|
1
|
Carneiro L, Fenech C, Liénard F, Grall S, Abed B, Haydar J, Allard C, Desmoulins L, Paccoud R, Brindisi MC, Mouillot T, Brondel L, Fioramonti X, Pénicaud L, Jacquin-Piques A, Leloup C. Hypothalamic Glucose Hypersensitivity-Induced Insulin Secretion in the Obese Zücker Rat Is Reversed by Central Ghrelin Treatment. Antioxid Redox Signal 2024; 40:837-849. [PMID: 36656675 DOI: 10.1089/ars.2022.0031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Aims: Part of hypothalamic (mediobasal hypothalamus [MBH]) neurons detect changes in blood glucose levels that in turn coordinate the vagal control of insulin secretion. This control cascade requires the production of mitochondrial reactive oxygen species (mROS), which is altered in models of obesity and insulin resistance. Obese, insulin-resistant Zücker rats are characterized by hypothalamic hypersensitivity to glucose. This initiates an abnormal vagus-induced insulin secretion, associated with an overproduction of mROS in response to a low glucose dose. Here, we hypothesized that ghrelin, known to buffer reactive oxygen species (ROS) via mitochondrial function, may be a major component of the hypothalamic glucose hypersensitivity in the hypoghrelinemic obese Zücker rat. Results: Hypothalamic glucose hypersensitivity-induced insulin secretion of Zücker obese rats was reversed by ghrelin pretreatment. The overproduction of MBH mROS in response to a low glucose load no longer occurred in obese rats that had previously received the cerebral ghrelin infusion. This decrease in mROS production was accompanied by a normalization of oxidative phosphorylation (OXPHOS). Conversely, blocking the action of ghrelin with a growth hormone secretagogue receptor antagonist in a model of hyperghrelinemia (fasted rats) completely restored hypothalamic glucose sensing-induced insulin secretion that was almost absent in this physiological situation. Accordingly, ROS signaling and mitochondrial activity were increased by the ghrelin receptor antagonist. Innovation: These results demonstrate for the first time that ghrelin addressed only to the brain could have a protective effect on the defective control of insulin secretion in the insulin-resistant, hypoghrelinemic obese subject. Conclusions: Ghrelin, through its action on OXPHOS, modulates mROS signaling in response to cerebral hyperglycemia and the consequent vagal control of insulin secretion. In insulin-resistant obese states, brain hypoghrelinemia could be responsible for the nervous defect in insulin secretion.
Collapse
Affiliation(s)
- Lionel Carneiro
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
- INSERM U1220, Institut de Recherche en Santé Digestive (IRSD), Université Paul Sabatier, Toulouse III, CHU Purpan, Toulouse, France
| | - Claire Fenech
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Fabienne Liénard
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Sylvie Grall
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Besma Abed
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Joulia Haydar
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Camille Allard
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
- University of Bordeaux, INSERM U1215, Neurocentre Magendie, Bordeaux, France
| | - Lucie Desmoulins
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
- Department of Physiology, School of Medicine, Tulane University, New Orleans, Louisiana, USA
| | - Romain Paccoud
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Marie-Claude Brindisi
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Thomas Mouillot
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Laurent Brondel
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Xavier Fioramonti
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
- NutriNeuro, UMR 1286 INRAE, Bordeaux University, Bordeaux INP, Neurocampus, Bordeaux, France
| | - Luc Pénicaud
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
- STROMALab, CNRS ERL 5311, Toulouse, France
| | - Agnès Jacquin-Piques
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| | - Corinne Leloup
- Centre des Sciences du Goût et de l'Alimentation, UMR Université de Bourgogne, CNRS 6265, INRAE 1324, Université Bourgogne Franche-Comté, Dijon, France
| |
Collapse
|
|
2
|
Notaro NM, Dyck DJ. Regulation of peripheral tissue substrate metabolism by the gut-derived hormone ghrelin. Metabol Open 2024; 21:100279. [PMID: 38487670 PMCID: PMC10937159 DOI: 10.1016/j.metop.2024.100279] [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: 01/30/2024] [Revised: 02/21/2024] [Accepted: 02/22/2024] [Indexed: 03/17/2024] Open
Abstract
Ghrelin increases in the circulation prior to entrained mealtimes, with the acylated (AG) form functioning to stimulate food intake and growth hormone release. Acutely, AG induces whole-body insulin resistance, potentially to maintain glycemia between meals. Alternatively, chronic administration of both AG and the unacylated isoform of ghrelin (unAG) is associated with improved skeletal muscle insulin sensitivity as well as reduced intramuscular lipids and inflammation. This may be due to effects on lipid metabolism, with ghrelin promoting storage of fat in adipose and liver while stimulating oxidation in skeletal muscle, preventing ectopic lipid accumulation. This is of specific relevance in the handling of meal-derived lipids, as ghrelin rises preprandially with effects persisting for 2-3 h following exposure in skeletal muscle, coinciding with elevated plasma FFAs. We hypothesize that ghrelin acts as a preparatory signal for incoming lipids, as well as a regulatory hormone for their use and storage. The effects of ghrelin on skeletal muscle are lost with high fat diet feeding and physical inactivity, potentially being implicated in the pathogenesis of metabolic disease. This review summarizes the metabolic effects of both ghrelin isoforms on peripheral tissues including the pancreas, adipose, liver, and skeletal muscle. Additionally, we speculate on the physiological relevance of these effects in vivo and suggest that ghrelin may be a key regulatory hormone for nutrient handling in the postprandial state.
Collapse
Affiliation(s)
- Nicole M. Notaro
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| | - David J. Dyck
- Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada
| |
Collapse
|
|
3
|
Zhang H, Yan X, Lin A, Xia P, Su Y. Inhibition of ghrelin activity by the receptor antagonist [D-Lys3]-GHRP-6 enhances hepatic fatty acid oxidation and gluconeogenesis in a growing pig model. Peptides 2023; 166:171041. [PMID: 37301480 DOI: 10.1016/j.peptides.2023.171041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/05/2023] [Accepted: 06/07/2023] [Indexed: 06/12/2023]
Abstract
Despite its central role in regulating energy intake and metabolism, ghrelin is little understood when it comes to its effects on hepatic lipid and glucose metabolism. Growing pigs were intravenously injected with ghrelin receptor antagonist [D-Lys3]-GHRP-6 (DLys; 6 mg/kg body weight) for seven days to determine whether ghrelin plays a role in glucose and lipid metabolism. DLys treatment significantly reduced body weight gain and adipose histopathology found that DLys treatment dramatically reduced adipocyte size. DLys treatment significantly increased serum NEFA and insulin levels, hepatic glucose level and HOMA-IR, and significantly decreased serum TBA level of growing pigs after fasting. Moreover, DLys treatment changed the dynamics of serum metabolic parameters, including glucose, NEFA, TBA, insulin, GH, leptin, and cortisol. Liver transcriptome showed that DLys treatment affected the metabolism-related pathways. Compared with the control group, adipose tissue lipolysis (the adipose triglyceride lipase level was significantly increased), hepatic gluconeogenesis (the G6PC protein level was significantly increased) and fatty acid oxidation (the CPT1A protein level was significantly increased) were promoted in the DLys group. DLys treatment expanded degrees of oxidative phosphorylation in the liver, coming about in a higher NAD+ /NADH proportion and enactment of the SIRT1 signaling pathway. Additionally, the liver protein levels of the DLys group were significantly higher than those of the control group for GHSR, PPAR alpha, and PGC-1. To summarize, inhibition of ghrelin activity can significantly affect metabolism and alter energy levels by enhancing fat mobilization, hepatic fatty acid oxidation and gluconeogenesis without affecting fatty acid uptake and synthesis in the liver.
Collapse
Affiliation(s)
- He Zhang
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China; College of Life Sciences, Xuzhou Medical University, 221004 Xuzhou, China
| | - Xiaoxi Yan
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China
| | - Ailian Lin
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China
| | - Pengke Xia
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China
| | - Yong Su
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, 210095 Nanjing, China; National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, 210095 Nanjing, China.
| |
Collapse
|
|
4
|
Iwakura H, Ensho T, Ueda Y. Desacyl-ghrelin, not just an inactive form of ghrelin?-A review of current knowledge on the biological actions of desacyl-ghrelin. Peptides 2023:171050. [PMID: 37392995 DOI: 10.1016/j.peptides.2023.171050] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 06/23/2023] [Accepted: 06/26/2023] [Indexed: 07/03/2023]
Abstract
Desacyl-ghrelin is a form of ghrelin which lacks acyl-modification of the third serine residue of ghrelin. Originally, desacyl-ghrelin was considered to be just an inactive form of ghrelin. More recently, however, it has been suggested to have various biological activities, including control of food intake, growth hormone, glucose metabolism, and gastric movement, and is involved in cell survival. In this review, we summarize the current knowledge of the biological actions of desacyl-ghrelin and the proposed mechanisms by which it exerts the effects.
Collapse
Affiliation(s)
- Hiroshi Iwakura
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan.
| | - Takuya Ensho
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan
| | - Yoko Ueda
- Department of Pharmacotherapeutics, School of Pharmaceutical Science, Wakayama Medical University, 25-1 Shichibancho, Wakayama 640-8156, Japan
| |
Collapse
|
|
5
|
Liu FS, Wang S, Guo XS, Ye ZX, Zhang HY, Li Z. State of art on the mechanisms of laparoscopic sleeve gastrectomy in treating type 2 diabetes mellitus. World J Diabetes 2023; 14:632-655. [PMID: 37383590 PMCID: PMC10294061 DOI: 10.4239/wjd.v14.i6.632] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2022] [Revised: 04/01/2023] [Accepted: 04/24/2023] [Indexed: 06/14/2023] Open
Abstract
Obesity and type-2 diabetes mellitus (T2DM) are metabolic disorders. Obesity increases the risk of T2DM, and as obesity is becoming increasingly common, more individuals suffer from T2DM, which poses a considerable burden on health systems. Traditionally, pharmaceutical therapy together with lifestyle changes is used to treat obesity and T2DM to decrease the incidence of comorbidities and all-cause mortality and to increase life expectancy. Bariatric surgery is increasingly replacing other forms of treatment of morbid obesity, especially in patients with refractory obesity, owing to its many benefits including good long-term outcomes and almost no weight regain. The bariatric surgery options have markedly changed recently, and laparoscopic sleeve gastrectomy (LSG) is gradually gaining popularity. LSG has become an effective and safe treatment for type-2 diabetes and morbid obesity, with a high cost-benefit ratio. Here, we review the me-chanism associated with LSG treatment of T2DM, and we discuss clinical studies and animal experiments with regard to gastrointestinal hormones, gut microbiota, bile acids, and adipokines to clarify current treatment modalities for patients with obesity and T2DM.
Collapse
Affiliation(s)
- Fa-Shun Liu
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Song Wang
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Xian-Shan Guo
- Department of Endocrinology, Xinxiang Central Hospital, Xinxiang 453000, Henan Province, China
| | - Zhen-Xiong Ye
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| | - Hong-Ya Zhang
- Central Laboratory, Yangpu District Control and Prevention Center, Shanghai 200090, China
| | - Zhen Li
- Department of General Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai 200090, China
| |
Collapse
|
|
6
|
Pierce MR, Hougland JL. A rising tide lifts all MBOATs: recent progress in structural and functional understanding of membrane bound O-acyltransferases. Front Physiol 2023; 14:1167873. [PMID: 37250116 PMCID: PMC10213974 DOI: 10.3389/fphys.2023.1167873] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Accepted: 04/19/2023] [Indexed: 05/31/2023] Open
Abstract
Acylation modifications play a central role in biological and physiological processes. Across a range of biomolecules from phospholipids to triglycerides to proteins, introduction of a hydrophobic acyl chain can dramatically alter the biological function and cellular localization of these substrates. Amongst the enzymes catalyzing these modifications, the membrane bound O-acyltransferase (MBOAT) family occupies an intriguing position as the combined substrate selectivities of the various family members span all three classes of these biomolecules. MBOAT-dependent substrates are linked to a wide range of health conditions including metabolic disease, cancer, and neurodegenerative disease. Like many integral membrane proteins, these enzymes have presented challenges to investigation due to their intractability to solubilization and purification. However, over the last several years new solubilization approaches coupled with computational modeling, crystallography, and cryoelectron microscopy have brought an explosion of structural information for multiple MBOAT family members. These studies enable comparison of MBOAT structure and function across members catalyzing modifications of all three substrate classes, revealing both conserved features amongst all MBOATs and distinct architectural features that correlate with different acylation substrates ranging from lipids to proteins. We discuss the methods that led to this renaissance of MBOAT structural investigations, our new understanding of MBOAT structure and implications for catalytic function, and the potential impact of these studies for development of new therapeutics targeting MBOAT-dependent physiological processes.
Collapse
Affiliation(s)
- Mariah R. Pierce
- Department of Chemistry, Syracuse University, Syracuse, NY, United States
| | - James L. Hougland
- Department of Chemistry, Syracuse University, Syracuse, NY, United States
- Department of Biology, Syracuse University, Syracuse, NY, United States
- BioInspired Syracuse, Syracuse University, Syracuse, NY, United States
| |
Collapse
|
|
7
|
Anbari DM, Al-Harithy RN. Ghrelin intronic lncRNAs, lnc-GHRL-3:2 and lnc-GHRL-3:3, as novel biomarkers in type 2 diabetes mellitus. Arch Physiol Biochem 2023; 129:241-245. [PMID: 32921167 DOI: 10.1080/13813455.2020.1817095] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND We aim to identify circulating lncRNAs located in the region of the ghrelin (GHRL) gene that play a role in the development of T2DM. METHODS Bioinformatic tool was used to identify candidates GHRL-lncRNAs. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to compare the expression levels of selected lncRNAs on diabetic patients and non-diabetic controls.Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory power of selected GHRL-lncRNAs. RESULTS The bioinformatic analysis predicted three antisense and eight sense-intronic GHRL- lncRNAs. Two differentially expressed GHRL-lncRNAs were detected in diabetic patients. The expression levels of lnc-GHRL-3:2, lnc-GHRL-3:3, and the GHRL mRNA were significantly (p ≤ .0001) lower in the diabetic patients. ROC analysis showed that the area under the curve (AUC) value was 0.93 for lnc-GHRL-3:2 and 0.90 for lnc-GHRL-3:3. CONCLUSION lnc-GHRL-3:2 and lnc-GHRL-3:3 are novel biomarkers and might play a regulatory role in T2DM pathogenesis.
Collapse
Affiliation(s)
- Dalia M Anbari
- Department of Biochemistry, King AbdulAziz University, Jeddah, Saudi Arabia
| | | |
Collapse
|
|
8
|
Chen RB, Wang QY, Wang YY, Wang YD, Liu JH, Liao ZZ, Xiao XH. Feeding-induced hepatokines and crosstalk with multi-organ: A novel therapeutic target for Type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1094458. [PMID: 36936164 PMCID: PMC10020511 DOI: 10.3389/fendo.2023.1094458] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 02/15/2023] [Indexed: 03/06/2023] Open
Abstract
Hyperglycemia, which can be caused by either an insulin deficit and/or insulin resistance, is the main symptom of Type 2 diabetes, a significant endocrine metabolic illness. Conventional medications, including insulin and oral antidiabetic medicines, can alleviate the signs of diabetes but cannot restore insulin release in a physiologically normal amount. The liver detects and reacts to shifts in the nutritional condition that occur under a wide variety of metabolic situations, making it an essential organ for maintaining energy homeostasis. It also performs a crucial function in glucolipid metabolism through the secretion of hepatokines. Emerging research shows that feeding induces hepatokines release, which regulates glucose and lipid metabolism. Notably, these feeding-induced hepatokines act on multiple organs to regulate glucolipotoxicity and thus influence the development of T2DM. In this review, we focus on describing how feeding-induced cross-talk between hepatokines, including Adropin, Manf, Leap2 and Pcsk9, and metabolic organs (e.g.brain, heart, pancreas, and adipose tissue) affects metabolic disorders, thus revealing a novel approach for both controlling and managing of Type 2 diabetes as a promising medication.
Collapse
Affiliation(s)
- Rong-Bin Chen
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Qi-Yu Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- Department of Clinical Laboratory Medicine, Institution of Microbiology and Infectious Diseases, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Yuan-Yuan Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Ya-Di Wang
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Jiang-Hua Liu
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
| | - Zhe-Zhen Liao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- *Correspondence: Xin-Hua Xiao, ; Zhe-Zhen Liao,
| | - Xin-Hua Xiao
- Department of Metabolism and Endocrinology, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, Hunan, China
- *Correspondence: Xin-Hua Xiao, ; Zhe-Zhen Liao,
| |
Collapse
|
|
9
|
Piper NBC, Whitfield EA, Stewart GD, Xu X, Furness SGB. Targeting appetite and satiety in diabetes and obesity, via G protein-coupled receptors. Biochem Pharmacol 2022; 202:115115. [PMID: 35671790 DOI: 10.1016/j.bcp.2022.115115] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 11/17/2022]
Abstract
Type 2 diabetes and obesity have reached pandemic proportions throughout the world, so much so that the World Health Organisation coined the term "Globesity" to help encapsulate the magnitude of the problem. G protein-coupled receptors (GPCRs) are highly tractable drug targets due to their wide involvement in all aspects of physiology and pathophysiology, indeed, GPCRs are the targets of approximately 30% of the currently approved drugs. GPCRs are also broadly involved in key physiologies that underlie type 2 diabetes and obesity including feeding reward, appetite and satiety, regulation of blood glucose levels, energy homeostasis and adipose function. Despite this, only two GPCRs are the target of approved pharmaceuticals for treatment of type 2 diabetes and obesity. In this review we discuss the role of these, and select other candidate GPCRs, involved in various facets of type 2 diabetic or obese pathophysiology, how they might be targeted and the potential reasons why pharmaceuticals against these targets have not progressed to clinical use. Finally, we provide a perspective on the current development pipeline of anti-obesity drugs that target GPCRs.
Collapse
Affiliation(s)
- Noah B C Piper
- Receptor Transducer Coupling Laboratory, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, QLD 4072, Australia
| | - Emily A Whitfield
- Receptor Transducer Coupling Laboratory, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, QLD 4072, Australia
| | - Gregory D Stewart
- Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology Monash University, Parkville, VIC 3052, Australia
| | - Xiaomeng Xu
- Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology Monash University, Parkville, VIC 3052, Australia
| | - Sebastian G B Furness
- Receptor Transducer Coupling Laboratory, School of Biomedical Sciences, Faculty of Medicine, University of Queensland, St. Lucia, QLD 4072, Australia; Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences & Department of Pharmacology Monash University, Parkville, VIC 3052, Australia.
| |
Collapse
|
|
10
|
Li J, Huang P, Xiong J, Liang X, Li M, Ke H, Chen C, Han Y, Huang Y, Zhou Y, Luo Z, Feng D, Chen C. Serum levels of ghrelin and LEAP2 in patients with type 2 diabetes mellitus: correlation with circulating glucose and lipids. Endocr Connect 2022; 11:e220012. [PMID: 35521798 PMCID: PMC9175609 DOI: 10.1530/ec-22-0012] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2022] [Accepted: 04/26/2022] [Indexed: 11/08/2022]
Abstract
Objective Ghrelin regulates body weight, food intake, and blood glucose. It also regulates insulin secretion from pancreatic islet cells. LEAP2 is a newly discovered endogenous ligand of the growth hormone secretagogue's receptor (GHSR). It not only antagonizes the stimulation of GHSR by ghrelin but also inhibits the constitutive activation of GHSR as an inverse agonist. Type 2 diabetes (T2D) patients have endocrine disorders with metabolic imbalance. Plasma levels of ghrelin and LEAP2 may be changed in obese and T2D patients. However, there is no report yet on circulating LEAP2 levels or ghrelin/LEAP2 ratio in T2D patients. In this study, fasting serum ghrelin and LEAP2 levels in healthy adults and T2D patients were assessed to clarify the association of two hormones with different clinical anthropometric and metabolic parameters. Design A total of 16 females and 40 males, ages 23-68 years old normal (n = 27), and T2D patients (n = 29) were enrolled as a cross-sectional cohort. Results Serum levels of ghrelin were lower but serum levels of LEAP2 were higher in T2D patients. Ghrelin levels were positively correlated with fasting serum insulin levels and HOMA-IR in healthy adults. LEAP2 levels were positively correlated with age and hemoglobin A1c (HbA1c) in all tested samples. Ghrelin/LEAP2 ratio was negatively correlated with age, fasting blood glucose, and HbA1c. Conclusions This study demonstrated a decrease in serum ghrelin levels and an increase in serum LEAP2 levels in T2D patients. LEAP2 levels were positively correlated with HbA1c, suggesting that LEAP2 was associated with T2D development. The ghrelin/LEAP2 ratio was closely associated with glycemic control in T2D patients showing a negative correlation with glucose and HbA1c.
Collapse
Affiliation(s)
- Jiaxi Li
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Pu Huang
- Department of Health Management Center, Changsha Central Hospital, University of South China, Changsha, Hunan, China
| | - Jing Xiong
- Department of Endocrinology, Xiangya Third Hospital, Central South University, Changsha, Hunan, China
| | - Xinyue Liang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Mei Li
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Hao Ke
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Chunli Chen
- Department of Dermatology, Xiangya Third Hospital, Central South University, Changsha, Hunan, China
| | - Yang Han
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yanhong Huang
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Yan Zhou
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
| | - Ziqiang Luo
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
| | - Dandan Feng
- Department of Physiology, Xiangya School of Medicine, Central South University, Changsha, Hunan, China
- Hunan Key Laboratory of Organ Fibrosis, Central South University, Changsha, Hunan, China
| | - Chen Chen
- School of Biomedical Sciences, University of Queensland, St Lucia, Brisbane, Queensland, Australia
| |
Collapse
|
|
11
|
Jeong H, Chong HJ, So J, Jo Y, Yune TY, Ju BG. Ghrelin Represses Thymic Stromal Lymphopoietin Gene Expression through Activation of Glucocorticoid Receptor and Protein Kinase C Delta in Inflamed Skin Keratinocytes. Int J Mol Sci 2022; 23:ijms23073977. [PMID: 35409338 PMCID: PMC8999772 DOI: 10.3390/ijms23073977] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/29/2022] [Accepted: 04/01/2022] [Indexed: 12/04/2022] Open
Abstract
Ghrelin, a peptide hormone secreted from enteroendocrine cells of the gastrointestinal tract, has anti-inflammatory activity in skin diseases, including dermatitis and psoriasis. However, the molecular mechanism underlying the beneficial effect of ghrelin on skin inflammation is not clear. In this study, we found that ghrelin alleviates atopic dermatitis (AD)-phenotypes through suppression of thymic stromal lymphopoietin (TSLP) gene activation. Knockdown or antagonist treatment of growth hormone secretagogue receptor 1a (GHSR1a), the receptor for ghrelin, suppressed ghrelin-induced alleviation of AD-like phenotypes and suppression of TSLP gene activation. We further found that ghrelin induces activation of the glucocorticoid receptor (GR), leading to the binding of GR with histone deacetylase 3 (HDAC3) and nuclear receptor corepressor (NCoR) NCoR corepressor to negative glucocorticoid response element (nGRE) on the TSLP gene promoter. In addition, ghrelin-induced protein kinase C δ (PKCδ)-mediated phosphorylation of p300 at serine 89 (S89), which decreased the acetylation and DNA binding activity of nuclear factor- κB (NF-κB) p65 to the TSLP gene promoter. Knockdown of PKCδ abolished ghrelin-induced suppression of TSLP gene activation. Our study suggests that ghrelin may help to reduce skin inflammation through GR and PKCδ-p300-NF-κB-mediated suppression of TSLP gene activation.
Collapse
Affiliation(s)
- Hayan Jeong
- Department of Life Science, Sogang University, Seoul 04107, Korea; (H.J.); (H.-J.C.); (J.S.); (Y.J.)
| | - Hyo-Jin Chong
- Department of Life Science, Sogang University, Seoul 04107, Korea; (H.J.); (H.-J.C.); (J.S.); (Y.J.)
| | - Jangho So
- Department of Life Science, Sogang University, Seoul 04107, Korea; (H.J.); (H.-J.C.); (J.S.); (Y.J.)
| | - Yejin Jo
- Department of Life Science, Sogang University, Seoul 04107, Korea; (H.J.); (H.-J.C.); (J.S.); (Y.J.)
| | - Tae-Young Yune
- Age-Related and Brain Diseases Research Center, Kyung Hee University, Seoul 02447, Korea;
- Department of Biochemistry and Molecular Biology, School of Medicine, Kyung Hee University, Seoul 02447, Korea
| | - Bong-Gun Ju
- Department of Life Science, Sogang University, Seoul 04107, Korea; (H.J.); (H.-J.C.); (J.S.); (Y.J.)
- Correspondence: ; Tel.: +82-2-705-8455
| |
Collapse
|
|
12
|
Mechanistic Investigation of GHS-R Mediated Glucose-Stimulated Insulin Secretion in Pancreatic Islets. Biomolecules 2022; 12:biom12030407. [PMID: 35327599 PMCID: PMC8945998 DOI: 10.3390/biom12030407] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/19/2022] [Accepted: 02/27/2022] [Indexed: 02/07/2023] Open
Abstract
Ghrelin receptor, a growth hormone secretagogue receptor (GHS-R), is expressed in the pancreas. Emerging evidence indicates that GHS-R is involved in the regulation of glucose-stimulated insulin secretion (GSIS), but the mechanism by which GHS-R regulates GSIS in the pancreas is unclear. In this study, we investigated the role of GHS-R on GSIS in detail using global Ghsr−/− mice (in vivo) and Ghsr-ablated pancreatic islets (ex vivo). GSIS was attenuated in both Ghsr−/− mice and Ghsr-ablated islets, while the islet morphology was similar between WT and Ghsr−/− mice. To elucidate the mechanism underpinning Ghsr-mediated GSIS, we investigated the key steps of the GSIS signaling cascade. The gene expression of glucose transporter 2 (Glut2) and the glucose-metabolic intermediate—glucose-6-phosphate (G6P) were reduced in Ghsr-ablated islets, supporting decreased glucose uptake. There was no difference in mitochondrial DNA content in the islets of WT and Ghsr−/− mice, but the ATP/ADP ratio in Ghsr−/− islets was significantly lower than that of WT islets. Moreover, the expression of pancreatic and duodenal homeobox 1 (Pdx1), as well as insulin signaling genes of insulin receptor (IR) and insulin receptor substrates 1 and 2 (IRS1/IRS2), was downregulated in Ghsr−/− islets. Akt is the key mediator of the insulin signaling cascade. Concurrently, Akt phosphorylation was reduced in the pancreas of Ghsr−/− mice under both insulin-stimulated and homeostatic conditions. These findings demonstrate that GHS-R ablation affects key components of the insulin signaling pathway in the pancreas, suggesting the existence of a cross-talk between GHS-R and the insulin signaling pathway in pancreatic islets, and GHS-R likely regulates GSIS via the Akt-Pdx1-GLUT2 pathway.
Collapse
|
|
13
|
Chen X, Dong J, Jiao Q, Du X, Bi M, Jiang H. "Sibling" battle or harmony: crosstalk between nesfatin-1 and ghrelin. Cell Mol Life Sci 2022; 79:169. [PMID: 35239020 PMCID: PMC11072372 DOI: 10.1007/s00018-022-04193-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Revised: 02/02/2022] [Accepted: 02/04/2022] [Indexed: 12/17/2022]
Abstract
Ghrelin was first identified as an endogenous ligand of the growth hormone secretagogue receptor (GHSR) in 1999, with the function of stimulating the release of growth hormone (GH), while nesfatin-1 was identified in 2006. Both peptides are secreted by the same kind of endocrine cells, X/A-like cells in the stomach. Compared with ghrelin, nesfatin-1 exerts opposite effects on energy metabolism, glucose metabolism, gastrointestinal functions and regulation of blood pressure, but exerts similar effects on anti-inflammation and neuroprotection. Up to now, nesfatin-1 remains as an orphan ligand because its receptor has not been identified. Several studies have shown the effects of nesfatin-1 are dependent on the receptor of ghrelin. We herein compare the effects of nesfatin-1 and ghrelin in several aspects and explore the possibility of their interactions.
Collapse
Affiliation(s)
- Xi Chen
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China
| | - Jing Dong
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China
| | - Qian Jiao
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China
| | - Xixun Du
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China
| | - Mingxia Bi
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China
| | - Hong Jiang
- Department of Physiology, Shandong Provincial Key Laboratory of Pathogenesis and Prevention of Neurological Disorders and State Key Disciplines: Physiology, School of Basic Medicine, Qingdao University, Qingdao, 266071, People's Republic of China.
| |
Collapse
|
|
14
|
Deschaine SL, Leggio L. From "Hunger Hormone" to "It's Complicated": Ghrelin Beyond Feeding Control. Physiology (Bethesda) 2022; 37:5-15. [PMID: 34964687 PMCID: PMC8742734 DOI: 10.1152/physiol.00024.2021] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Discovered as a peptide involved in releasing growth hormone, ghrelin was initially characterized as the "hunger hormone." However, emerging research indicates that ghrelin appears to play an important part in relaying information regarding nutrient availability and value and adjusting physiological and motivational processes accordingly. These functions make ghrelin an interesting therapeutic candidate for metabolic and neuropsychiatric diseases involving disrupted nutrition that can further potentiate the rewarding effect of maladaptive behaviors.
Collapse
Affiliation(s)
- Sara L. Deschaine
- 1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, Maryland
| | - Lorenzo Leggio
- 1Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, Maryland,2Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland,3Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, Rhode Island,4Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, Maryland,5Department of Neuroscience, Georgetown University Medical Center, Washington, District of Columbia
| |
Collapse
|
|
15
|
Targeting the Ghrelin Receptor as a Novel Therapeutic Option for Epilepsy. Biomedicines 2021; 10:biomedicines10010053. [PMID: 35052733 PMCID: PMC8773216 DOI: 10.3390/biomedicines10010053] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 12/12/2022] Open
Abstract
Epilepsy is a neurological disease affecting more than 50 million individuals worldwide. Notwithstanding the availability of a broad array of antiseizure drugs (ASDs), 30% of patients suffer from pharmacoresistant epilepsy. This highlights the urgent need for novel therapeutic options, preferably with an emphasis on new targets, since “me too” drugs have been shown to be of no avail. One of the appealing novel targets for ASDs is the ghrelin receptor (ghrelin-R). In epilepsy patients, alterations in the plasma levels of its endogenous ligand, ghrelin, have been described, and various ghrelin-R ligands are anticonvulsant in preclinical seizure and epilepsy models. Up until now, the exact mechanism-of-action of ghrelin-R-mediated anticonvulsant effects has remained poorly understood and is further complicated by multiple downstream signaling pathways and the heteromerization properties of the receptor. This review compiles current knowledge, and discusses the potential mechanisms-of-action of the anticonvulsant effects mediated by the ghrelin-R.
Collapse
|
|
16
|
Nunez-Salces M, Li H, Young RL, Page AJ. The secretion of total and acyl ghrelin from the mouse gastric mucosa: Role of nutrients and the lipid chemosensors FFAR4 and CD36. Peptides 2021; 146:170673. [PMID: 34627956 DOI: 10.1016/j.peptides.2021.170673] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 10/20/2022]
Abstract
AIMS This study investigated the nutrient-mediated modulation of total ghrelin (TG) and acyl ghrelin (AG) secretion from the mouse gastric mucosa, and the role of long-chain fatty acid chemosensors, FFAR4 and CD36, in lipid-mediated modulation of TG and AG release. METHODS Ex-vivo experiments were conducted using mouse gastric mucosa to examine the effects of nutrients (D-glucose, L-phenylalanine, peptone (mixture of oligopeptides & single amino acids), D-mannitol, α-linolenic acid and fat emulsion (intralipid)) on TG and AG secretion. Additionally, inhibition of FFAR4 and CD36 on α-linolenic acid and intralipid-mediated regulation of TG and AG secretion was assessed. RESULTS TG and AG secretion were unaffected by glucose and D-mannitol. Peptone stimulated the release of TG and AG. In contrast, L-phenylalanine reduced AG secretion only. Intralipid reduced TG secretion and stimulated AG secretion, and α-linolenic acid reduced AG release, without affecting TG mobilisation. Modulation of ghrelin secretion by lipids occurred in an FFAR4 and CD36-independent manner. CONCLUSION Ghrelin secretion is modulated in a nutrient-specific manner by proteins and lipids, with TG and AG displaying independent responses to the same stimuli. In addition, FFAR4 and CD36 do not participate in modulation of TG and AG secretion by α-linolenic acid and intralipid.
Collapse
Affiliation(s)
- Maria Nunez-Salces
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Hui Li
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Richard L Young
- Intestinal Nutrient Sensing Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia
| | - Amanda J Page
- Vagal Afferent Research Group, Australia; Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, 5005, Australia; Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, 5000, Australia.
| |
Collapse
|
|
17
|
Protective and Healing Effects of Ghrelin and Risk of Cancer in the Digestive System. Int J Mol Sci 2021; 22:ijms221910571. [PMID: 34638910 PMCID: PMC8509076 DOI: 10.3390/ijms221910571] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 01/19/2023] Open
Abstract
Ghrelin is an endogenous ligand for the ghrelin receptor, previously known as the growth hormone secretagogue receptor. This hormone is mainly produced by endocrine cells present in the gastric mucosa. The ghrelin-producing cells are also present in other organs of the body, mainly in the digestive system, but in much smaller amount. Ghrelin exhibits a broad spectrum of physiological effects, such as stimulation of growth hormone secretion, gastric secretion, gastrointestinal motility, and food intake, as well as regulation of glucose homeostasis and bone formation, and inhibition of inflammatory processes. This review summarizes the recent findings concerning animal and human data showing protective and therapeutic effects of ghrelin in the gut, and also presents the role of growth hormone and insulin-like growth factor-1 in these effects. In addition, the current data on the possible influence of ghrelin on the carcinogenesis, its importance in predicting the risk of developing gastrointestinal malignances, as well as the potential usefulness of ghrelin in the treatment of cancer, have been presented.
Collapse
|
|
18
|
Jin ZL, Liu W. Progress in treatment of type 2 diabetes by bariatric surgery. World J Diabetes 2021; 12:1187-1199. [PMID: 34512886 PMCID: PMC8394224 DOI: 10.4239/wjd.v12.i8.1187] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/29/2021] [Accepted: 07/06/2021] [Indexed: 02/06/2023] Open
Abstract
The incidence of type 2 diabetes (T2D) is increasing at an alarming rate worldwide. Bariatric surgical procedures, such as the vertical sleeve gastrectomy and Roux-en-Y gastric bypass, are the most efficient approaches to obtain substantial and durable remission of T2D. The benefits of bariatric surgery are realized through the consequent increased satiety and alterations in gastrointestinal hormones, bile acids, and the intestinal microbiota. A comprehensive understanding of the mechanisms by which various bariatric surgical procedures exert their benefits on T2D could contribute to the design of better non-surgical treatments for T2D. In this review, we describe the classification and evolution of bariatric surgery and explore the multiple mechanisms underlying the effect of bariatric surgery on insulin resistance. Based upon our summarization of the current knowledge on the underlying mechanisms, we speculate that the gut might act as a new target for improving T2D. Our ultimate goal with this review is to provide a better understanding of T2D pathophysiology in order to support development of T2D treatments that are less invasive and more scalable.
Collapse
Affiliation(s)
- Zhang-Liu Jin
- Department of General Surgery & Department of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| | - Wei Liu
- Department of General Surgery & Department of Biliopancreatic and Metabolic Surgery, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan Province, China
| |
Collapse
|
|
19
|
Davis TR, Pierce MR, Novak SX, Hougland JL. Ghrelin octanoylation by ghrelin O-acyltransferase: protein acylation impacting metabolic and neuroendocrine signalling. Open Biol 2021; 11:210080. [PMID: 34315274 PMCID: PMC8316800 DOI: 10.1098/rsob.210080] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The acylated peptide hormone ghrelin impacts a wide range of physiological processes but is most well known for controlling hunger and metabolic regulation. Ghrelin requires a unique posttranslational modification, serine octanoylation, to bind and activate signalling through its cognate GHS-R1a receptor. Ghrelin acylation is catalysed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. The ghrelin/GOAT/GHS-R1a system is defined by multiple unique aspects within both protein biochemistry and endocrinology. Ghrelin serves as the only substrate for GOAT within the human proteome and, among the multiple hormones involved in energy homeostasis and metabolism such as insulin and leptin, acts as the only known hormone in circulation that directly stimulates appetite and hunger signalling. Advances in GOAT enzymology, structural modelling and inhibitor development have revolutionized our understanding of this enzyme and offered new tools for investigating ghrelin signalling at the molecular and organismal levels. In this review, we briefly summarize the current state of knowledge regarding ghrelin signalling and ghrelin/GOAT enzymology, discuss the GOAT structural model in the context of recently reported MBOAT enzyme superfamily member structures, and highlight the growing complement of GOAT inhibitors that offer options for both ghrelin signalling studies and therapeutic applications.
Collapse
Affiliation(s)
- Tasha R Davis
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA
| | - Mariah R Pierce
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA
| | - Sadie X Novak
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA
| | - James L Hougland
- Department of Chemistry, Syracuse University, Syracuse, NY 13244 USA.,BioInspired Syracuse, Syracuse University, Syracuse, NY 13244 USA
| |
Collapse
|
|
20
|
[Body composition, mineral metabolism, and endocrine function of adipose tissue: influence of a nutritional supplement of propolis]. NUTR HOSP 2021; 38:585-591. [PMID: 33666089 DOI: 10.20960/nh.03438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
Introduction Introduction: propolis and its components influence lipid metabolism; however, its effect on body composition and mineral metabolism remains unknown. Objectives: to determine the effect of natural propolis supplementation on body composition, mineral metabolism, and the endocrine function of adipose tissue. Material and methods: twenty albino male Wistar rats (8 weeks old) were divided into two groups of 10 animals each. The rats were fed two different types of diet for 90 days: a standard diet for the control group (group C) and the same standard diet + 2 % propolis (group P). Thyroid hormones, ghrelin, leptin, adiponectin and insulin, non-esterified fatty acids (NEFA) in plasma, body composition (lean mass, fat mass and body water), and mineral deposition in target organs (spleen, brain, heart, lungs, testicles, kidneys and femur) were assessed. Results: thyroid stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) did not show any differences after supplementation with propolis, while ghrelin and adiponectin decreased (p < 0.01 and p < 0.05, respectively) and insulin (p < 0.01), leptin (p < 0.05) and NEFA (p < 0.05) increased when 2 % propolis was supplied, while weight and body fat were reduced (p < 0.05) and lean mass increased. Lastly, the propolis supplement improves calcium deposition in the spleen, lungs, testes, and femur (p < 0.05). Conclusion: propolis supplementation of the diet (2 %) causes a decrease in the secretion of ghrelin and adiponectin, increasing the release of non-esterified fatty acids and the rate of insulin secretion. In addition, propolis supplementation induces an improvement in calcium deposition in target organs without affecting the rest of minerals, which improves body composition by inducing a reduction in weight and visceral adipose tissue, and improvement in lean mass.
Collapse
|
|
21
|
Nunez-Salces M, Li H, Feinle-Bisset C, Young RL, Page AJ. Nutrient-sensing components of the mouse stomach and the gastric ghrelin cell. Neurogastroenterol Motil 2020; 32:e13944. [PMID: 32666613 DOI: 10.1111/nmo.13944] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 04/22/2020] [Accepted: 06/22/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND The ability of the gut to detect nutrients is critical to the regulation of gut hormone secretion, food intake, and postprandial blood glucose control. Ingested nutrients are detected by specific gut chemosensors. However, knowledge of these chemosensors has primarily been derived from the intestine, while available information on gastric chemosensors is limited. This study aimed to investigate the nutrient-sensing repertoire of the mouse stomach with particular emphasis on ghrelin cells. METHODS Quantitative RT-PCR was used to determine mRNA levels of nutrient chemosensors (protein: G protein-coupled receptor 93 [GPR93], calcium-sensing receptor [CaSR], metabotropic glutamate receptor type 4 [mGluR4]; fatty acids: CD36, FFAR2&4; sweet/umami taste: T1R3), taste transduction components (TRPM5, GNAT2&3), and ghrelin and ghrelin-processing enzymes (PC1/3, ghrelin O-acyltransferase [GOAT]) in the gastric corpus and antrum of adult male C57BL/6 mice. Immunohistochemistry was performed to assess protein expression of chemosensors (GPR93, T1R3, CD36, and FFAR4) and their co-localization with ghrelin. KEY RESULTS Most nutrient chemosensors had higher mRNA levels in the antrum compared to the corpus, except for CD36, GNAT2, ghrelin, and GOAT. Similar regional distribution was observed at the protein level. At least 60% of ghrelin-positive cells expressed T1R3 and FFAR4, and over 80% expressed GPR93 and CD36. CONCLUSIONS AND INFERENCES The cellular mechanisms for the detection of nutrients are expressed in a region-specific manner in the mouse stomach and gastric ghrelin cells. These gastric nutrient chemosensors may play a role modulating gastrointestinal responses, such as the inhibition of ghrelin secretion following food intake.
Collapse
Affiliation(s)
- Maria Nunez-Salces
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
| | - Hui Li
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
| | - Christine Feinle-Bisset
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Richard L Young
- Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia.,Intestinal Nutrient Sensing Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Amanda J Page
- Vagal Afferent Research Group, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Centre of Research Excellence in Translating Nutritional Science to Good Health, Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia.,Nutrition, Diabetes & Gut Health, Lifelong Health Theme, South Australian Health & Medical Research Institute (SAHMRI), Adelaide, SA, Australia
| |
Collapse
|
|
22
|
Dagher-Hamalian C, Stephan J, Zeeni N, Harhous Z, Shebaby WN, Abdallah MS, Faour WH. Ghrelin-induced multi-organ damage in mice fed obesogenic diet. Inflamm Res 2020; 69:1019-1026. [PMID: 32719925 DOI: 10.1007/s00011-020-01383-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/13/2020] [Accepted: 07/16/2020] [Indexed: 02/08/2023] Open
Abstract
OBJECTIVE AND DESIGN Ghrelin has a key role in modulating energy metabolism and weight gain. The present study aimed at studying the potential role of ghrelin in the development and/or exacerbation of organ damage in a mouse model of diet-induced obesity. OBJECTIVE AND DESIGN Adult mice were fed one of two diets for 20 weeks: standard high carbohydrate (HC) or high-fat high-sugar (HFHS). Starting week 17, the animals were given regular intraperitoneal ghrelin (160 µg/kg) or saline injections Abdominal fat, serum creatinine, and glucose levels, as well as kidney, liver and heart weight and pathology were assessed. RESULTS Ghrelin-injected mice showed significant organ damage, which was more exacerbated in HFHS-fed animals. While the HFHS diet was associated with significant liver damage, ghrelin administration did not reverse it. Interestingly, ghrelin administration induced moderate kidney damage and significantly affected the heart by increasing perivascular and myocardium fibrosis, steatosis as well as inflammation. Moreover, serum creatinine levels were higher in the animal group injected with ghrelin. CONCLUSION Ghrelin administration was associated with increased functional and structural organ damage, regardless of diet. The present study provides novel evidence of multi-organ physiologic alterations secondary to ghrelin administration.
Collapse
Affiliation(s)
- Carole Dagher-Hamalian
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, PO Box 36, Byblos, Lebanon
| | - Joseph Stephan
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, PO Box 36, Byblos, Lebanon
| | - Nadine Zeeni
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon
| | - Zeina Harhous
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, PO Box 36, Byblos, Lebanon
| | - Wassim N Shebaby
- Department of Natural Sciences, School of Arts and Sciences, Lebanese American University, PO Box 36, Byblos, Lebanon
| | - Maya S Abdallah
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, PO Box 36, Byblos, Lebanon
| | - Wissam H Faour
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, PO Box 36, Byblos, Lebanon.
| |
Collapse
|
|
23
|
Moose JE, Leets KA, Mate NA, Chisholm JD, Hougland JL. An overview of ghrelin O-acyltransferase inhibitors: a literature and patent review for 2010-2019. Expert Opin Ther Pat 2020; 30:581-593. [PMID: 32564644 DOI: 10.1080/13543776.2020.1776263] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The peptide hormone ghrelin regulates physiological processes associated with energy homeostasis such as appetite, insulin signaling, glucose metabolism, and adiposity. Ghrelin has also been implicated in a growing number of neurological pathways involved in stress response and addiction behavior. For ghrelin to bind the growth hormone secretagogue receptor 1a (GHS-R1a) and activate signaling, the hormone must first be octanoylated on a specific serine side chain. This key transformation is performed by the enzyme ghrelin O-acyltransferase (GOAT), and therefore GOAT inhibitors may be useful in treating disorders related to ghrelin signaling such as diabetes, obesity, and related metabolic syndromes. AREAS COVERED This report covers ghrelin and GOAT as potential therapeutic targets and summarizes work on GOAT inhibitors through the end of 2019, highlighting recent successes with both peptidomimetics and small molecule GOAT inhibitors as potent modulators of GOAT-catalyzed ghrelin octanoylation. EXPERT OPINION A growing body of biochemical and structural knowledge regarding the ghrelin/GOAT system now enables multiple avenues for identifying and optimizing GOAT inhibitors. We are at the beginning of a new era with increased opportunities for leveraging ghrelin and GOAT in the understanding and treatment of multiple health conditions including diabetes, obesity, and addiction.
Collapse
Affiliation(s)
- Jacob E Moose
- Department of Chemistry and BioInspired Syracuse, Syracuse University , Syracuse, NY, USA
| | - Katelyn A Leets
- Department of Chemistry and BioInspired Syracuse, Syracuse University , Syracuse, NY, USA
| | - Nilamber A Mate
- Department of Chemistry and BioInspired Syracuse, Syracuse University , Syracuse, NY, USA
| | - John D Chisholm
- Department of Chemistry and BioInspired Syracuse, Syracuse University , Syracuse, NY, USA
| | - James L Hougland
- Department of Chemistry and BioInspired Syracuse, Syracuse University , Syracuse, NY, USA
| |
Collapse
|
|
24
|
Yin TC, Bauchle CJ, Rouault AAJ, Stephens SB, Sebag JA. The Insulinostatic Effect of Ghrelin Requires MRAP2 Expression in δ Cells. iScience 2020; 23:101216. [PMID: 32535024 PMCID: PMC7300157 DOI: 10.1016/j.isci.2020.101216] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 04/07/2020] [Accepted: 05/26/2020] [Indexed: 02/01/2023] Open
Abstract
Ghrelin regulates both energy intake and glucose homeostasis. In the endocrine pancreas, ghrelin inhibits insulin release to prevent hypoglycemia during fasting. The mechanism through which this is accomplished is unclear, but recent studies suggest that ghrelin acts on δ cells to stimulate somatostatin release, which in turn inhibits insulin release from β cells. Recently, the Melanocortin Receptor Accessory Protein 2 (MRAP2) was identified as an essential partner of the ghrelin receptor (GHSR1a) in mediating the central orexigenic action of ghrelin. In this study we show that MRAP2 is expressed in islet δ cells and is required for ghrelin to elicit a calcium response in those cells. Additionally, we show that both global and δ cell targeted deletion of MRAP2 abrogates the insulinostatic effect of ghrelin. Together, these findings establish that ghrelin signaling within δ cells is essential for the inhibition of insulin release and identify MRAP2 as a regulator of insulin secretion.
δ Cells are responsible for the action of ghrelin in the endocrine pancreas MRAP2 is expressed in multiple cell types in the endocrine pancreas including δ cells MRAP2 is required for GHSR1a signaling in δ cells Deletion of MRAP2 results in loss of ghrelin-mediated inhibition of insulin secretion
Collapse
Affiliation(s)
- Terry C Yin
- Department of Molecular Physiology and Biophysics, Fraternal Order of Eagle Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA
| | - Casey J Bauchle
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Fraternal Order of Eagle Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA
| | - Alix A J Rouault
- Department of Molecular Physiology and Biophysics, Fraternal Order of Eagle Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA
| | - Samuel B Stephens
- Department of Internal Medicine, Division of Endocrinology and Metabolism, Fraternal Order of Eagle Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA
| | - Julien A Sebag
- Department of Molecular Physiology and Biophysics, Fraternal Order of Eagle Diabetes Research Center, Pappajohn Biomedical Institute, University of Iowa, Iowa City, IA 52242, USA.
| |
Collapse
|
|
25
|
|
|
26
|
Exploring G Protein-Coupled Receptor Signaling in Primary Pancreatic Islets. Biol Proced Online 2020; 22:4. [PMID: 32082084 PMCID: PMC7023723 DOI: 10.1186/s12575-019-0116-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 12/29/2019] [Indexed: 12/14/2022] Open
Abstract
Background Targeting G protein-coupled receptors (GPCRs) in pancreatic cells is feasible to modulate glucose-induced insulin secretion. Because pancreatic islets consist of several cell types and GPCRs can couple to more than one G-protein family, results obtained in pancreatic cell lines do not always match the response in primary cells or intact islets. Therefore, we set out to establish a protocol to analyze second messenger activation in mouse pancreatic islets. Results Activation of Gq/11-coupled receptor expressed in primary β cells increased the second messenger IP1 in an accumulation assay. Applying a Gq/11 protein inhibitor completely abolished this signal. Activation of the V1 vasopressin and ghrelin receptors, predominantly expressed in the less abundant alpha and delta cells, was not sufficient to induce a significant IP1 increase in this assay. However, fura-2-based fluorescence imaging showed calcium signals upon application of arginine vasopressin or ghrelin within intact pancreatic islets. Using the here established protocol we were also able to determine changes in intracellular cAMP levels induced by receptors coupling to Gs and Gi/o proteins. Conclusions Detection of the second messengers IP1, cAMP, and calcium, can be used to reliably analyze GPCR activation in intact islets.
Collapse
|
|
27
|
Noguchi GM, Huising MO. Integrating the inputs that shape pancreatic islet hormone release. Nat Metab 2019; 1:1189-1201. [PMID: 32694675 PMCID: PMC7378277 DOI: 10.1038/s42255-019-0148-2] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 11/07/2019] [Indexed: 02/06/2023]
Abstract
The pancreatic islet is a complex mini organ composed of a variety of endocrine cells and their support cells, which together tightly control blood glucose homeostasis. Changes in glucose concentration are commonly regarded as the chief signal controlling insulin-secreting beta cells, glucagon-secreting alpha cells and somatostatin-secreting delta cells. However, each of these cell types is highly responsive to a multitude of endocrine, paracrine, nutritional and neural inputs, which collectively shape the final endocrine output of the islet. Here, we review the principal inputs for each islet-cell type and the physiological circumstances in which these signals arise, through the prism of the insights generated by the transcriptomes of each of the major endocrine-cell types. A comprehensive integration of the factors that influence blood glucose homeostasis is essential to successfully improve therapeutic strategies for better diabetes management.
Collapse
Affiliation(s)
- Glyn M Noguchi
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA
| | - Mark O Huising
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California, Davis, Davis, CA, USA.
- Department of Physiology & Membrane Biology, School of Medicine, University of California, Davis, Davis, CA, USA.
| |
Collapse
|
|
28
|
Murai N, Saito N, Kodama E, Iida T, Mikura K, Imai H, Kaji M, Hashizume M, Kigawa Y, Koizumi G, Tadokoro R, Sugisawa C, Endo K, Iizaka T, Saiki R, Otsuka F, Shun I, Nagasaka S. Association of ghrelin dynamics with beta cell function in Japanese subjects with normal glucose tolerance. Clin Endocrinol (Oxf) 2019; 91:616-623. [PMID: 31408197 DOI: 10.1111/cen.14073] [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] [Received: 07/12/2019] [Revised: 08/02/2019] [Accepted: 08/12/2019] [Indexed: 01/06/2023]
Abstract
BACKGROUND Ghrelin is involved in feeding regulation and energy metabolism and is also known to inhibit insulin secretion (β). However, few clinical studies have demonstrated the relationship between β and ghrelin dynamics. This study tested the hypothesis that, in oral glucose tolerance tests (OGTT), ghrelin dynamics are associated with β. METHODS Subjects were 1145 healthy individuals <40 years old who tested normal on the 75-g OGTT. The following indicators and the ghrelin suppression ratio (GSR) during OGTT were calculated: insulin sensitivity (SI) [1/homoeostasis model assessment of insulin resistance, insulin sensitivity index-Matsuda and 1/fasting insulin (1/FIRI)]; and β [Stumvoll first-phase index (Stumvoll-1), Stumvoll second-phase index and insulinogenic index]. From nine combinations of SI and β, combinations that produce hyperbolic relationships were identified. RESULTS Stumvoll-1 and 1/FIRI showed a hyperbolic relationship in nonobese subjects, and the product of Stumvoll-1 and 1/FIRI was used as the disposition index (DI). When analyzed by BMI quartiles, post-loading glucose and insulin levels at each time point increased from Q1 (low BMI) through Q4 (high BMI), whereas the DI, ghrelin levels at each time point, and GSR decreased from Q1 to Q4. On multivariate and bivariate analysis, GSR and DI were positive and independent, and fasting ghrelin and FIRI were negatively and independently correlated. CONCLUSIONS Ghrelin dynamics were associated with beta cell function in subjects with normal glucose tolerance. Glucose intolerance in obesity may be due not only to insulin resistance but also to impaired beta cell function associated with abnormalities of ghrelin dynamics.
Collapse
Affiliation(s)
- Norimitsu Murai
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Naoko Saito
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Eriko Kodama
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Tatsuya Iida
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Kentaro Mikura
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Hideyuki Imai
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Mariko Kaji
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Mai Hashizume
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Yasuyoshi Kigawa
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Go Koizumi
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Rie Tadokoro
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Chiho Sugisawa
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Kei Endo
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Toru Iizaka
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Ryo Saiki
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Fumiko Otsuka
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
| | - Ishibashi Shun
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| | - Shoichiro Nagasaka
- Division of Diabetes, Metabolism and Endocrinology, Showa University Fujigaoka Hospital, Yokohama, Japan
- Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Japan
| |
Collapse
|
|
29
|
Faim F, Passaglia P, Batalhao M, Lacchini R, Stabile AM, Carnio EC. Role of ghrelin on growth hormone/insulin-like growth factor-1 axis during endotoxemia. Growth Horm IGF Res 2019; 48-49:36-44. [PMID: 31494533 DOI: 10.1016/j.ghir.2019.08.004] [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] [Received: 05/30/2019] [Revised: 08/26/2019] [Accepted: 08/29/2019] [Indexed: 01/10/2023]
Abstract
OBJECTIVE To investigate the anti-inflammatory property of ghrelin treatment on the Growth Hormone (GH)/Insulin-like Growth Factor-I (IGF-1) axis in Wistar rats that have undergone endotoxemia. DESIGN In this randomized animal study, lipopolysaccharide (LPS) (5 mg/kg; intraperitoneal) was administered to induce endotoxemia, and ghrelin (15 nmol/kg; endovenous) was injected simultaneously. Blood and liver samples were collected 2 h, 6 h and 12 h after LPS administration for analysis. MEASUREMENTS Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, beta (IL-1β), and IL-6 from both blood and liver were determined by ELISA assay. Serum nitrate was determined by chemiluminescense. Growth hormone receptor (GHR) and growth hormone secretagogue receptor 1a (GHSR-1a) were determined by western blotting. GHR mRNA and IGF-1 mRNA were determined by RT-PCR. RESULTS LPS administration induced a decrease in IGF-1 and GH serum levels, characterizing GH/IGF-1 axis disruption. Ghrelin treatment attenuated the decrease of serum levels of IGF-1 as well as the increase of TNF-α, IL-1β, IL-6 and nitrate induced by LPS. The increase of induced GHSR-1a protein expression seen in the LPS group after 2 h remained until 6 h after ghrelin treatment. However, attenuation of the circulating IGF-1 decrease by ghrelin treatment was not accompanied by changes in GHR protein expression nor GHR and IGF-1 gene expression. CONCLUSION Ghrelin was able to attenuate changes in the GH/IGF-1 axis observed during systemic inflammation, which may be due to the modulation of pro-inflammatory mediators release.
Collapse
Affiliation(s)
- Felipe Faim
- Department of Physiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Patricia Passaglia
- Department of Physiology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
| | - Marcelo Batalhao
- Department of General and Specialized Nursing, Nursing School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
| | - Riccardo Lacchini
- Department of Psychiatry and Human Science, Nursing School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
| | - Angelita Maria Stabile
- Department of General and Specialized Nursing, Nursing School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
| | - Evelin Capellari Carnio
- Department of General and Specialized Nursing, Nursing School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
| |
Collapse
|
|
30
|
Gray SM, Niu J, Zhang A, Svendsen B, Campbell JE, D'Alessio DA, Tong J. Intraislet Ghrelin Signaling Does Not Regulate Insulin Secretion From Adult Mice. Diabetes 2019; 68:1795-1805. [PMID: 31201280 PMCID: PMC6702634 DOI: 10.2337/db19-0079] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 06/06/2019] [Indexed: 01/08/2023]
Abstract
Exogenous ghrelin reduces glucose-stimulated insulin secretion and endogenous ghrelin protects against hypoglycemia during starvation. Islet ε-cells produce ghrelin and δ-cells express growth hormone secretagogue receptor (GHSR), suggesting the possibility of a paracrine mechanism for islet ghrelin to reach high local concentrations and affect insulin secretion. GHSR has high constitutive activity and may act independently of ghrelin. The objective in this study was to determine whether an intraislet ghrelin-GHSR axis modulates insulin secretion and glucose metabolism using mouse models lacking ghrelin (Ghrl-/- ) or GHSR (Ghsr-/- ). Ghsr-/- and Ghsr+/+ mice had comparable islet ghrelin concentrations. Exogenous ghrelin decreased insulin secretion in perifused isolated islets in a GHSR-dependent manner. Islets isolated from Ghrl-/- or Ghsr-/- mice did not differ from controls in glucose-, alanine-, or GLP-1-stimulated insulin secretion during perifusion. Consistent with this finding, Ghrl-/- and Ghsr-/- male mice studied after either 6 or 16 h of fasting had blood glucose concentrations comparable with those of controls following intraperitoneal glucose, or insulin tolerance tests, or after mixed nutrient meals. Collectively, our data provide strong evidence against a paracrine ghrelin-GHSR axis mediating insulin secretion or glucose tolerance in lean, chow-fed adult mice.
Collapse
Affiliation(s)
| | | | | | | | - Jonathan E Campbell
- Duke Molecular Physiology Institute, Durham, NC
- Department of Pharmacology and Cancer Biology, Duke University, Durham, NC
| | - David A D'Alessio
- Duke Molecular Physiology Institute, Durham, NC
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
| | - Jenny Tong
- Duke Molecular Physiology Institute, Durham, NC
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC
| |
Collapse
|
|
31
|
Gray SM, Page LC, Tong J. Ghrelin regulation of glucose metabolism. J Neuroendocrinol 2019; 31:e12705. [PMID: 30849212 PMCID: PMC6688917 DOI: 10.1111/jne.12705] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 03/04/2019] [Accepted: 03/05/2019] [Indexed: 12/14/2022]
Abstract
Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are implicated in the regulation of glucose metabolism via direct actions in the pancreatic islet, as well as peripheral insulin-sensitive tissues and the brain. Although many studies have explored the role of ghrelin in glucose tolerance and insulin secretion, a complete mechanistic understanding remains to be clarified. This review highlights the local expression and function of ghrelin and GHSR1a in pancreatic islets and how this axis may modulate insulin secretion from pancreatic β-cells. Additionally, we discuss the effect of ghrelin on in vivo glucose metabolism in rodents and humans, as well as the metabolic circumstances under which the action of ghrelin may predominate.
Collapse
Affiliation(s)
- Sarah. M. Gray
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27701
| | - Laura C. Page
- Division of Endocrinology, Department of Pediatrics, Duke University, Durham, NC 27701
| | - Jenny Tong
- Duke Molecular Physiology Institute, Duke University, Durham, NC 27701
- Division of Endocrinology, Department of Pediatrics, Duke University, Durham, NC 27701
- Division of Endocrinology, Metabolism, and Nutrition, Department of Medicine, Duke University, Durham, NC 27701
| |
Collapse
|
|
32
|
Abstract
The peptide ghrelin is mainly produced in some of the epithelial cells in the stomach, but also, during starvation, by the ε-cells in the endocrine pancreas. Ghrelin, as an endogenous ligand for the growth hormone secretagogue receptor (GHS-R1α), exerts a variety of metabolic functions including stimulation of appetite and weight gain. Its complete role is not yet fully understood, including whether it has any vascular functions. The present study evaluated if ghrelin affects pancreatic and islet blood flow. Ghrelin and the GHS-R1α receptor antagonist GHRP-6 were injected intravenously in rats followed by blood flow measurements using a microsphere technique. Ghrelin decreased, while GHRP-6 in fasted, but not fed, rats selectively increased islet blood flow fourfold. GHS-R1α was identified not only on glucagon-producing cells but also seemed to be present in the islet arterioles. GHRP-6 in fasted rats, only, also improved the peak insulin response to glucose in vivo, thereby substantially blunting the hyperglycemia. GHRP-6 doubled glucose-stimulated insulin release in vitro of both islets obtained from fed and fasted rats. Our results indicate a novel role for endogenous ghrelin acting directly or indirectly as a local vasoconstrictor in the islets during fasting, thereby restricting the insulin response to hyperglycemia. This is to the best of our knowledge the first report that shows this physiological mechanism to restrict insulin delivery from the islets by acting on the vasculature; a mode of action that can be envisaged to complement the previously well-described mechanisms of ghrelin acting directly on the islet endocrine cells.
Collapse
Affiliation(s)
- Carl Johan Drott
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
| | - Petra Franzén
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
| | - Per-Ola Carlsson
- Department of Medical Cell Biology, Uppsala University , Uppsala , Sweden
- Department of Medical Sciences, Uppsala University , Uppsala , Sweden
| |
Collapse
|
|
33
|
Mani BK, Shankar K, Zigman JM. Ghrelin's Relationship to Blood Glucose. Endocrinology 2019; 160:1247-1261. [PMID: 30874792 PMCID: PMC6482034 DOI: 10.1210/en.2019-00074] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2019] [Accepted: 03/09/2019] [Indexed: 12/16/2022]
Abstract
Much effort has been directed at studying the orexigenic actions of administered ghrelin and the potential effects of the endogenous ghrelin system on food intake, food reward, body weight, adiposity, and energy expenditure. Although endogenous ghrelin's actions on some of these processes remain ambiguous, its glucoregulatory actions have emerged as well-recognized features during extreme metabolic conditions. The blood glucose-raising actions of ghrelin are beneficial during starvation-like conditions, defending against life-threatening falls in blood glucose, but they are seemingly detrimental in obese states and in certain monogenic forms of diabetes, contributing to hyperglycemia. Also of interest, blood glucose negatively regulates ghrelin secretion. This article reviews the literature suggesting the existence of a blood glucose-ghrelin axis and highlights the factors that mediate the glucoregulatory actions of ghrelin, especially during metabolic extremes such as starvation and diabetes.
Collapse
Affiliation(s)
- Bharath K Mani
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Kripa Shankar
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeffrey M Zigman
- Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
- Correspondence: Jeffrey M. Zigman, MD, PhD, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390. E-mail:
| |
Collapse
|
|
34
|
El Zein N, Abdallah MS, Daher CF, Mroueh M, Stephan J, Bahous SA, Eid A, Faour WH. Ghrelin modulates intracellular signalling pathways that are critical for podocyte survival. Cell Biochem Funct 2019; 37:245-255. [DOI: 10.1002/cbf.3397] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2018] [Accepted: 04/01/2019] [Indexed: 11/08/2022]
Affiliation(s)
| | - Maya S. Abdallah
- Gilbert and Rose‐Marie Chagoury, School of MedicineLebanese American University Byblos Lebanon
- Institut Européen des MembranesUniversité de Montpellier Montpellier France
| | - Costantine F. Daher
- School of Arts and Sciences, Natural Sciences DepartmentLebanese American University Byblos Lebanon
| | - Mohammad Mroueh
- Department of Pharmaceutical Sciences, School of PharmacyLebanese American University Byblos Lebanon
| | - Joseph Stephan
- Gilbert and Rose‐Marie Chagoury, School of MedicineLebanese American University Byblos Lebanon
| | - Sola Aoun Bahous
- Gilbert and Rose‐Marie Chagoury, School of MedicineLebanese American University Byblos Lebanon
| | - Assaad Eid
- Department of Anatomy, Cell Biology and Physiology, Faculty of MedicineAmerican University of Beirut Beirut Lebanon
| | - Wissam H. Faour
- Gilbert and Rose‐Marie Chagoury, School of MedicineLebanese American University Byblos Lebanon
| |
Collapse
|
|
35
|
Rasineni K, Thomes PG, Kubik JL, Harris EN, Kharbanda KK, Casey CA. Chronic alcohol exposure alters circulating insulin and ghrelin levels: role of ghrelin in hepatic steatosis. Am J Physiol Gastrointest Liver Physiol 2019; 316:G453-G461. [PMID: 30702902 PMCID: PMC6483023 DOI: 10.1152/ajpgi.00334.2018] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Fatty liver is the earliest response of the liver to excessive ethanol consumption. Central in the development of alcoholic steatosis is increased mobilization of nonesterified free fatty acids (NEFAs) to the liver from the adipose tissue. In this study, we hypothesized that ethanol-induced increase in ghrelin by impairing insulin secretion, could be responsible for the altered lipid metabolism observed in adipose and liver tissue. Male Wistar rats were fed for 5-8 wk with control or ethanol Lieber-DeCarli diet, followed by biochemical analyses in serum and liver tissues. In addition, in vitro studies were conducted on pancreatic islets isolated from experimental rats. We found that ethanol increased serum ghrelin and decreased serum insulin levels in both fed and fasting conditions. These results were corroborated by our observations of a significant accumulation of insulin in pancreatic islets of ethanol-fed rats, indicating that its secretion was impaired. Furthermore, ethanol-induced reduction in circulating insulin was associated with lower adipose weight and increased NEFA levels observed in these rats. Additionally, we found that increased concentration of serum ghrelin was due to increased synthesis and maturation in the stomach of the ethanol-fed rats. We also report that in addition to its effect on the pancreas, ghrelin can also directly act on hepatocytes via the ghrelin receptors and promote fat accumulation. In conclusion, alcohol-induced elevation of circulating ghrelin levels impairs insulin secretion. Consequently, reduced circulating insulin levels likely contribute to increased free fatty acid mobilization from adipose tissue to liver, thereby contributing to hepatic steatosis. NEW & NOTEWORTHY Our studies are the first to report that ethanol-induced increases in ghrelin contribute to impaired insulin secretion, which results in the altered lipid metabolism observed in adipose and liver tissue in the setting of alcoholic fatty liver disease.
Collapse
Affiliation(s)
- Karuna Rasineni
- 1Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,2Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Paul G. Thomes
- 1Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,2Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Jacy L. Kubik
- 1Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,2Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Edward N. Harris
- 3Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, Nebraska
| | - Kusum K. Kharbanda
- 1Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,2Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| | - Carol A. Casey
- 1Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska,2Research Service, Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska
| |
Collapse
|
|
36
|
Stempniewicz A, Ceranowicz P, Warzecha Z. Potential Therapeutic Effects of Gut Hormones, Ghrelin and Obestatin in Oral Mucositis. Int J Mol Sci 2019; 20:ijms20071534. [PMID: 30934722 PMCID: PMC6479885 DOI: 10.3390/ijms20071534] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/15/2019] [Accepted: 03/19/2019] [Indexed: 12/16/2022] Open
Abstract
Chemotherapy and/or head and neck radiotherapy are frequently associated with oral mucositis. Oral pain, odynophagia and dysphagia, opioid use, weight loss, dehydration, systemic infection, hospitalization and introduction of a feeding tube should be mentioned as the main determinated effect of oral mucositis. Oral mucositis leads to a decreased quality of life and an increase in treatment costs. Moreover, oral mucositis is a life-threatening disease. In addition to its own direct life-threatening consequences, it can also lead to a reduced survival due to the discontinuation or dose reduction of anti-neoplasm therapy. There are numerous strategies for the prevention or treatment of oral mucositis; however, their effectiveness is limited and does not correspond to expectations. This review is focused on the ghrelin and obestatin as potentially useful candidates for the prevention and treatment of chemo- or/and radiotherapy-induced oral mucositis.
Collapse
Affiliation(s)
- Agnieszka Stempniewicz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Grzegórzecka 16 St., 31-531 Krakow, Poland.
| | - Piotr Ceranowicz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Grzegórzecka 16 St., 31-531 Krakow, Poland.
| | - Zygmunt Warzecha
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Grzegórzecka 16 St., 31-531 Krakow, Poland.
| |
Collapse
|
|
37
|
Taira A, Arita E, Matsumoto E, Oohira A, Iwase K, Hiwasa T, Yokote K, Shibata S, Takiguchi M. Systemic oscillator-driven and nutrient-responsive hormonal regulation of daily expression rhythms for gluconeogenic enzyme genes in the mouse liver. Chronobiol Int 2019; 36:591-615. [PMID: 30714432 DOI: 10.1080/07420528.2019.1570246] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
Gluconeogenesis is de novo glucose synthesis from substrates such as amino acids and is vital when glucose is lacking in the diurnal nutritional fluctuation. Accordingly, genes for hepatic gluconeogenic enzymes exhibit daily expression rhythms, whose detailed regulations under nutritional variations remain elusive. As a first step, we performed general systematic characterization of daily expression profiles of gluconeogenic enzyme genes for phosphoenolpyruvate carboxykinase (PEPCK), cytosolic form (Pck1), glucose-6-phosphatase (G6Pase), catalytic subunit (G6pc), and tyrosine aminotransferase (TAT) (Tat) in the mouse liver. On a standard diet fed ad libitum, mRNA levels of these genes showed robust daily rhythms with a peak or an elevation phase during the late sleep-fasting period in the diurnal feeding/fasting (wake/sleep) cycle. The rhythmicity was preserved in constant darkness, modulated with prolonged fasting, attenuated by Clock mutation, and entrained to varied photoperiods and time-restricted feedings. These results are concordant with the notion that gluconeogenic enzyme genes are under the control of the intrinsic circadian oscillator, which is entrained by the light/dark cycle, and which in turn entrains the feeding/fasting cycle and also drives systemic signaling pathways such as the hypothalamic-pituitary-adrenal axis. On the other hand, time-restricted feedings also showed that the ingestion schedule, when separated from the light/dark cycle, can serve as an independent entrainer to daily expression rhythms of gluconeogenic enzyme genes. Moreover, nutritional changes dramatically modified expression profiles of the genes. In addition to prolonged fasting, a high-fat diet and a high-carbohydrate (no-protein) diet caused modification of daily expression rhythms of the genes, with characteristic changes in profiles of glucoregulatory hormones such as corticosterone, glucagon, and insulin, as well as their modulators including ghrelin, leptin, resistin, glucose-dependent insulinotropic polypeptide (GIP), and glucagon-like peptide-1 (GLP-1). Remarkably, high-protein (60% casein or soy-protein) diets activated the gluconeogenic enzyme genes atypically during the wake-feeding period, with paradoxical up-regulation of glucagon, which frequently formed correlation networks with other humoral factors. Based on these results, we propose that daily expression rhythms of gluconeogenic enzyme genes are under the control of systemic oscillator-driven and nutrient-responsive hormones.
Collapse
Affiliation(s)
- Akiko Taira
- a Department of Biochemistry and Genetics , Chiba University Graduate School of Medicine , Chiba , Japan.,b Department of Endocrinology, Hematology, and Gerontology , Chiba University Graduate School of Medicine , Chiba , Japan
| | - Emiko Arita
- a Department of Biochemistry and Genetics , Chiba University Graduate School of Medicine , Chiba , Japan
| | - Eriko Matsumoto
- a Department of Biochemistry and Genetics , Chiba University Graduate School of Medicine , Chiba , Japan
| | - Ayano Oohira
- a Department of Biochemistry and Genetics , Chiba University Graduate School of Medicine , Chiba , Japan
| | - Katsuro Iwase
- a Department of Biochemistry and Genetics , Chiba University Graduate School of Medicine , Chiba , Japan
| | - Takaki Hiwasa
- a Department of Biochemistry and Genetics , Chiba University Graduate School of Medicine , Chiba , Japan
| | - Koutaro Yokote
- b Department of Endocrinology, Hematology, and Gerontology , Chiba University Graduate School of Medicine , Chiba , Japan
| | - Shigenobu Shibata
- c Department of Pharmacology , School of Science and Engineering, Waseda University , Shinjuku , Tokyo , Japan
| | - Masaki Takiguchi
- a Department of Biochemistry and Genetics , Chiba University Graduate School of Medicine , Chiba , Japan
| |
Collapse
|
|
38
|
Ghrelin octanoylation by ghrelin O-acyltransferase: Unique protein biochemistry underlying metabolic signaling. Biochem Soc Trans 2019; 47:169-178. [PMID: 30626708 DOI: 10.1042/bst20180436] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/26/2018] [Accepted: 11/28/2018] [Indexed: 02/08/2023]
Abstract
Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Ghrelin signaling is implicated in a variety of neurological and physiological processes, but is most well known for its roles in controlling hunger and metabolic regulation. Ghrelin octanoylation is catalyzed by ghrelin O-acyltransferase (GOAT), a member of the membrane-bound O-acyltransferase (MBOAT) enzyme family. From the status of ghrelin as the only substrate for GOAT in the human genome to the source and requirement for the octanoyl acyl donor, the ghrelin-GOAT system is defined by multiple unique aspects within both protein biochemistry and endocrinology. In this review, we examine recent advances in our understanding of the interactions and mechanisms leading to ghrelin modification by GOAT, discuss the potential sources for the octanoyl acyl donor required for ghrelin's activation, and summarize the current landscape of molecules targeting ghrelin octanoylation through GOAT inhibition.
Collapse
|
|
39
|
Dominguez Gutierrez G, Kim J, Lee AH, Tong J, Niu J, Gray SM, Wei Y, Ding Y, Ni M, Adler C, Murphy AJ, Gromada J, Xin Y. Gene Signature of the Human Pancreatic ε Cell. Endocrinology 2018; 159:4023-4032. [PMID: 30380031 PMCID: PMC6963699 DOI: 10.1210/en.2018-00833] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 10/17/2018] [Indexed: 12/31/2022]
Abstract
The ghrelin-producing ε cell represents the fifth endocrine cell type in human pancreatic islets. The abundance of ε cells in adult pancreas is extremely low, which has hampered the investigation on the molecular pathways regulating the development and the function of this cell type. In this study, we explored the molecular features defining the function of pancreatic ε cells isolated from adult nondiabetic donors using single-cell RNA sequencing technology. We focus on transcription factors, cell surface receptors, and genes involved in metabolic pathways that contribute to regulation of cellular function. Furthermore, the genes that separate ε cells from the other islet endocrine cell types are presented. This study expands prior knowledge about the genes important for ε cell functioning during development and provides a resource to interrogate the transcriptome of this rare human islet cell type.
Collapse
Affiliation(s)
| | - Jinrang Kim
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Ann-Hwee Lee
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Jenny Tong
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - JingJing Niu
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Sarah M Gray
- Division of Endocrinology, Metabolism and Nutrition, Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Yi Wei
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Yueming Ding
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | - Min Ni
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| | | | | | | | - Yurong Xin
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York
| |
Collapse
|
|
40
|
Huising MO, van der Meulen T, Huang JL, Pourhosseinzadeh MS, Noguchi GM. The Difference δ-Cells Make in Glucose Control. Physiology (Bethesda) 2018; 33:403-411. [PMID: 30303773 PMCID: PMC6347098 DOI: 10.1152/physiol.00029.2018] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2018] [Revised: 08/13/2018] [Accepted: 08/13/2018] [Indexed: 12/17/2022] Open
Abstract
The role of beta and α-cells to glucose control are established, but the physiological role of δ-cells is poorly understood. Delta-cells are ideally positioned within pancreatic islets to modulate insulin and glucagon secretion at their source. We review the evidence for a negative feedback loop between delta and β-cells that determines the blood glucose set point and suggest that local δ-cell-mediated feedback stabilizes glycemic control.
Collapse
Affiliation(s)
- Mark O Huising
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California , Davis, California
- Department of Physiology and Membrane Biology, School of Medicine, University of California , Davis, California
| | - Talitha van der Meulen
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California , Davis, California
| | - Jessica L Huang
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California , Davis, California
| | - Mohammad S Pourhosseinzadeh
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California , Davis, California
| | - Glyn M Noguchi
- Department of Neurobiology, Physiology & Behavior, College of Biological Sciences, University of California , Davis, California
| |
Collapse
|
|
41
|
Emerging Role of Adipocytokines in Type 2 Diabetes as Mediators of Insulin Resistance and Cardiovascular Disease. Can J Diabetes 2018; 42:446-456.e1. [PMID: 29229313 DOI: 10.1016/j.jcjd.2017.10.040] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Revised: 10/06/2017] [Accepted: 10/06/2017] [Indexed: 12/13/2022]
|
|
42
|
Abstract
Ghrelin, a gastric-derived acylated peptide, regulates energy homeostasis by transmitting information about peripheral nutritional status to the brain, and is essential for protecting organisms against famine. Ghrelin operates brain circuits to regulate homeostatic and hedonic feeding. Recent research advances have shed new light on ghrelin's multifaceted roles in cellular homeostasis, which could maintain the internal environment and overcome metaflammation in metabolic organs. Here, we highlight our current understanding of the regulatory mechanisms of the ghrelin system in energy metabolism and cellular homeostasis and its clinical trials. Future studies of ghrelin will further elucidate how the stomach regulates systemic homeostasis.
Collapse
Affiliation(s)
- Shigehisa Yanagi
- Divisions of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan
| | - Takahiro Sato
- Molecular Genetics, Institute of Life Science, Kurume University, Kurume 839-0864, Japan
| | - Kenji Kangawa
- Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan
| | - Masamitsu Nakazato
- Divisions of Neurology, Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Kiyotake, Miyazaki 889-1692, Japan; AMED-CREST, Japan Agency for Medical Research and Development, Chiyoda-ku, Tokyo 100-0004, Japan.
| |
Collapse
|
|
43
|
Abstract
Islets of Langerhans are islands of endocrine cells scattered throughout the pancreas. A number of new studies have pointed to the potential for conversion of non-β islet cells in to insulin-producing β-cells to replenish β-cell mass as a means to treat diabetes. Understanding normal islet cell mass and function is important to help advance such treatment modalities: what should be the target islet/β-cell mass, does islet architecture matter to energy homeostasis, and what may happen if we lose a particular population of islet cells in favour of β-cells? These are all questions to which we will need answers for islet replacement therapy by transdifferentiation of non-β islet cells to be a reality in humans. We know a fair amount about the biology of β-cells but not quite as much about the other islet cell types. Until recently, we have not had a good grasp of islet mass and distribution in the human pancreas. In this review, we will look at current data on islet cells, focussing more on non-β cells, and on human pancreatic islet mass and distribution.
Collapse
Affiliation(s)
- Gabriela Da Silva Xavier
- Section of Functional Genomics and Cell Biology, Department of Medicine, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK.
- Institute of Metabolism and Systems Research (IMSR), University of Birmingham, Edgbaston B15 2TT, UK.
| |
Collapse
|
|
44
|
Rhodes L, Zollers B, Wofford JA, Heinen E. Capromorelin: a ghrelin receptor agonist and novel therapy for stimulation of appetite in dogs. Vet Med Sci 2018; 4:3-16. [PMID: 29468076 PMCID: PMC5813110 DOI: 10.1002/vms3.83] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Ghrelin is a hormone, secreted from cells in the stomach, which is important in the regulation of appetite and food intake in mammals. It exerts its action by binding to a specific G-protein-coupled receptor, the growth hormone secretagogue receptor 1a (GHS-R1a) which is found in areas of the brain associated with the regulation of food intake. Ghrelin causes a release of growth hormone (GH) through binding to GHS-R1a in the hypothalamus and pituitary gland. A class of compounds known as growth hormone secretagogues, or ghrelin receptor agonists, were developed for therapeutic use in humans for the stimulation of GH in the frail elderly, and have subsequently been studied for their effects on increasing appetite and food intake, increasing body weight, building lean muscle mass, and treating cachexia. Subsequent research has shown that ghrelin has anti-inflammatory and immunomodulatory effects. This article reviews the basic physiology of ghrelin and the ghrelin receptor agonists, including the available evidence of these effects in vitro and in vivo in rodent models, humans, dogs and cats. One of these compounds, capromorelin, has been FDA-approved for the stimulation of appetite in dogs (ENTYCE ®). The data available on the safety and effectiveness of capromorelin is reviewed, along with a discussion of the potential clinical applications for ghrelin receptor agonists in both human and veterinary medicine.
Collapse
|
|
45
|
Poher AL, Tschöp MH, Müller TD. Ghrelin regulation of glucose metabolism. Peptides 2018; 100:236-242. [PMID: 29412824 PMCID: PMC5805851 DOI: 10.1016/j.peptides.2017.12.015] [Citation(s) in RCA: 99] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/15/2017] [Accepted: 12/16/2017] [Indexed: 02/07/2023]
Abstract
The a 28-amino acid peptide ghrelin was discovered in 1999 as a growth hormone (GH) releasing peptide. Soon after its discovery, ghrelin was found to increase body weight and adiposity by acting on the hypothalamic melanocortinergic system. Subsequently, ghrelin was found to exert a series of metabolic effects, overall testifying ghrelin a pleiotropic nature of broad pharmacological interest. Ghrelin acts through the growth hormone secretagogue-receptor (GHS-R), a seven transmembrane G protein-coupled receptor with high expression in the anterior pituitary, pancreatic islets, thyroid gland, heart and various regions of the brain. Among ghrelins numerous metabolic effects are the most prominent the stimulation of appetite via activation of orexigenic hypothalamic neurocircuits and the food-intake independent stimulation of lipogenesis, which both together lead to an increase in body weight and adiposity. Ghrelin effects beyond the regulation of appetite and GH secretion include the regulation of gut motility, sleep-wake rhythm, taste sensation, reward seeking behaviour, and the regulation of glucose metabolism. The latter received recently increasing recognition because pharmacological inhibition of ghrelin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes. In this review we highlight the multifaceted nature of ghrelin and summarize its glucoregulatory action and discuss the pharmacological value of ghrelin pathway inhibition for the treatment of glucose intolerance and type 2 diabetes.
Collapse
Affiliation(s)
- Anne-Laure Poher
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany
| | - Matthias H Tschöp
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333, Munich, Germany
| | - Timo D Müller
- Institute for Diabetes and Obesity, Helmholtz Diabetes Center (HDC), Helmholtz Zentrum München and German National Diabetes Center (DZD), 85764, Neuherberg, Germany.
| |
Collapse
|
|
46
|
Sun EWL, Martin AM, Young RL, Keating DJ. The Regulation of Peripheral Metabolism by Gut-Derived Hormones. Front Endocrinol (Lausanne) 2018; 9:754. [PMID: 30662430 PMCID: PMC6328484 DOI: 10.3389/fendo.2018.00754] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Accepted: 11/27/2018] [Indexed: 12/13/2022] Open
Abstract
Enteroendocrine cells lining the gut epithelium constitute the largest endocrine organ in the body and secrete over 20 different hormones in response to cues from ingested foods and changes in nutritional status. Not only do these hormones convey signals from the gut to the brain via the gut-brain axis, they also act directly on metabolically important peripheral targets in a highly concerted fashion to maintain energy balance and glucose homeostasis. Gut-derived hormones released during fasting tend to be orexigenic and have hyperglycaemic potential. Conversely, gut hormones secreted postprandially generally promote satiety and facilitate glucose clearance. Although some of the metabolic benefits conferred by bariatric surgeries have been ascribed to changes in the secretory profiles of various gut hormones, the therapeutic potential of the enteroendocrine system as a viable target against metabolic diseases remain largely underexploited, except for incretin-mimetics. This review provides a brief overview of the physiological importance and highlights the therapeutic potential of the following gut hormones: serotonin, glucose-dependent insulinotropic peptide, glucagon-like peptide 1, oxyntomodulin, peptide YY, insulin-like peptide 5, and ghrelin.
Collapse
Affiliation(s)
- Emily W. L. Sun
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Alyce M. Martin
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
| | - Richard L. Young
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia
| | - Damien J. Keating
- College of Medicine and Public Health, Flinders University, Adelaide, SA, Australia
- Nutrition and Metabolism, South Australian Health and Medical Research Institute, Adelaide, SA, Australia
- *Correspondence: Damien J. Keating
| |
Collapse
|
|
47
|
Cleverdon ER, McGovern-Gooch KR, Hougland JL. The octanoylated energy regulating hormone ghrelin: An expanded view of ghrelin's biological interactions and avenues for controlling ghrelin signaling. Mol Membr Biol 2017; 33:111-124. [PMID: 29143554 DOI: 10.1080/09687688.2017.1388930] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Ghrelin is a small peptide hormone that requires a unique post-translational modification, serine octanoylation, to bind and activate the GHS-R1a receptor. Initially demonstrated to stimulate hunger and appetite, ghrelin-dependent signaling is implicated in a variety of neurological and physiological processes influencing diseases such as diabetes, obesity, and Prader-Willi syndrome. In addition to its cognate receptor, recent studies have revealed ghrelin interacts with a range of binding partners within the bloodstream. Defining the scope of ghrelin's interactions within the body, understanding how these interactions work in concert to modulate ghrelin signaling, and developing molecular tools for controlling ghrelin signaling are essential for exploiting ghrelin for therapeutic effect. In this review, we discuss recent findings regarding the biological effects of ghrelin signaling, outline binding partners that control ghrelin trafficking and stability in circulation, and summarize the current landscape of inhibitors targeting ghrelin octanoylation.
Collapse
Affiliation(s)
| | | | - James L Hougland
- a Department of Chemistry , Syracuse University , Syracuse , NY , USA
| |
Collapse
|
|
48
|
Sjögren M, Duarte AI, McCourt AC, Shcherbina L, Wierup N, Björkqvist M. Ghrelin rescues skeletal muscle catabolic profile in the R6/2 mouse model of Huntington's disease. Sci Rep 2017; 7:13896. [PMID: 29066728 PMCID: PMC5654969 DOI: 10.1038/s41598-017-13713-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Accepted: 09/27/2017] [Indexed: 12/14/2022] Open
Abstract
Accumulating evidence suggests altered energy metabolism as a key feature in Huntington’s disease (HD) pathology. Hyper-catabolism, including weight loss and muscle atrophy, is seen in HD patients and HD mouse models. Metabolic hormones are key players, not only in energy metabolism, but also in neurodegenerative processes. Ghrelin, a gut peptide-hormone, plays an important role in regulating energy metabolism, stimulating appetite, and affects brain function and increases neuronal survival. The R6/2 mouse model of HD has previously been shown to exhibit progressive weight loss, dysregulated glucose metabolism, skeletal muscle atrophy and altered body composition. In this study, we targeted energy metabolism in R6/2 mice using ghrelin administration, with the primary aim to delay weight loss and reduce muscle atrophy. We also evaluated glucose metabolism and behaviour. We here demonstrate that ghrelin administration (subcutaneous 150 μg/kg daily injections) for 4 weeks, reversed the catabolic gene expression profile (increased expression of Caspase 8, Traf-5 and Creb1) seen in R6/2 mouse skeletal muscle. Skeletal muscle morphology was also improved with ghrelin, and importantly, ghrelin administration normalized behavioural deficits in R6/2 mice. Taken together, our findings encourage further studies targeting metabolism in HD.
Collapse
Affiliation(s)
- Marie Sjögren
- Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Brain Disease Biomarker Unit, Lund University, Lund, Sweden.
| | - Ana I Duarte
- Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Brain Disease Biomarker Unit, Lund University, Lund, Sweden.,CNC - Center for Neuroscience and Cell Biology, Rua Larga, Faculty of Medicine (Pólo 1, 1st Floor), University of Coimbra, 3004-517, Coimbra, Portugal.,Institute for Interdisciplinary Research (IIIUC), University of Coimbra, Casa Costa Alemão - Pólo II, Rua D. Francisco de Lemos, 3030-789, Coimbra, Portugal
| | - Andrew C McCourt
- Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Brain Disease Biomarker Unit, Lund University, Lund, Sweden
| | - Liliya Shcherbina
- Lund University Diabetes Centre, Neuroendocrine Cell Biology, Department of Clinical Sciences in Malmö, Clinical research center, Lund University, Malmö, Sweden
| | - Nils Wierup
- Lund University Diabetes Centre, Neuroendocrine Cell Biology, Department of Clinical Sciences in Malmö, Clinical research center, Lund University, Malmö, Sweden
| | - Maria Björkqvist
- Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Brain Disease Biomarker Unit, Lund University, Lund, Sweden
| |
Collapse
|
|
49
|
Gao H, Ho E, Balakrishnan M, Yechoor V, Yallampalli C. Decreased insulin secretion in pregnant rats fed a low protein diet. Biol Reprod 2017; 97:627-635. [PMID: 29025046 PMCID: PMC9630396 DOI: 10.1093/biolre/iox100] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 07/28/2017] [Accepted: 08/24/2017] [Indexed: 12/07/2023] Open
Abstract
Low protein (LP) diet during pregnancy leads to reduced plasma insulin levels in rodents, but the underlying mechanisms remain unclear. Glucose is the primary insulin secretagogue, and enhanced glucose-stimulated insulin secretion (GSIS) in beta cells contributes to compensation for insulin resistance and maintenance of glucose homeostasis during pregnancy. In this study, we hypothesized that plasma insulin levels in pregnant rats fed LP diet are reduced due to disrupted GSIS of pancreatic islets. We first confirmed reduced plasma insulin levels, then investigated in vivo insulin secretion by glucose tolerance test and ex vivo GSIS of pancreatic islets in the presence of glucose at different doses, and KCl, glibenclamide, and L-arginine. Main findings include (1) plasma insulin levels were unaltered on day 10, but significantly reduced on days 14-22 of pregnancy in rats fed LP diet compared to those of control (CT) rats; (2) insulin sensitivity was unchanged, but glucose intolerance was more severe in pregnant rats fed LP diet; (3) GSIS in pancreatic islets was lower in LP rats compared to CT rats in the presence of glucose, KCl, and glibenclamide, and the response to L-arginine was abolished in LP rats; and (4) the total insulin content in pancreatic islets and expression of Ins2 were reduced in LP rats, but expression of Gcg was unaltered. These studies demonstrate that decreased GSIS in beta cells of LP rats contributes to reduced plasma insulin levels, which may lead to placental and fetal growth restriction and programs hypertension and other metabolic diseases in offspring.
Collapse
Affiliation(s)
- Haijun Gao
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Hospital, Houston, Texas, USA
| | - Eric Ho
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Hospital, Houston, Texas, USA
| | - Meena Balakrishnan
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Hospital, Houston, Texas, USA
| | - Vijay Yechoor
- Department of Medicine, Baylor College of Medicine, Houston, Texas, USA
| | - Chandra Yallampalli
- Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas, USA
- Texas Children's Hospital, Houston, Texas, USA
| |
Collapse
|
|
50
|
Santiago-Fernández C, García-Serrano S, Tome M, Valdes S, Ocaña-Wilhelmi L, Rodríguez-Cañete A, Tinahones FJ, García-Fuentes E, Garrido-Sánchez L. Ghrelin levels could be involved in the improvement of insulin resistance after bariatric surgery. ACTA ACUST UNITED AC 2017; 64:355-362. [PMID: 28745606 DOI: 10.1016/j.endinu.2017.05.002] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2017] [Revised: 05/04/2017] [Accepted: 05/11/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND OBJECTIVE Ghrelin is a gastrointestinal peptide involved in regulation of body weight and energy balance. However, its behavior after bariatric surgery and its relationship to insulin resistance are still controversial. A simultaneous assessment was made of the association between changes in ghrelin levels and different variables after three types of bariatric surgery. PATIENTS AND METHODS Ghrelin levels were measured in 103 morbidly obese subjects before and 6 months after bariatric surgery (Roux-en-Y gastric bypass (RYGB), biliopancreatic diversion of Scopinaro (BPD), and sleeve gastrectomy (SG)), and in 21 non-obese subjects. RESULTS Ghrelin levels increased after RYGB (p<0.05), were unchanged after BPD, and decreased after SG (p<0.05). The percent change in ghrelin levels (Δ-ghrelin) was associated to the type of surgery in a multiple linear regression model (p=0.017). When the same analysis was only performed in subjects in whom the gastric fundus was maintained (RYGB and BPD), Δ-ghrelin was negatively associated to Δ-HOMA-IR (p=0.001). In morbidly obese subjects who underwent RYGB and BPD, the odds ratio of a lower Δ-HOMA-IR in patients with Δ-ghrelin in the Q1 quartile versus those with Δ-ghrelin in the Q4 quartile was 8.74 (1.73-44.06) (p=0.009). CONCLUSIONS Changes in ghrelin levels after bariatric surgery are associated to the presence or absence of the gastric fundus. After bariatric surgery, the decrease in insulin resistance was associated to increased ghrelin levels in procedures in which the fundus is not excluded.
Collapse
Affiliation(s)
- Concepción Santiago-Fernández
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Spain
| | - Sara García-Serrano
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Málaga, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Malaga, Spain
| | - Mónica Tome
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Spain
| | - Sergio Valdes
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Málaga, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Malaga, Spain
| | - Luis Ocaña-Wilhelmi
- Unidad de Gestión Clínica de Cirugía General, Digestiva y Transplantes, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga, Spain
| | - Alberto Rodríguez-Cañete
- Unidad de Gestión Clínica de Cirugía General, Digestiva y Transplantes, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario, Málaga, Spain
| | - Francisco J Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Málaga, Spain.
| | - Eduardo García-Fuentes
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Málaga, Spain; Unidad de Gestión Clínica de Aparato Digestivo, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Málaga, Spain.
| | - Lourdes Garrido-Sánchez
- Unidad de Gestión Clínica de Endocrinología y Nutrición, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Virgen de la Victoria, Universidad de Málaga, Spain; CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Málaga, Spain
| |
Collapse
|