.P., A.T.), Faculty of Biology, Phillips University, D-35043 Marburg, Germany; and Department of Physiology (A.T.), Otago School of Medical Sciences, University of Otago, Dunedin 9054, New Zealand
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25
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Khatib MN, Gaidhane S, Gaidhane AM, Simkhada P, Zahiruddin QS. Ghrelin O Acyl Transferase (GOAT) as a Novel Metabolic Regulatory Enzyme. J Clin Diagn Res 2015; 9:LE01-5. [PMID: 25859472 PMCID: PMC4378754 DOI: 10.7860/jcdr/2015/9787.5514] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 12/06/2014] [Indexed: 01/12/2023]
Abstract
BACKGROUND Obesity and Type 2 Diabetes Mellitus (T2DM) presents a growing threat to the global health. Evidences highlight an important role of ghrelin as a key regulator of glucose metabolism. The physiological functions of ghrelin are mediated by enzyme ghrelin-O-acyltransferase (GOAT) which is capable of generating the active form of this metabolic hormone. However, its exact mechanism of action and influence on energy balance and glucose metabolism is yet to be explored. OBJECTIVES To review the physiological role of GOAT in the regulation of energy balance and glucose metabolism and explore the potential therapeutic avenues of modulators of GOAT to counter the progression of obesity and T2DM. METHODS Publications were sought through electronic searches. The bibliographies of all papers, book, chapters and editorials were scanned and hand searches were also conducted for journals, and conference proceedings. CONCLUSION GOAT peptide modulates the insulin secretion as well as insulin sensitivity. Modulators of GOAT signaling like inhibitors of GOAT increases insulin secretion, enhance peripheral insulin sensitivity and thus counters obesity and T2DM. Modulators of GOAT can be a probable therapy for modifying food intake and for countering obesity and T2DM.
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Affiliation(s)
- Mahalaqua Nazli Khatib
- Professor, Department of Physiology, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Shilpa Gaidhane
- Associate Professor, Department of Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Abhay M. Gaidhane
- Professor, Department of Community Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Padam Simkhada
- Senior Lecturer in International Health ScHARR, University of Sheffield, UK and Centre for public Health Liverpool Johns Moores University, Liverpool, UK
| | - Quazi Syed Zahiruddin
- Professor, Department of Community Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
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Mayerl S, Liebsch C, Visser TJ, Heuer H. Absence of TRH receptor 1 in male mice affects gastric ghrelin production. Endocrinology 2015; 156:755-67. [PMID: 25490146 DOI: 10.1210/en.2014-1395] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
TRH not only functions as a thyrotropin releasing hormone but also acts as a neuropeptide in central circuits regulating food intake and energy expenditure. As one suggested mode of action, TRH expressed in the caudal brainstem influences vagal activity by activating TRH receptor 1 (TRH-R1). In order to evaluate the impact of a diminished medullary TRH signaling on ghrelin metabolism, we analyzed metabolic changes of TRH-R1 knockout (R1ko) mice in response to 24 hours of food deprivation. Because R1ko mice are hypothyroid, we also studied eu- and hypothyroid wild-type (wt) animals and R1ko mice rendered euthyroid by thyroid hormone treatment. Independent of their thyroidal state, R1ko mice displayed a higher body weight loss than wt animals and a delayed reduction in locomotor activity upon fasting. Ghrelin transcript levels in the stomach as well as total ghrelin levels in the circulation were equally high in fasted wt and R1ko mice. In contrast, only wt mice responded to fasting with a rise in ghrelin-O-acyltransferase mRNA expression and consequently an increase in serum levels of acylated ghrelin. Together, our data suggest that an up-regulation of medullary TRH expression and subsequently enhanced activation of TRH-R1 in the vagal system represents a critical step in the stimulation of ghrelin-O-acyltransferase expression upon starvation that in turn is important for adjusting the circulating levels of acylated ghrelin to the fasting condition.
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Affiliation(s)
- Steffen Mayerl
- Leibniz Institute for Age Research/Fritz Lipmann Institute (S.M., C.L., H.H.), D-07745 Jena, Germany; Brandenburg University of Technology Cottbus-Senftenberg (C.L.), D-01968 Senftenberg, Germany; Department of Internal Medicine (T.J.V.), Erasmus Medical Center, Rotterdam, The Netherlands; and Leibniz Research Institute for Environmental Medicine (H.H.), Düsseldorf, Germany
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27
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Nass R, Nikolayev A, Liu J, Pezzoli SS, Farhy LS, Patrie J, Gaylinn BD, Heiman M, Thorner MO. The level of circulating octanoate does not predict ghrelin O-acyl transferase (GOAT)-mediated acylation of ghrelin during fasting. J Clin Endocrinol Metab 2015; 100:E110-3. [PMID: 25337923 PMCID: PMC4283022 DOI: 10.1210/jc.2014-1318] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Acyl-ghrelin is a 28-amino acid peptide released from the stomach. Ghrelin O-acyl transferase (GOAT) attaches an 8-carbon medium-chain fatty acid (MCFA) (octanoate) to serine 3 of ghrelin. This acylation is necessary for the activity of ghrelin. Animal data suggest that MCFAs provide substrate for GOAT and an increase in nutritional octanoate increases acyl-ghrelin. OBJECTIVES To address the question of the source of substrate for acylation, we studied whether the decline in ghrelin acylation during fasting is associated with a decline in circulating MCFAs. METHODS Eight healthy young men (aged 18-28 years, body mass index range, 20.6-26.2 kg/m(2)) had blood drawn every 10 minutes for acyl- and desacyl-ghrelin and every hour for free fatty acids (FFAs) during the last 24 hours of a 61.5-hour fast and during a fed day. FFAs were measured by a highly sensitive liquid chromatography-mass spectroscopy method. Acyl- and desacyl-ghrelin were measured in an in-house assay; the results were published previously. Ghrelin acylation was assessed by the ratio of acyl-ghrelin to total ghrelin. RESULTS With the exception of MCFAs C8 and C10, all other FFAs, the MCFAs (C6 and C12), and the long-chain fatty acids (C14-C18) significantly increased with fasting (P < .05). There was no significant association between the fold change in ghrelin acylation and circulating FFAs. CONCLUSIONS These results suggest that changes in circulating MCFAs are not linked to the decline in ghrelin acylation during fasting and support the hypothesis that acylation of ghrelin depends at least partially on the availability of gastroluminal MCFAs or the regulation of GOAT activity.
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Affiliation(s)
- Ralf Nass
- Division of Endocrinology and Metabolism (R.N., J.L., S.S.P., L.S.F., B.D.G., M.O.T.), Department of Medicine, Center for Diabetes Technology (L.S.F.), and Department of Health Sciences (J.P.), University of Virginia, Charlottesville, Virginia 22908; and Eli Lilly (A.N., M.H.), Lilly Research Laboratories, Indianapolis, Indiana 46285
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28
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Differential effects of laparoscopic sleeve gastrectomy and laparoscopic gastric bypass on appetite, circulating acyl-ghrelin, peptide YY3-36 and active GLP-1 levels in non-diabetic humans. Obes Surg 2014; 24:241-52. [PMID: 23996294 PMCID: PMC3890046 DOI: 10.1007/s11695-013-1066-0] [Citation(s) in RCA: 199] [Impact Index Per Article: 18.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Laparoscopic Roux-en-Y gastric bypass (LRYGBP) reduces appetite and induces significant and sustainable weight loss. Circulating gut hormones changes engendered by LRYGBP are implicated in mediating these beneficial effects. Laparoscopic sleeve gastrectomy (LSG) is advocated as an alternative to LRYGBP, with comparable short-term weight loss and metabolic outcomes. LRYGBP and LSG are anatomically distinct procedures causing differential entero-endocrine cell nutrient exposure and thus potentially different gut hormone changes. Studies reporting the comparative effects of LRYGBP and LSG on appetite and circulating gut hormones are controversial, with no data to date on the effects of LSG on circulating peptide YY3-36 (PYY3-36) levels, the specific PYY anorectic isoform. In this study, we prospectively investigated appetite and gut hormone changes in response to LRYGBP and LSG in adiposity-matched non-diabetic patients. Anthropometric indices, leptin, fasted and nutrient-stimulated acyl-ghrelin, active glucagon-like peptide-1 (GLP-1), PYY3-36 levels and appetite were determined pre-operatively and at 6 and 12 weeks post-operatively in obese, non-diabetic females, with ten undergoing LRYGBP and eight adiposity-matched females undergoing LSG. LRYGBP and LSG comparably reduced adiposity. LSG decreased fasting and post-prandial plasma acyl-ghrelin compared to pre-surgery and to LRYGBP. Nutrient-stimulated PYY3-36 and active GLP-1 concentrations increased post-operatively in both groups. However, LRYGBP induced greater, more sustained PYY3-36 and active GLP-1 increments compared to LSG. LRYGBP suppressed fasting hunger compared to LSG. A similar increase in post-prandial fullness was observed post-surgery following both procedures. LRYGBP and LSG produced comparable enhanced satiety and weight loss. However, LSG and LRYGBP differentially altered gut hormone profiles.
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29
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Uchida A, Zechner JF, Mani BK, Park WM, Aguirre V, Zigman JM. Altered ghrelin secretion in mice in response to diet-induced obesity and Roux-en-Y gastric bypass. Mol Metab 2014; 3:717-30. [PMID: 25353000 PMCID: PMC4209356 DOI: 10.1016/j.molmet.2014.07.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2014] [Revised: 07/22/2014] [Accepted: 07/25/2014] [Indexed: 01/06/2023] Open
Abstract
The current study examined potential mechanisms for altered circulating ghrelin levels observed in diet-induced obesity (DIO) and following weight loss resulting from Roux-en-Y gastric bypass (RYGB). We hypothesized that circulating ghrelin levels were altered in obesity and after weight loss through changes in ghrelin cell responsiveness to physiological cues. We confirmed lower ghrelin levels in DIO mice and demonstrated elevated ghrelin levels in mice 6 weeks post-RYGB. In both DIO and RYGB settings, these changes in ghrelin levels were associated with altered ghrelin cell responsiveness to two key physiological modulators of ghrelin secretion - glucose and norepinephrine. In DIO mice, increases in ghrelin cell density within both the stomach and duodenum and in somatostatin-immunoreactive D cell density in the duodenum were observed. Our findings provide new insights into the regulation of ghrelin secretion and its relation to circulating ghrelin within the contexts of obesity and weight loss.
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Affiliation(s)
- Aki Uchida
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology & Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Juliet F Zechner
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Digestive and Liver Diseases, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Bharath K Mani
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology & Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Won-Mee Park
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology & Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Vincent Aguirre
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Digestive and Liver Diseases, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Jeffrey M Zigman
- Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology & Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA
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Garcés MF, Sanchez E, Torres-Sierra AL, Ruíz-Parra AI, Angel-Müller E, Alzate JP, Sánchez ÁY, Gomez MA, Romero XC, Castañeda ZE, Sanchez-Rebordelo E, Diéguez C, Nogueiras R, Caminos JE. Brain-derived neurotrophic factor is expressed in rat and human placenta and its serum levels are similarly regulated throughout pregnancy in both species. Clin Endocrinol (Oxf) 2014; 81:141-51. [PMID: 24372023 DOI: 10.1111/cen.12391] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 10/28/2013] [Accepted: 12/15/2013] [Indexed: 12/31/2022]
Abstract
OBJECTIVE Pregnancy is characterized by several metabolic changes that promote fat gain and later onset of insulin resistance. As Brain-derived neurotrophic factor (BDNF) decreases hyperglycaemia and hyperphagia, we aimed to investigate the potential role of placental and circulating BDNF levels in these pregnancy-related metabolic changes in rats and humans. DESIGN AND METHODS We identified the mRNA and protein expression of placental BDNF and its receptor TrkB using real-time PCR, Western blot and immunohistochemical approaches in both rat and humans. Serum BDNF was measured by ELISA. We also did a longitudinal prospective cohort study in 42 pregnant women to assess BDNF levels and correlations with other metabolic parameters. RESULTS We found that BDNF and TrkB are expressed in both rat and human placenta. In rat, both placental mRNA and serum levels are increased throughout pregnancy, whereas their protein levels are significantly decreased at the end of gestation. Serum BDNF levels in pregnant women are significantly lower in the first trimester when compared to the second and third trimester (P < 0·0148, P < 0·0012, respectively). Serum BDNF levels were negatively correlated with gestational age at birth and fasting glucose levels. CONCLUSION Our findings suggest that both BDNF and its receptor TrkB are expressed in rodent and human placenta being regulated during pregnancy. Taken together, these findings support a role of BDNF in the regulation of several metabolic functions during pregnancy.
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Affiliation(s)
- María F Garcés
- Department of Physiology, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia
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Garcés MF, Poveda NE, Sanchez E, Sánchez ÁY, Bravo SB, Vázquez MJ, Diéguez C, Nogueiras R, Caminos JE. Regulation of NucB2/Nesfatin-1 throughout rat pregnancy. Physiol Behav 2014; 133:216-22. [DOI: 10.1016/j.physbeh.2014.05.042] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 04/16/2014] [Accepted: 05/28/2014] [Indexed: 01/26/2023]
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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: 112] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [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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Seim I, Jeffery PL, de Amorim L, Walpole CM, Fung J, Whiteside EJ, Lourie R, Herington AC, Chopin LK. Ghrelin O-acyltransferase (GOAT) is expressed in prostate cancer tissues and cell lines and expression is differentially regulated in vitro by ghrelin. Reprod Biol Endocrinol 2013; 11:70. [PMID: 23879975 PMCID: PMC3724588 DOI: 10.1186/1477-7827-11-70] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2013] [Accepted: 07/05/2013] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Ghrelin is a 28 amino acid peptide hormone that is expressed in the stomach and a range of peripheral tissues, where it frequently acts as an autocrine/paracrine growth factor. Ghrelin is modified by a unique acylation required for it to activate its cognate receptor, the growth hormone secretagogue receptor (GHSR), which mediates many of the actions of ghrelin. Recently, the enzyme responsible for adding the fatty acid residue (octanoyl/acyl group) to the third amino acid of ghrelin, GOAT (ghrelin O-acyltransferase), was identified. METHODS We used cell culture, quantitative real-time reverse transcription (RT)-PCR and immunohistochemistry to demonstrate the expression of GOAT in prostate cancer cell lines and tissues from patients. Real-time RT-PCR was used to demonstrate the expression of prohormone convertase (PC)1/3, PC2 and furin in prostate cancer cell lines. Prostate-derived cell lines were treated with ghrelin and desacyl ghrelin and the effect on GOAT expression was measured using quantitative RT-PCR. RESULTS We have demonstrated that GOAT mRNA and protein are expressed in the normal prostate and human prostate cancer tissue samples. The RWPE-1 and RWPE-2 normal prostate-derived cell lines and the LNCaP, DU145, and PC3 prostate cancer cell lines express GOAT and at least one other enzyme that is necessary to produce mature, acylated ghrelin from proghrelin (PC1/3, PC2 or furin). Finally, ghrelin, but not desacyl ghrelin (unacylated ghrelin), can directly regulate the expression of GOAT in the RWPE-1 normal prostate derived cell line and the PC3 prostate cancer cell line. Ghrelin treatment (100nM) for 6 hours significantly decreased GOAT mRNA expression two-fold (P < 0.05) in the PC3 prostate cancer cell line, however, ghrelin did not regulate GOAT expression in the DU145 and LNCaP prostate cancer cell lines. CONCLUSIONS This study demonstrates that GOAT is expressed in prostate cancer specimens and cell lines. Ghrelin regulates GOAT expression, however, this is likely to be cell-type specific. The expression of GOAT in prostate cancer supports the hypothesis that the ghrelin axis has autocrine/paracrine roles. We propose that the RWPE-1 prostate cell line and the PC3 prostate cancer cell line may be useful for investigating GOAT regulation and function.
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Affiliation(s)
- Inge Seim
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
- Australian Prostate Cancer Research Centre, Queensland, Princess Alexandra Hospital, 199 Ipswich Road, Brisbane, Queensland, 4102, Australia
| | - Penny L Jeffery
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
- Australian Prostate Cancer Research Centre, Queensland, Princess Alexandra Hospital, 199 Ipswich Road, Brisbane, Queensland, 4102, Australia
- Mater Medical Research Institute, Mater Health Services, University of Queensland, South Brisbane, Queensland,, 4103, Australia
| | - Laura de Amorim
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
| | - Carina M Walpole
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
| | - Jenny Fung
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
| | - Eliza J Whiteside
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
| | - Rohan Lourie
- Mater Medical Research Institute, Mater Health Services, University of Queensland, South Brisbane, Queensland,, 4103, Australia
- Department of Pathology, Mater Health Services, South Brisbane, Queensland, 4103, Australia
| | - Adrian C Herington
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
- Australian Prostate Cancer Research Centre, Queensland, Princess Alexandra Hospital, 199 Ipswich Road, Brisbane, Queensland, 4102, Australia
| | - Lisa K Chopin
- Ghrelin Research Group, Translational Research Institute - Institute of Health and Biomedical Innovation, Queensland University of Technology, 37 Kent St, Woolloongabba, Queensland, 4102, Australia
- Australian Prostate Cancer Research Centre, Queensland, Princess Alexandra Hospital, 199 Ipswich Road, Brisbane, Queensland, 4102, Australia
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Abstract
Ingestion of food affects the secretion of hormones from specialized endocrine cells scattered within the intestinal mucosa. Upon release, these hormones mostly decrease food intake by signaling information to the brain. Although enteroendocrine cells in the small intestine were thought to represent the predominant gut-brain regulators of food intake, recent advances also established a major role for gastric hormones in these regulatory pathways. First and foremost, the gastric endocrine X/A-like cell was in the focus of many studies due to the production of ghrelin, which is until now the only known orexigenic hormone that is peripherally produced and centrally acting. Although X/A-cells were initially thought to only release one hormone that stimulates food intake, this view has changed with the identification of additional peptide products also derived from this cell, namely desacyl ghrelin, obestatin, and nesfatin-1. Desacyl ghrelin may play a counter-regulatory role to the food intake stimulatory effect of ghrelin. The same property was suggested for obestatin; however, this hypothesis could not be confirmed in numerous subsequent studies. Moreover, the description of the stomach as the major source of the novel anorexigenic hormone nesfatin-1 derived from the NUCB2 gene further corroborated the assumption that the gastric X/A-like cell products are not only stimulant but also inhibitors of feeding, thereby acting as so far unique dual regulator of food intake located in a logistically important place where the gastrointestinal tract has initial contact with food.
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Affiliation(s)
- Andreas Stengel
- Charité Center for Internal Medicine and Dermatology, Division Psychosomatic Medicine, Obesity Center Berlin, Charité Universitätsmedizin Berlin, Campus Mitte, Charitéplatz 1, 10117 Berlin, Germany.
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Barazzoni R, Zanetti M, Nagliati C, Cattin MR, Ferreira C, Giuricin M, Palmisano S, Edalucci E, Dore F, Guarnieri G, de Manzini N. Gastric bypass does not normalize obesity-related changes in ghrelin profile and leads to higher acylated ghrelin fraction. Obesity (Silver Spring) 2013; 21:718-22. [PMID: 23712974 DOI: 10.1002/oby.20272] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2011] [Accepted: 05/12/2012] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Gastric bypass (GBP) lowers food intake, body weight, and insulin resistance in severe obesity (SO). Ghrelin is a gastric orexigenic and adipogenic hormone contributing to modulate energy balance and insulin action. Total plasma ghrelin (T-Ghr) level is low and inversely related to body weight and insulin resistance in moderately obese patients, but these observations may not extend to the orexigenic acylated form (A-Ghr) whose plasma concentration increase in moderate obesity. DESIGN AND METHODS We investigated the impact of GBP on plasma T-, A-, and A/T-Ghr in SO patients (n = 28, 20 women), with measurements at baseline and 1, 3, 6, and 12 months after surgery. Additional cross-sectional comparison was performed between nonobese, moderately obese, and SO individuals before GBP and at the end of the follow-up period. RESULTS Before GBP, SO had lowest T-Ghr and highest A/T-Ghr profile compared with both nonobese and moderately obese individuals. Lack of early (0-3 months from GBP) T-Ghr changes masked a sharp increase in A-Ghr and A/T-Ghr profile (P < 0.05) that remained elevated following later increments (6-12 months) of both T- and A-Ghr (P < 0.05). Levels of A-Ghr and A/T-Ghr at 12 months of follow-up remained higher than in matched moderately obese individuals not treated with surgery (P < 0.05). CONCLUSIONS The data show that following GBP, early T-Ghr stability masks elevation of A/T-Ghr, that is stabilized after later increments of both T- and A-hormones. GBP does not normalize the obesity-associated elevated A/T-Ghr ratio, instead resulting in enhanced A-Ghr excess. Excess A-Ghr is unlikely to contribute to, and might limit, the common GBP-induced declines of appetite, body weight, and insulin resistance.
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Affiliation(s)
- Rocco Barazzoni
- Department of Medical, Surgical and Health Sciences, Internal Medicine Clinics, University of Trieste, Trieste, Italy.
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Méquinion M, Langlet F, Zgheib S, Dickson S, Dehouck B, Chauveau C, Viltart O. Ghrelin: central and peripheral implications in anorexia nervosa. Front Endocrinol (Lausanne) 2013; 4:15. [PMID: 23549309 PMCID: PMC3581855 DOI: 10.3389/fendo.2013.00015] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 02/01/2013] [Indexed: 11/15/2022] Open
Abstract
Increasing clinical and therapeutic interest in the neurobiology of eating disorders reflects their dramatic impact on health. Chronic food restriction resulting in severe weight loss is a major symptom described in restrictive anorexia nervosa (AN) patients, and they also suffer from metabolic disturbances, infertility, osteopenia, and osteoporosis. Restrictive AN, mostly observed in young women, is the third largest cause of chronic illness in teenagers of industrialized countries. From a neurobiological perspective, AN-linked behaviors can be considered an adaptation that permits the endurance of reduced energy supply, involving central and/or peripheral reprograming. The severe weight loss observed in AN patients is accompanied by significant changes in hormones involved in energy balance, feeding behavior, and bone formation, all of which can be replicated in animals models. Increasing evidence suggests that AN could be an addictive behavior disorder, potentially linking defects in the reward mechanism with suppressed food intake, heightened physical activity, and mood disorder. Surprisingly, the plasma levels of ghrelin, an orexigenic hormone that drives food-motivated behavior, are increased. This increase in plasma ghrelin levels seems paradoxical in light of the restrained eating adopted by AN patients, and may rather result from an adaptation to the disease. The aim of this review is to describe the role played by ghrelin in AN focusing on its central vs. peripheral actions. In AN patients and in rodent AN models, chronic food restriction induces profound alterations in the « ghrelin » signaling that leads to the development of inappropriate behaviors like hyperactivity or addiction to food starvation and therefore a greater depletion in energy reserves. The question of a transient insensitivity to ghrelin and/or a potential metabolic reprograming is discussed in regard of new clinical treatments currently investigated.
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Affiliation(s)
- Mathieu Méquinion
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
| | - Fanny Langlet
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
| | - Sara Zgheib
- Pathophysiology of inflammatory of bone diseases, Université Lille Nord de France-ULCO – Lille 2Boulogne sur Mer, France
| | - Suzanne Dickson
- Department of Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
- Department of Endocrinology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of GothenburgGothenburg, Sweden
| | - Bénédicte Dehouck
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
- Université Lille Nord de France – Université d’ArtoisLiévin, France
| | - Christophe Chauveau
- Pathophysiology of inflammatory of bone diseases, Université Lille Nord de France-ULCO – Lille 2Boulogne sur Mer, France
| | - Odile Viltart
- UMR INSERM 837, Development and Plasticity of Postnatal BrainLille, France
- Université Lille Nord de France-USTL (Lille 1)Villeneuve d’Ascq, France
- *Correspondence: Odile Viltart, Development and Plasticity of the Postnatal Brain, Team 2, Jean-Pierre Aubert Research Center, UMR INSERM 837, Bât Biserte, 1 place de Verdun, 59,045 Lille cedex, France. e-mail:
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Davis JF, Perello M, Choi DL, Magrisso IJ, Kirchner H, Pfluger PT, Tschoep M, Zigman JM, Benoit SC. GOAT induced ghrelin acylation regulates hedonic feeding. Horm Behav 2012; 62:598-604. [PMID: 22982020 PMCID: PMC3489978 DOI: 10.1016/j.yhbeh.2012.08.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2012] [Revised: 07/10/2012] [Accepted: 08/29/2012] [Indexed: 11/21/2022]
Abstract
Ghrelin is an orexigenic hormone that regulates homeostatic and reward-related feeding behavior. Recent evidence indicates that acylation of ghrelin by the gut enzyme ghrelin O-acyl transferase (GOAT) is necessary to render ghrelin maximally active within its target tissues. Here we tested the hypothesis that GOAT activity modulates food motivation and food hedonics using behavioral pharmacology and mutant mice deficient for GOAT and the ghrelin receptor (GHSR). We evaluated operant responding following pharmacological administration of acyl-ghrelin and assessed the necessity of endogenous GOAT activity for operant responding in GOAT and GHSR-null mice. Hedonic-based feeding behavior also was examined in GOAT-KO and GHSR-null mice using a "Dessert Effect" protocol in which the intake of a palatable high fat diet "dessert" was assessed in calorically-sated mice. Pharmacological administration of acyl-ghrelin augmented operant responding; notably, this effect was dependent on intact GHSR signaling. GOAT-KO mice displayed attenuated operant responding and decreased hedonic feeding relative to controls. These behavioral results correlated with decreased expression of the orexin-1 receptor in reward-related brain regions in GOAT-KO mice. In summary, the ability of ghrelin to stimulate food motivation is dependent on intact GHSR signaling and modified by endogenous GOAT activity. Furthermore, GOAT activity is required for hedonic feeding behavior, an effect potentially mediated by forebrain orexin signaling. These data highlight the significance of the GOAT-ghrelin system for the mediation of food motivation and hedonic feeding.
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Affiliation(s)
- J F Davis
- Department of Psychiatry, Metabolic Diseases Institute, University of Cincinnati, OH, USA.
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38
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Rucinski M, Ziolkowska A, Szyszka M, Hochol A, Malendowicz LK. Evidence suggesting that ghrelin O-acyl transferase inhibitor acts at the hypothalamus to inhibit hypothalamo-pituitary-adrenocortical axis function in the rat. Peptides 2012; 35:149-59. [PMID: 22543218 DOI: 10.1016/j.peptides.2012.04.007] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2012] [Revised: 04/10/2012] [Accepted: 04/10/2012] [Indexed: 10/28/2022]
Abstract
Production of n-octanoyl-modified ghrelin (GHREL), an active form of the peptide requires prohormone processing protease and GHREL O-acyltransferase (GOAT), as well as n-octanoic acid. Recently a selective GOAT antagonist (GO-CoA-Tat) was invented and this tool was used to study the possible role of endogenous GHREL in regulating HPA axis function in the rat. Administration of GOAT inhibitor (GOATi) resulted in a notable decrease in plasma ACTH, aldosterone and corticosterone concentrations at min 60 of experiment. Octanoic acid (OA) administration had no effect on levels of studied hormones. Plasma levels of unacylated and acylated GHREL remained unchanged for 60min after either GOATi or OA administration. Under experimental conditions applied, no significant changes were observed in the levels of GOAT mRNA in hypothalamus, pituitary, adrenal and stomach fundus. After GOATi injection hypothalamic CRH mRNA levels were elevated at 30 min and pituitary POMC mRNA levels at 60 min. Both GOATi and OA lowered basal, but not K(+)-stimulated CRH release by hypothalamic explants and had no effect on basal or CRH-stimulated ACTH release by pituitary slices. Neither GOATi nor OA affected corticosterone secretion by freshly isolated or cultured rat adrenocortical cells. Thus, results of our study suggest that in the rat endogenous GHREL exerts tonic stimulating effect on hypothalamic CRH release. This effect could be demonstrated by administering rats with selected inhibitor of ghrelin O-acyltransferase, the enzyme responsible for GHREL acylation, a process which is absolutely required for both GHSR-1a binding and its central endocrine activities.
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Affiliation(s)
- Marcin Rucinski
- Department of Histology and Embryology, Medical University, Poznan, Poland
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Kasai A, Gama P, Alvares EP. Protein restriction inhibits gastric cell proliferation during rat postnatal growth in parallel to ghrelin changes. Nutrition 2012; 28:707-12. [DOI: 10.1016/j.nut.2011.10.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Revised: 10/07/2011] [Accepted: 10/11/2011] [Indexed: 12/14/2022]
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Garces M, Sanchez E, Acosta B, Angel E, Ruíz A, Rubio-Romero J, Diéguez C, Nogueiras R, Caminos J. Expression and regulation of chemerin during rat pregnancy. Placenta 2012; 33:373-8. [DOI: 10.1016/j.placenta.2012.02.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2011] [Revised: 02/04/2012] [Accepted: 02/06/2012] [Indexed: 12/26/2022]
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41
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Stengel A, Taché Y. Yin and Yang - the Gastric X/A-like Cell as Possible Dual Regulator of Food Intake. J Neurogastroenterol Motil 2012; 18:138-49. [PMID: 22523723 PMCID: PMC3325299 DOI: 10.5056/jnm.2012.18.2.138] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/29/2012] [Accepted: 03/11/2012] [Indexed: 01/14/2023] Open
Abstract
Ingestion of food affects secretion of hormones from enteroendocrine cells located in the gastrointestinal mucosa. These hormones are involved in the regulation of various gastrointestinal functions including the control of food intake. One cell in the stomach, the X/A-like has received much attention over the past years due to the production of ghrelin. Until now, ghrelin is the only known orexigenic hormone that is peripherally produced and centrally acting to stimulate food intake. Subsequently, additional peptide products of this cell have been described including desacyl ghrelin, obestatin and nesfatin-1. Desacyl ghrelin seems to be involved in the regulation of food intake as well and could play a counter-balancing role of ghrelin's orexigenic effect. In contrast, the initially proposed anorexigenic action of obestatin did not hold true and therefore the involvement of this peptide in the regulation of feeding is questionable. Lastly, the identification of nesfatin-1 in the same cell in different vesicles than ghrelin extended the function of this cell type to the inhibition of feeding. Therefore, this X/A-like cell could play a unique role by encompassing yin and yang properties to mediate not only hunger but also satiety.
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Affiliation(s)
- Andreas Stengel
- Department of Medicine, Division Psychosomatic Medicine and Psychotherapy, Charité, Campus Mitte, Universitätsmedizin Berlin, Berlin, Germany
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Stengel A, Taché Y. Ghrelin - a pleiotropic hormone secreted from endocrine x/a-like cells of the stomach. Front Neurosci 2012; 6:24. [PMID: 22355282 PMCID: PMC3280431 DOI: 10.3389/fnins.2012.00024] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2011] [Accepted: 01/29/2012] [Indexed: 12/13/2022] Open
Abstract
The gastric X/A-like endocrine cell receives growing attention due to its peptide products with ghrelin being the best characterized. This peptide hormone was identified a decade ago as a stimulator of food intake and to date remains the only known peripherally produced and centrally acting orexigenic hormone. In addition, subsequent studies identified numerous other functions of this peptide including the stimulation of gastrointestinal motility, the maintenance of energy homeostasis and an impact on reproduction. Moreover, ghrelin is also involved in the response to stress and assumed to play a role in coping functions and exert a modulatory action on immune pathways. Our knowledge on the regulation of ghrelin has markedly advanced during the past years by the identification of the ghrelin acylating enzyme, ghrelin-O-acyltransferase, and by the description of changes in expression, activation, and release under different metabolic as well as physically and psychically challenging conditions. However, our insight on regulatory processes of ghrelin at the cellular and subcellular levels is still very limited and warrants further investigation.
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Affiliation(s)
- Andreas Stengel
- Division Psychosomatic Medicine and Psychotherapy, Department of Medicine, Charité - Universitätsmedizin Berlin Berlin, Germany
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Stengel A, Taché Y. Activation of somatostatin 2 receptors in the brain and the periphery induces opposite changes in circulating ghrelin levels: functional implications. Front Endocrinol (Lausanne) 2012; 3:178. [PMID: 23335913 PMCID: PMC3542632 DOI: 10.3389/fendo.2012.00178] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Accepted: 12/17/2012] [Indexed: 12/26/2022] Open
Abstract
Somatostatin is an important modulator of neurotransmission in the central nervous system and acts as a potent inhibitor of hormone and exocrine secretion and regulator of cell proliferation in the periphery. These pleiotropic actions occur through interaction with five G protein-coupled somatostatin receptor subtypes (sst(1) (-) (5)) that are widely expressed in the brain and peripheral organs. The characterization of somatostatin's effects can be investigated by pharmacological or genetic approaches using newly developed selective sst agonists and antagonists and mice lacking specific sst subtypes. Recent evidence points toward a divergent action of somatostatin in the brain and in the periphery to regulate circulating levels of ghrelin, an orexigenic hormone produced by the endocrine X/A-like cells in the rat gastric mucosa. Somatostatin interacts with the sst(2) in the brain to induce an increase in basal ghrelin plasma levels and counteracts the visceral stress-related decrease in circulating ghrelin. By contrast, stimulation of peripheral somatostatin-sst(2) signaling results in the inhibition of basal ghrelin release and mediates the postoperative decrease in circulating ghrelin. The peripheral sst(2)-mediated reduction of plasma ghrelin is likely to involve a paracrine action of D cell-derived somatostatin acting on sst(2) bearing X/A-like ghrelin cells in the gastric mucosa. The other member of the somatostatin family, named cortistatin, in addition to binding to sst(1) (-) (5) also directly interacts with the ghrelin receptor and therefore may simultaneously modulate ghrelin release and actions at target sites bearing ghrelin receptors representing a link between the ghrelin and somatostatin systems.
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Affiliation(s)
- Andreas Stengel
- Division Psychosomatic Medicine and Psychotherapy, Department of Medicine, Obesity Center Berlin, Charité, Universitätsmedizin BerlinBerlin, Germany
- *Correspondence: Andreas Stengel, Division Psychosomatic Medicine and Psychotherapy, Department of Medicine, Obesity Center Berlin, Charité, Universitätsmedizin Berlin, Luisenstr. 13a, 10117 Berlin, Germany. e-mail: ; Yvette Taché, Digestive Diseases Division, CURE: Digestive Diseases Research Center, Center for Neurobiology of Stress and Women’s Health, Department of Medicine, VA Greater Los Angeles Health Care System, University of California at Los Angeles, CURE Building 115, Room 117, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. e-mail:
| | - Yvette Taché
- Digestive Diseases Division, CURE: Digestive Diseases Research Center, Center for Neurobiology of Stress and Women’s Health, Department of Medicine, VA Greater Los Angeles Health Care System, University of California at Los AngelesLos Angeles, CA, USA
- *Correspondence: Andreas Stengel, Division Psychosomatic Medicine and Psychotherapy, Department of Medicine, Obesity Center Berlin, Charité, Universitätsmedizin Berlin, Luisenstr. 13a, 10117 Berlin, Germany. e-mail: ; Yvette Taché, Digestive Diseases Division, CURE: Digestive Diseases Research Center, Center for Neurobiology of Stress and Women’s Health, Department of Medicine, VA Greater Los Angeles Health Care System, University of California at Los Angeles, CURE Building 115, Room 117, 11301 Wilshire Boulevard, Los Angeles, CA 90073, USA. e-mail:
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Abstract
Ghrelin is the only potent orexigenic peptide in circulation. It stimulates food intake and leads to positive energy balance, adipogenesis, and body weight gain. However, the physiological significance of ghrelin in the regulation of energy homeostasis is controversial, since loss of ghrelin function in rodents does not necessarily lead to anorexia and weight loss. In this chapter, we discuss the metabolic function of ghrelin and are highlighting recent findings including the discovery and function of ghrelin-acylating enzyme ghrelin O-acyltransferase (GOAT). Based on available published data, we conclude that ghrelin is a principally important endogenous regulator of energy balance, which however may affect both food intake and systemic metabolism via independent mechanisms. Importantly, ghrelin, when acylated by GOAT, might represent a key molecular link between the sensing of consumed calories and the neuroendocrine control of energy homeostasis. Thus, agents antagonizing the action of ghrelin may have therapeutic potential in the therapy of obesity.
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45
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Delporte C. Recent advances in potential clinical application of ghrelin in obesity. J Obes 2012; 2012:535624. [PMID: 22523666 PMCID: PMC3317165 DOI: 10.1155/2012/535624] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2011] [Accepted: 12/04/2011] [Indexed: 02/07/2023] Open
Abstract
Ghrelin is the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). Ghrelin is a 28 amino acid peptide possessing a unique acylation on the serine in position 3 catalyzed by ghrelin O-acyltransferase (GOAT). Ghrelin stimulates growth hormone secretion, but also appetite, food intake, weight gain, and gastric emptying. Ghrelin is involved in weight regulation, obesity, type 2 diabetes, and metabolic syndrome. Furthermore, a better understanding of ghrelin biology led to the identification of molecular targets modulating ghrelin levels and/or its biological effects: GOAT, ghrelin, and GHS-R1a. Furthermore, a recent discovery, showing the involvement of bitter taste receptor T2R in ghrelin secretion and/or synthesis and food intake, suggested that T2R could represent an additional interesting molecular target. Several classes of ghrelin-related pharmacological tools for the treatment of obesity have been or could be developed to modulate the identified molecular targets.
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Affiliation(s)
- Christine Delporte
- Laboratory of Biological Chemistry and Nutrition, Faculty of Medicine, Université libre de Bruxelles, 1070 Brussels, Belgium
- *Christine Delporte:
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46
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Baragli A, Lanfranco F, Allasia S, Granata R, Ghigo E. Neuroendocrine and metabolic activities of ghrelin gene products. Peptides 2011; 32:2323-32. [PMID: 22056513 DOI: 10.1016/j.peptides.2011.10.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2011] [Revised: 10/03/2011] [Accepted: 10/25/2011] [Indexed: 12/15/2022]
Abstract
Acylated ghrelin (AG) is a 28 amino acid gastric peptide a natural ligand for the growth hormone secretagogue (GHS) receptor type 1a (GHS-R1a), endowed with GH-secreting and orexigenic properties. Besides, ghrelin exerts several peripheral metabolic actions, including modulation of glucose homeostasis and stimulation of adipogenesis. Notably, AG administration causes hyperglycemia in rodents as in humans. Ghrelin pleiotropy is supported by a widespread expression of the ghrelin gene, of GHS-R1a and other unknown ghrelin binding sites. The existence of alternative receptors for AG, of several natural ligands for GHS-R1a and of acylation-independent ghrelin non-neuroendocrine activities, suggests that there might be a complex 'ghrelin system' not yet completely explored. Moreover, the patho-physiological implications of unacylated ghrelin (UAG), and obestatin (Ob), the other two ghrelin gene-derived peptides, need to be clarified. Within the next few years, we may better understand the 'ghrelin system', where we might envisage clinical applications.
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Affiliation(s)
- Alessandra Baragli
- Laboratory of Molecular and Cellular Endocrinology, Division of Endocrinology, Department of Internal Medicine, University of Turin, Turin, Italy.
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Al Massadi O, Tschöp MH, Tong J. Ghrelin acylation and metabolic control. Peptides 2011; 32:2301-8. [PMID: 21893140 DOI: 10.1016/j.peptides.2011.08.020] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2011] [Revised: 08/19/2011] [Accepted: 08/22/2011] [Indexed: 01/26/2023]
Abstract
Since its discovery, many physiologic functions have been ascribed to ghrelin, a gut derived hormone. The presence of a median fatty acid side chain on the ghrelin peptide is required for the binding and activation of the classical ghrelin receptor, the growth hormone secretagogue receptor (GHSR)-1a. Ghrelin O-acyl transferase (GOAT) was recently discovered as the enzyme responsible for this acylation process. GOAT is expressed in all tissues that have been found to express ghrelin and has demonstrated actions on several complex endocrine organ systems such as the hypothalamus-pituitary-gonadal, insular and adrenal axis as well as the gastrointestinal (GI) tract, bone and gustatory system. Ghrelin acylation is dependent on the function of GOAT and the availability of substrates such as proghrelin and short- to medium-chain fatty acids (MCFAs). This process is governed by GOAT activity and has been shown to be modified by dietary lipids. In this review, we provided evidence that support an important role of GOAT in the regulation of energy homeostasis and glucose metabolism by modulating acyl ghrelin (AG) production. The relevance of GOAT and AG during periods of starvation remains to be defined. In addition, we summarized the recent literature on the metabolic effects of GOAT specific inhibitors and shared our view on the potential of targeting GOAT for the treatment of metabolic disorders such as obesity and type 2 diabetes.
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Affiliation(s)
- O Al Massadi
- Division of Endocrinology, Department of Medicine, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
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Stengel A, Wang L, Taché Y. Stress-related alterations of acyl and desacyl ghrelin circulating levels: mechanisms and functional implications. Peptides 2011; 32:2208-17. [PMID: 21782868 PMCID: PMC3220774 DOI: 10.1016/j.peptides.2011.07.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2011] [Revised: 07/04/2011] [Accepted: 07/05/2011] [Indexed: 12/11/2022]
Abstract
Ghrelin is the only known peripherally produced and centrally acting peptide hormone that stimulates food intake and digestive functions. Ghrelin circulates as acylated and desacylated forms and recently the acylating enzyme, ghrelin-O-acyltransferase (GOAT) and the de-acylating enzyme, thioesterase 1/lysophospholipase 1 have been identified adding new layers of complexity to the regulation of ghrelin. Stress is known to alter gastrointestinal motility and food intake and was recently shown to modify circulating ghrelin and GOAT levels with differential responses related to the type of stressors including a reduction induced by physical stressors (abdominal surgery and immunological/endotoxin injection, exercise) and elevation by metabolic (cold exposure, acute fasting and caloric restriction) and psychological stressors. However, the pathways underlying the alterations of ghrelin under these various stress conditions are still largely to be defined and may relate to stress-associated autonomic changes. There is evidence that alterations of circulating ghrelin may contribute to the neuroendocrine and behavioral responses along with sustaining the energetic requirement needed upon repeated exposure to stressors. A better understanding of these mechanisms will allow targeting components of ghrelin signaling that may improve food intake and gastric motility alterations induced by stress.
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Affiliation(s)
- Andreas Stengel
- CURE: Digestive Diseases Research Center, David Geffen School of Medicine, University of California Los Angeles and Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073, United States.
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Leptin and fasting regulate rat gastric glucose-regulated protein 58. INTERNATIONAL JOURNAL OF PEPTIDES 2011; 2011:969818. [PMID: 22121381 PMCID: PMC3205658 DOI: 10.1155/2011/969818] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Revised: 08/19/2011] [Accepted: 08/19/2011] [Indexed: 12/30/2022]
Abstract
The stomach secretes a wide range of peptides with essential metabolic functions, and thereby plays an important role in the regulation of energy homeostasis. Disulfide isomerase glucose-regulated protein 58 (GRp58) is a molecular chaperone member of the endoplasmic reticulum (ER) stress signaling pathway, which is a marker for human gastric cancer. Since GRp58 seems to be regulated by a phosphorylation/dephosphorylation pattern shift, we used the 2DE gel methodology and peptide mass fingerprinting-protein identification by means of MALDI-TOF mass spectrometry. We show that gastric mucosa GRp58 is dephosphorylated by fasting, and this effect is blunted when fasted rats are treated with leptin. Furthermore, we assessed the gene expression of GRp58 under different physiological settings known to be associated with energy homeostasis (fasting, leptin treatment and leptin deficiency). We found that intraperitoneal administration of leptin increases whereas leptin deficiency decreases GRp58 mRNA levels. However, GRp58 expression remains unchanged after fasting, indicating that leptin actions on GRp58 are no direct sensitivity to fasting. Dissection of the molecular pathways mediating the interactions between ER stress-related factors and nutrient availability, as well as their target genes, may open a new avenue for the study of obesity and other metabolic disorders.
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Ghrelin o-acyl transferase: bridging ghrelin and energy homeostasis. INTERNATIONAL JOURNAL OF PEPTIDES 2011; 2011:217957. [PMID: 21941572 PMCID: PMC3175403 DOI: 10.1155/2011/217957] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2011] [Accepted: 07/20/2011] [Indexed: 11/30/2022]
Abstract
Ghrelin O-acyl transferase (GOAT) is a recently identified enzyme responsible for the unique n-acyl modification of ghrelin, a multifunctional metabolic hormone. GOAT structure and activity appears to be conserved from fish to man. Since the acyl modification is critical for most of the biological actions of ghrelin, especially metabolic functions, GOAT emerged as a very important molecule of interest. The research on GOAT is on the rise, and several important results reiterating its significance have been reported. Notable among these discoveries are the identification of GOAT tissue expression patterns, effects on insulin secretion, blood glucose levels, feeding, body weight, and metabolism. Several attempts have been made to design and test synthetic compounds that can modulate endogenous GOAT, which could turn beneficial in favorably regulating whole body energy homeostasis. This paper will focus to provide an update on recent advances in GOAT research and its broader implications in the regulation of energy balance.
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