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Ma Y, Zhang H, Yan Q, Wang P, Guo W, Yu L. The antidiabetic effect of safflower yellow by regulating the GOAT/ghrelin/GHS-R1a/cAMP/TRPM2 pathway. Sci Rep 2025; 15:5037. [PMID: 39934157 PMCID: PMC11814266 DOI: 10.1038/s41598-025-87201-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 01/16/2025] [Indexed: 02/13/2025] Open
Abstract
Safflower yellow (SY), derived from Carthamus tinctorius L., is a valuable natural edible pigment that exhibits anti-type 2 diabetes mellitus (T2DM) efficacy; however, its mechanism of action is unclear, which hinders its effective use. In this study, we examined the impact of SY on glucose metabolism and insulin secretion both in vivo and in vitro and elucidated the possible underlying mechanism. First, molecular docking demonstrated a strong binding affinity between SY and ghrelin O-acyltransferase (GOAT) protein, which was validated by a cell heat transfer assay (CETSA) and drug affinity response target stability (DARTS) in MIN6 cells. In MIN6 cells, SY increased insulin secretion and showed time- and dose-dependent inhibition of GOAT expression and acyl ghrelin (AG) secretion without affecting the overall levels of ghrelin. Furthermore, ELISA revealed that SY enhanced high glucose (HG)-induced insulin secretion, and immunofluorescence revealed the co-localization of GOAT and ghrelin in MIN6 cells, which was suppressed by SY treatment. The mechanism analysis by Western blot demonstrated that SY downregulated the protein levels of GOAT and GHS-R1a in MIN6 cells while increasing HG-stimulated cAMP and activation of transient receptor potential melastatin 2 (TRPM2). In in vivo experiments, the intraperitoneal injection of SY significantly improved pathological damage to the pancreas, glucose tolerance, and insulin resistance in a mouse model of high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM in a dose-dependent manner. SY enhanced insulin secretion by inhibiting the GOAT/ghrelin system in vivo. In conclusion, we demonstrated that SY exhibits an observable protective effect on diabetes through the GOAT/ghrelin/GHS-R1a/cAMP/TRPM2 pathway. Our findings provide a basis for further investigation of the hypoglycemic mechanism of SY and its potential for further development and utilization.
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Affiliation(s)
- Yunxiao Ma
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Haifeng Zhang
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Qihui Yan
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Ping Wang
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China
| | - Weiying Guo
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China.
| | - Lu Yu
- Department of Endocrinology, Interventional Therapy, and Otolaryngology-Head and Neck Surgery of First Hospital of Jilin University, State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Key Laboratory for Zoonosis Research, Ministry of Education, Institute of Zoonosis, College of Veterinary Medicine, Jilin University, Changchun, 130000, China.
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Acosta-Rodríguez VA, Rijo-Ferreira F, van Rosmalen L, Izumo M, Park N, Joseph C, Hepler C, Thorne AK, Stubblefield J, Bass J, Green CB, Takahashi JS. Misaligned feeding uncouples daily rhythms within brown adipose tissue and between peripheral clocks. Cell Rep 2024; 43:114523. [PMID: 39046875 DOI: 10.1016/j.celrep.2024.114523] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 04/24/2024] [Accepted: 07/05/2024] [Indexed: 07/27/2024] Open
Abstract
Extended food consumption during the rest period perturbs the phase relationship between circadian clocks in the periphery and the brain, leading to adverse health effects. Beyond the liver, how metabolic organs respond to a timed hypocaloric diet is largely unexplored. We investigated how feeding schedules impacted circadian gene expression in epididymal white and brown adipose tissue (eWAT and BAT) compared to the liver and hypothalamus. We restricted food to either daytime or nighttime in C57BL/6J male mice, with or without caloric restriction. Unlike the liver and eWAT, rhythmic clock genes in the BAT remained insensitive to feeding time, similar to the hypothalamus. We uncovered an internal split within the BAT in response to conflicting environmental cues, displaying inverted oscillations on a subset of metabolic genes without modifying its local core circadian machinery. Integrating tissue-specific responses on circadian transcriptional networks with metabolic outcomes may help elucidate the mechanism underlying the health burden of eating at unusual times.
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Affiliation(s)
- Victoria A Acosta-Rodríguez
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
| | - Filipa Rijo-Ferreira
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; Berkeley Public Health, Molecular Cell Biology Department, University of California, Berkeley, Berkeley, CA, USA
| | - Laura van Rosmalen
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
| | - Mariko Izumo
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA
| | - Noheon Park
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA
| | - Chryshanthi Joseph
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA
| | - Chelsea Hepler
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Anneke K Thorne
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Jeremy Stubblefield
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; Benedictine College, Atchison, KS, USA
| | - Joseph Bass
- Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
| | - Carla B Green
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
| | - Joseph S Takahashi
- Department of Neuroscience, Peter O'Donnell Jr. Brain Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA; Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390-9111, USA.
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Han HW, Pradhan G, Villarreal D, Kim DM, Jain A, Gaharwar A, Tian Y, Guo S, Sun Y. GHSR Deletion in β-Cells of Male Mice: Ineffective in Obesity, but Effective in Protecting against Streptozotocin-Induced β-Cell Injury in Aging. Nutrients 2024; 16:1464. [PMID: 38794702 PMCID: PMC11123813 DOI: 10.3390/nu16101464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 05/09/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Insulin secretion from pancreatic β cells is a key pillar of glucose homeostasis, which is impaired under obesity and aging. Growth hormone secretagogue receptor (GHSR) is the receptor of nutrient-sensing hormone ghrelin. Previously, we showed that β-cell GHSR regulated glucose-stimulated insulin secretion (GSIS) in young mice. In the current study, we further investigated the effects of GHSR on insulin secretion in male mice under diet-induced obesity (DIO) and streptozotocin (STZ)-induced β-cell injury in aging. β-cell-specific-Ghsr-deficient (Ghsr-βKO) mice exhibited no glycemic phenotype under DIO but showed significantly improved ex vivo GSIS in aging. We also detected reduced insulin sensitivity and impaired insulin secretion during aging both in vivo and ex vivo. Accordingly, there were age-related alterations in expression of glucose transporter, insulin signaling pathway, and inflammatory genes. To further determine whether GHSR deficiency affected β-cell susceptibility to acute injury, young, middle-aged, and old Ghsr-βKO mice were subjected to STZ. We found that middle-aged and old Ghsr-βKO mice were protected from STZ-induced hyperglycemia and impaired insulin secretion, correlated with increased expression of insulin signaling regulators but decreased pro-inflammatory cytokines in pancreatic islets. Collectively, our findings indicate that β-cell GHSR has a major impact on insulin secretion in aging but not obesity, and GHSR deficiency protects against STZ-induced β-cell injury in aging.
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Affiliation(s)
- Hye Won Han
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.W.H.)
| | - Geetali Pradhan
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Daniel Villarreal
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.W.H.)
| | - Da Mi Kim
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.W.H.)
| | - Abhishek Jain
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Akhilesh Gaharwar
- Department of Biomedical Engineering, College of Engineering, Texas A&M University, College Station, TX 77843, USA
| | - Yanan Tian
- Department of Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Shaodong Guo
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.W.H.)
| | - Yuxiang Sun
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (H.W.H.)
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA
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Elibol E, Akdevelioğlu Y, Yılmaz C, Narlı B, Şen S, Take Kaplanoğlu G, Seymen CM. Acyl ghrelin, desacyl ghrelin and their ratio affect hepatic steatosis via PPARγ signaling pathway. Arab J Gastroenterol 2024; 25:109-117. [PMID: 38383264 DOI: 10.1016/j.ajg.2023.12.007] [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: 12/31/2021] [Revised: 09/11/2023] [Accepted: 12/30/2023] [Indexed: 02/23/2024]
Abstract
BACKGROUND AND STUDY AIMS Ghrelin is an appetite hormone-containing 28-amino acid and has 4 different forms in the body. Ghrelin forms have different physiological functions in the body. This study aims to analyze the effect of acyl and desacyl ghrelin hormone on hepatic steatosis and biochemical findings in 36 male Wistar rats. MATERIALS AND METHODS Rats were split into 6 equal groups, consisting of control, acyl ghrelin, desacyl ghrelin, acyl/desacyl 3:1, acyl/desacyl 1:1, and acyl/desacyl 1:3 groups, and administered placebo or 200 ng/kg hormone subcutaneous twice a day for 14 days. Oral Glucose Tolerance Test (OGTT) was performed on Day 15, Insulin Tolerance Test (ITT) on Day 16, and scarification procedure on Day 17. Certain biochemical data and liver diacylglycerol (DAG), glycogen, protein kinase C and PPAR-γ levels were detected in the blood. Histological analyses were also conducted on the liver tissues. RESULTS The highest plasma total cholesterol and VLDL-K levels were found in the acyl/desacyl 1:3 group, and lower insulin, and HOMA-IR levels were found in groups where acyl and desacyl were administered together (p < 0.05). PPAR-γ gene expression level increased in acyl ghrelin and acyl/desacyl 1:3 groups compared to the control group. Protein kinase C gene expression was highest in the acyl/desacyl 1:3 group. The most severe degenerative findings compliant with steatosis in the liver were observed in the acyl ghrelin group (p < 0.05). CONCLUSION It was determined that administering rats acyl alone and acyl/desacyl by 1:3 caused the highest PPAR-γ gene expression, serum total cholesterol, HDL-K, and VLDL-K levels in the body. Besides, it is shown that desacyl ghrelin effectively regulates the blood glucose level when administered alone.
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Affiliation(s)
- Emine Elibol
- Departments of Nutrition and Dietetic, Ankara Yıldırım Beyazıt University, Dumlupınar Mahallesi, 06760 Çubuk, Ankara, Turkey.
| | - Yasemin Akdevelioğlu
- Departments of Nutrition and Dietetic, Gazi University, Emek mah. Bişkek Cad. 6. Cad. No:2 06490 Çankaya, Ankara, Turkey.
| | - Canan Yılmaz
- Departments of Medical Biochemistry, Gazi University, Faculty of Medicine, 06500 Beşevler, Ankara, Turkey.
| | - Belkıs Narlı
- Departments of Medical Biochemistry, Gazi University, Faculty of Medicine, 06500 Beşevler, Ankara, Turkey.
| | - Serkan Şen
- Departments of Medical Biochemistry, Afyonkarahisar Health Sciences University, Ali Çetinkaya Kampüsü Afyon- İzmir Karayolu 5.km, Afyonkarahisar, Turkey.
| | - Gülnur Take Kaplanoğlu
- Departments of Histology and Embryology, Gazi University Faculty of Medicine, 06500 Beşevler, Ankara, Turkey.
| | - Cemile Merve Seymen
- Departments of Histology and Embryology, Gazi University Faculty of Medicine, 06500 Beşevler, Ankara, Turkey.
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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.
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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
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Singh O, Ogden SB, Varshney S, Shankar K, Gupta D, Paul S, Osborne-Lawrence S, Richard CP, Metzger NP, Lawrence C, Leon Mercado L, Zigman JM. Ghrelin-responsive mediobasal hypothalamic neurons mediate exercise-associated food intake and exercise endurance. JCI Insight 2023; 8:e172549. [PMID: 37962950 PMCID: PMC10807726 DOI: 10.1172/jci.insight.172549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Accepted: 11/08/2023] [Indexed: 11/16/2023] Open
Abstract
Previous studies have implicated the orexigenic hormone ghrelin as a mediator of exercise endurance and the feeding response postexercise. Specifically, plasma ghrelin levels nearly double in mice when they are subjected to an hour-long bout of high-intensity interval exercise (HIIE) using treadmills. Also, growth hormone secretagogue receptor-null (GHSR-null) mice exhibit decreased food intake following HIIE and diminished running distance (time until exhaustion) during a longer, stepwise exercise endurance protocol. To investigate whether ghrelin-responsive mediobasal hypothalamus (MBH) neurons mediate these effects, we stereotaxically delivered the inhibitory designer receptor exclusively activated by designer drugs virus AAV2-hSyn-DIO-hM4(Gi)-mCherry to the MBH of Ghsr-IRES-Cre mice, which express Cre recombinase directed by the Ghsr promoter. We found that chemogenetic inhibition of GHSR-expressing MBH neurons (upon delivery of clozapine-N-oxide) 1) suppressed food intake following HIIE, 2) reduced maximum running distance and raised blood glucose and blood lactate levels during an exercise endurance protocol, 3) reduced food intake following ghrelin administration, and 4) did not affect glucose tolerance. Further, HIIE increased MBH Ghsr expression. These results indicate that activation of ghrelin-responsive MBH neurons is required for the normal feeding response to HIIE and the usual amount of running exhibited during an exercise endurance protocol.
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Affiliation(s)
- Omprakash Singh
- Center for Hypothalamic Research, Department of Internal Medicine
| | - Sean B. Ogden
- Center for Hypothalamic Research, Department of Internal Medicine
| | - Salil Varshney
- Center for Hypothalamic Research, Department of Internal Medicine
| | - Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine
| | - Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine
| | - Subhojit Paul
- Center for Hypothalamic Research, Department of Internal Medicine
| | | | | | | | - Connor Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine
| | | | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Department of Internal Medicine
- Division of Endocrinology & Metabolism, Department of Internal Medicine; and
- Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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7
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Tagliamonte S, Barone Lumaga R, De Filippis F, Valentino V, Ferracane R, Guerville M, Gandolfi I, Barbara G, Ercolini D, Vitaglione P. Milk protein digestion and the gut microbiome influence gastrointestinal discomfort after cow milk consumption in healthy subjects. Food Res Int 2023; 170:112953. [PMID: 37316045 DOI: 10.1016/j.foodres.2023.112953] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Revised: 04/07/2023] [Accepted: 05/10/2023] [Indexed: 06/16/2023]
Abstract
Many healthy people suffer from milk-related gastrointestinal discomfort (GID) despite not being lactose intolerant; the mechanisms underpinning such condition are unknown. This study aimed to explore milk protein digestion and related physiological responses (primary outcome), gut microbiome and gut permeability in 19 lactose-tolerant healthy nonhabitual milk consumers [NHMCs] reporting GID after consuming cow milk compared to 20 habitual milk consumers [HMCs] without GID. NHMCs and HMCs participated in a milk-load (250 mL) test, underwent blood sample collection at 6 time points over 6 h after milk consumption and collected urine samples and GID self-reports over 24 h. We measured the concentrations of 31 milk-derived bioactive peptides (BAPs), 20 amino acids, 4 hormones, 5 endocannabinoid system mediators, glucose and the dipeptidyl peptidase-IV (DPPIV) activity in blood and indoxyl sulfate in urine samples. Subjects also participated in a gut permeability test and delivered feces sample for gut microbiome analysis. Results showed that, compared to HMCs, milk consumption in NHMCs, along with GID, elicited a slower and lower increase in circulating BAPs, lower responses of ghrelin, insulin, and anandamide, a higher glucose response and serum DPPIV activity. The gut permeability of the two groups was similar, while the habitual diet, which was lower in dairy products and higher in the dietary-fibre-to-protein ratio in NHMCs, possibly shaped the gut microbiome; NHMCs exhibited lower abundance of Bifidobacteria, higher abundance of Prevotella and lower abundance of protease-coding genes, which may have reduced protein digestion, as evidenced by lower urinary excretion of indoxyl sulfate. In conclusion, the findings showed that a less efficient digestion of milk proteins, supported by a lower proteolytic capability of the gut microbiome, may explain GID in healthy people after milk consumption.
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Affiliation(s)
- Silvia Tagliamonte
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy
| | - Roberta Barone Lumaga
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy
| | - Francesca De Filippis
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy; Task Force on Microbiome Studies, University of Naples Federico II, 80134 Naples, Italy
| | - Vincenzo Valentino
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy; Task Force on Microbiome Studies, University of Naples Federico II, 80134 Naples, Italy
| | - Rosalia Ferracane
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy
| | - Mathilde Guerville
- Nutrition Department, Lactalis Research & Development, 35240 Retiers, France
| | - Ivana Gandolfi
- Nutrition Department, Lactalis Research & Development, 43038 Sala Baganza, Italy
| | - Giovanni Barbara
- Dipartimento di Scienze Mediche e Chirurgiche, University of Bologna, 40138 Bologna, Italy
| | - Danilo Ercolini
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy; Task Force on Microbiome Studies, University of Naples Federico II, 80134 Naples, Italy
| | - Paola Vitaglione
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy; Task Force on Microbiome Studies, University of Naples Federico II, 80134 Naples, Italy.
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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.
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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
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9
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Obstructive Sleep Apnea, Circadian Clock Disruption, and Metabolic Consequences. Metabolites 2022; 13:metabo13010060. [PMID: 36676985 PMCID: PMC9863434 DOI: 10.3390/metabo13010060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 12/26/2022] [Accepted: 12/27/2022] [Indexed: 01/03/2023] Open
Abstract
Obstructive sleep apnea (OSA) is a chronic disorder characterized by recurrent episodes of apnea and hypopnea during sleep. It is associated with various cardiovascular and metabolic complications, including type 2 diabetes mellitus (T2DM) and obesity. Many pathways can be responsible for T2DM development in OSA patients, e.g., those related to HIF-1 and SIRT1 expression. Moreover, epigenetic mechanisms, such as miRNA181a or miRNA199, are postulated to play a pivotal role in this link. It has been proven that OSA increases the occurrence of circadian clock disruption, which is also a risk factor for metabolic disease development. Circadian clock disruption impairs the metabolism of glucose, lipids, and the secretion of bile acids. Therefore, OSA-induced circadian clock disruption may be a potential, complex, underlying pathway involved in developing and exacerbating metabolic diseases among OSA patients. The current paper summarizes the available information pertaining to the relationship between OSA and circadian clock disruption in the context of potential mechanisms leading to metabolic disorders.
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10
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Yin Y, Guo Q, Zhou X, Duan Y, Yang Y, Gong S, Han M, Liu Y, Yang Z, Chen Q, Li F. Role of brain-gut-muscle axis in human health and energy homeostasis. Front Nutr 2022; 9:947033. [PMID: 36276808 PMCID: PMC9582522 DOI: 10.3389/fnut.2022.947033] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 09/02/2022] [Indexed: 11/26/2022] Open
Abstract
The interrelationship between brain, gut and skeletal muscle plays a key role in energy homeostasis of the body, and is becoming a hot topic of research. Intestinal microbial metabolites, such as short-chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites, communicate with the central nervous system (CNS) by binding to their receptors. In fact, there is a cross-talk between the CNS and the gut. The CNS, under the stimulation of pressure, will also affect the stability of the intestinal system, including the local intestinal transport, secretion and permeability of the intestinal system. After the gastrointestinal tract collects information about food absorption, it sends signals to the central system through vagus nerve and other channels to stimulate the secretion of brain-gut peptide and produce feeding behavior, which is also an important part of maintaining energy homeostasis. Skeletal muscle has receptors for SCFAs and BAs. Therefore, intestinal microbiota can participate in skeletal muscle energy metabolism and muscle fiber conversion through their metabolites. Skeletal muscles can also communicate with the gut system during exercise. Under the stimulation of exercise, myokines secreted by skeletal muscle causes the secretion of intestinal hormones, and these hormones can act on the central system and affect food intake. The idea of the brain-gut-muscle axis is gradually being confirmed, and at present it is important for regulating energy homeostasis, which also seems to be relevant to human health. This article focuses on the interaction of intestinal microbiota, central nervous, skeletal muscle energy metabolism, and feeding behavior regulation, which will provide new insight into the diagnostic and treatment strategies for obesity, diabetes, and other metabolic diseases.
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Affiliation(s)
- Yunju Yin
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
| | - Qiuping Guo
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
| | - Xihong Zhou
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
| | - Yehui Duan
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
| | - Yuhuan Yang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
| | - Saiming Gong
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
| | - Mengmeng Han
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
| | - Yating Liu
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Zhikang Yang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Qinghua Chen
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, China
| | - Fengna Li
- Hunan Provincial Key Laboratory of Animal Nutritional Physiology and Metabolic Process, Key Laboratory of Agro-Ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Hunan Provincial Engineering Research Center for Healthy Livestock and Poultry Production, National Engineering Laboratory for Pollution Control and Waste Utilization in Livestock and Poultry Production, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Changsha, China
- College of Advanced Agricultural Sciences, University of Chinese Academy of Sciences, Beijing, China
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11
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Conde K, Kulyk D, Vanschaik A, Daisey S, Rojas C, Wiersielis K, Yasrebi A, Degroat TJ, Sun Y, Roepke TA. Deletion of Growth Hormone Secretagogue Receptor in Kisspeptin Neurons in Female Mice Blocks Diet-Induced Obesity. Biomolecules 2022; 12:1370. [PMID: 36291579 PMCID: PMC9599822 DOI: 10.3390/biom12101370] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2022] [Revised: 09/16/2022] [Accepted: 09/22/2022] [Indexed: 01/19/2023] Open
Abstract
The gut peptide, ghrelin, mediates energy homeostasis and reproduction by acting through its receptor, growth hormone secretagogue receptor (GHSR), expressed in hypothalamic neurons in the arcuate (ARC). We have shown 17β-estradiol (E2) increases Ghsr expression in Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons, enhancing sensitivity to ghrelin. We hypothesized that E2-induced Ghsr expression augments KNDy sensitivity in a fasting state by elevating ghrelin to disrupt energy expenditure in females. We produced a Kiss1-GHSR knockout to determine the role of GHSR in ARC KNDy neurons. We found that changes in ARC gene expression with estradiol benzoate (EB) treatment were abrogated by the deletion of GHSR and ghrelin abolished these differences. We also observed changes in metabolism and fasting glucose levels. Additionally, knockouts were resistant to body weight gain on a high fat diet (HFD). Behaviorally, we found that knockouts on HFD exhibited reduced anxiety-like behavior. Furthermore, knockouts did not refeed to the same extent as controls after a 24 h fast. Finally, in response to cold stress, knockout females had elevated metabolic parameters compared to controls. These data indicate GHSR in Kiss1 neurons modulate ARC gene expression, metabolism, glucose homeostasis, behavior, and thermoregulation, illustrating a novel mechanism for E2 and ghrelin to control Kiss1 neurons.
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Affiliation(s)
- Kristie Conde
- Graduate Program in Neuroscience, Rutgers University Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Danielle Kulyk
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Allison Vanschaik
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Sierra Daisey
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Catherine Rojas
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Kimberly Wiersielis
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
| | - Ali Yasrebi
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Thomas J. Degroat
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
| | - Yuxiang Sun
- Department of Nutrition, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX 77843, USA
| | - Troy A. Roepke
- Graduate Program in Neuroscience, Rutgers University Robert Wood Johnson Medical School, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
- Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA
- Rutgers Center for Lipid Research, the Center for Nutrition, Microbiome, and Health, and the New Jersey Institute of Food, Nutrition, and Health, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA
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12
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Overton DL, Mastracci TL. Exocrine-Endocrine Crosstalk: The Influence of Pancreatic Cellular Communications on Organ Growth, Function and Disease. Front Endocrinol (Lausanne) 2022; 13:904004. [PMID: 35769082 PMCID: PMC9234176 DOI: 10.3389/fendo.2022.904004] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2022] [Accepted: 04/26/2022] [Indexed: 12/12/2022] Open
Abstract
Diabetes mellitus, a disease that affects nearly 536.6 million people worldwide, is characterized by the death or dysfunction of insulin-producing beta cells of the pancreas. The beta cells are found within the islets of Langerhans, which are composed of multiple hormone-producing endocrine cells including the alpha (glucagon), delta (somatostatin), PP (pancreatic polypeptide), and epsilon (ghrelin) cells. There is direct evidence that physical and paracrine interactions between the cells in the islet facilitate and support beta cell function. However, communication between endocrine and exocrine cells in the pancreas may also directly impact beta cell growth and function. Herein we review literature that contributes to the view that "crosstalk" between neighboring cells within the pancreas influences beta cell growth and function and the maintenance of beta cell health.
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Affiliation(s)
- Danielle L. Overton
- Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States
| | - Teresa L. Mastracci
- Department of Biology, Indiana University-Purdue University Indianapolis, Indianapolis, IN, United States
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, United States
- Center for Diabetes and Metabolic Diseases, Indiana University School of Medicine, Indianapolis, IN, United States
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13
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Prins K, Huisman M, McLuskey A, Mies R, Karels B, Delhanty PJD, Visser JA. Ghrelin deficiency sex-dependently affects food intake, locomotor activity, and adipose and hepatic gene expression in a binge-eating mouse model. Am J Physiol Endocrinol Metab 2022; 322:E494-E507. [PMID: 35403437 DOI: 10.1152/ajpendo.00432.2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Binge-eating disorder is the most prevalent eating disorder diagnosed, affecting three times more women than men. Ghrelin stimulates appetite and reward signaling, and loss of its receptor reduces binge-eating behavior in male mice. Here, we examined the influence of ghrelin itself on binge-eating behavior in both male and female mice. Five-wk-old wild-type (WT) and ghrelin-deficient (Ghrl-/-) mice were housed individually in indirect calorimetry cages for 9 wks. Binge-like eating was induced by giving mice ad libitum chow, but time-restricted access to a Western-style diet (WD; 2 h access, 3 days/wk) in the light phase (BE); control groups received ad libitum chow (CO), or ad libitum access to both diets (CW). All groups of BE mice showed binge-eating behavior, eating up to 60% of their 24-h intake during the WD access period. Subsequent dark phase chow intake was decreased in Ghrl-/- mice and remained decreased in Ghrl-/- females on nonbinge days. Also, nonbinge day locomotor activity was lower in Ghrl-/- than in WT BE females. Upon euthanasia, Ghrl-/- BE mice weighed less and had a lower lean body mass percentage than WT BE mice. In BE and CW groups, ghrelin and sex altered the expression of genes involved in lipid processing, thermogenesis, and aging in white adipose tissue and livers. We conclude that, although ghrelin deficiency does not hamper the development of binge-like eating, it sex-dependently alters food intake timing, locomotor activity, and metabolism. These results add to the growing body of evidence that ghrelin signaling is sexually dimorphic.NEW & NOTEWORTHY Ghrelin, a peptide hormone secreted from the gut, is involved in hunger and reward signaling, which are altered in binge-eating disorder. Although sex differences have been described in both binge-eating and ghrelin signaling, this interaction has not been fully elucidated. Here, we show that ghrelin deficiency affects the behavior and metabolism of mice in a binge-like eating paradigm, and that the sex of the mice impacts the magnitude and direction of these effects.
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Affiliation(s)
- Karina Prins
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Martin Huisman
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Anke McLuskey
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Rosinda Mies
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Bas Karels
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Patric J D Delhanty
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | - Jenny A Visser
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
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14
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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.
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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
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15
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Qian Y, Xia F, Zuo Y, Zhong M, Yang L, Jiang Y, Zou C. Do patients with Prader-Willi syndrome have favorable glucose metabolism? Orphanet J Rare Dis 2022; 17:187. [PMID: 35525976 PMCID: PMC9077846 DOI: 10.1186/s13023-022-02344-3] [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: 01/08/2022] [Accepted: 04/26/2022] [Indexed: 11/26/2022] Open
Abstract
Background In recent years, more studies have observed that patients with Prader–Willi syndrome have lower insulin levels and lower insulin resistance than body mass index-matched controls, which may suggest protected glucose metabolism. Method The PubMed and Web of Science online databases were searched to identify relevant studies published in the English language using the terms “Prader–Willi syndrome” with “glucose”, “insulin”, “diabetes mellitus”, “fat”, “adipo*”, “ghrelin”, “oxytocin”, “irisin” or “autonomic nervous system”. Results The prevalence of impaired glucose intolerance, type 2 diabetes mellitus and some other obesity-associated complications in patients with Prader–Willi syndrome tends to be lower when compared to that in general obesity, which is consistent with the hypothetically protected glucose metabolism. Factors including adipose tissue, adiponectin, ghrelin, oxytocin, irisin, growth hormone and the autonomic nervous system possibly modulate insulin sensitivity in patients with Prader–Willi syndrome. Conclusion Although lower insulin levels, lower IR and protected glucose metabolism are widely reported in PWS patients, the causes are still mysterious. Based on existing knowledge, we cannot determine which factor is of utmost importance and what are the underlying mechanisms, and further research is in urgent need.
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Affiliation(s)
- Yanjie Qian
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No 3333 Binsheng Road, Hangzhou, 310051, China
| | - Fangling Xia
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No 3333 Binsheng Road, Hangzhou, 310051, China
| | - Yiming Zuo
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No 3333 Binsheng Road, Hangzhou, 310051, China
| | - Mianling Zhong
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No 3333 Binsheng Road, Hangzhou, 310051, China
| | - Lili Yang
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No 3333 Binsheng Road, Hangzhou, 310051, China
| | - Yonghui Jiang
- Department of Genetics, Yale University School of Medicine, New Haven, USA
| | - Chaochun Zou
- Department of Endocrinology, The Children's Hospital of Zhejiang University School of Medicine, National Clinical Research Center for Child Health, No 3333 Binsheng Road, Hangzhou, 310051, China.
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16
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Villarreal D, Pradhan G, Zhou Y, Xue B, Sun Y. Diverse and Complementary Effects of Ghrelin and Obestatin. Biomolecules 2022; 12:517. [PMID: 35454106 PMCID: PMC9028691 DOI: 10.3390/biom12040517] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 03/21/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Ghrelin and obestatin are two "sibling proteins" encoded by the same preproghrelin gene but possess an array of diverse and complex functions. While there are ample literature documenting ghrelin's functions, the roles of obestatin are less clear and controversial. Ghrelin and obestatin have been perceived to be antagonistic initially; however, recent studies challenge this dogma. While they have opposing effects in some systems, they function synergistically in other systems, with many functions remaining debatable. In this review, we discuss their functional relationship under three "C" categories, namely complex, complementary, and contradictory. Their functions in food intake, weight regulation, hydration, gastrointestinal motility, inflammation, and insulin secretion are complex. Their functions in pancreatic beta cells, cardiovascular, muscle, neuroprotection, cancer, and digestive system are complementary. Their functions in white adipose tissue, thermogenesis, and sleep regulation are contradictory. Overall, this review accumulates the multifaceted functions of ghrelin and obestatin under both physiological and pathological conditions, with the intent of contributing to a better understanding of these two important gut hormones.
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Affiliation(s)
- Daniel Villarreal
- Department of Nutrition, Texas A & M University, College Station, TX 77843, USA;
| | - Geetali Pradhan
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;
- Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yu Zhou
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Qingdao University, Qingdao 266071, China;
| | - Bingzhong Xue
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
| | - Yuxiang Sun
- Department of Nutrition, Texas A & M University, College Station, TX 77843, USA;
- USDA/ARS Children’s Nutrition Research Center, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA;
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17
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Ghrelin and Cancer: Examining the Roles of the Ghrelin Axis in Tumor Growth and Progression. Biomolecules 2022; 12:biom12040483. [PMID: 35454071 PMCID: PMC9032665 DOI: 10.3390/biom12040483] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 02/07/2023] Open
Abstract
Ghrelin, a hormone produced and secreted from the stomach, is prim arily known as an appetite stimulant. Recently, it has emerged as a potential regulator/biomarker of cancer progression. Inconsistent results on this subject make this body of literature difficult to interpret. Here, we attempt to identify commonalities in the relationships between ghrelin and various cancers, and summarize important considerations for future research. The main players in the ghrelin family axis are unacylated ghrelin (UAG), acylated ghrelin (AG), the enzyme ghrelin O-acyltransferase (GOAT), and the growth hormone secretagogue receptor (GHSR). GOAT is responsible for the acylation of ghrelin, after which ghrelin can bind to the functional ghrelin receptor GHSR-1a to initiate the activation cascade. Splice variants of ghrelin also exist, with the most prominent being In1-ghrelin. In this review, we focus primarily on the potential of In1-ghrelin as a biomarker for cancer progression, the unique characteristics of UAG and AG, the importance of the two known receptor variants GHSR-1a and 1b, as well as the possible mechanisms through which the ghrelin axis acts. Further understanding of the role of the ghrelin axis in tumor cell proliferation could lead to the development of novel therapeutic approaches for various cancers.
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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.
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Lugilde J, Casado S, Beiroa D, Cuñarro J, Garcia-Lavandeira M, Álvarez CV, Nogueiras R, Diéguez C, Tovar S. LEAP-2 Counteracts Ghrelin-Induced Food Intake in a Nutrient, Growth Hormone and Age Independent Manner. Cells 2022; 11:cells11030324. [PMID: 35159134 PMCID: PMC8834077 DOI: 10.3390/cells11030324] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 01/16/2022] [Accepted: 01/17/2022] [Indexed: 12/30/2022] Open
Abstract
Data gleaned recently shows that ghrelin, a stomach derived peptide, and liver-expressed-antimicrobial peptide 2 (LEAP-2) play opposite roles on food intake. However, the data available with LEAP-2 in relation to in vivo studies are still very scanty and some key questions regarding the interplay among ghrelin and LEAP-2 remain to be answered. In this work, using rats and mice, we study fasting-induced food intake as well as testing the effect of diet exposure, e.g., standard diet and high fat diet, in terms of ghrelin-induced food intake. The anorexigenic effect of LEAP-2 on fasting induced food intake appears to be dependent on energy stores, being more evident in ob/ob than in wild type mice and also in animals exposed to high fat diet. On the other hand, LEAP-2 administration markedly inhibited ghrelin-induced food intake in lean, obese (ob/ob and DIO) mice, aged rats and GH-deficient dwarf rats. In contrast, the inhibitory effect on glucose levels can only be observed in some specific experimental models indicating that the mechanisms involved are likely to be quite different. Taken together from these data, LEAP-2 emerged as a potential candidate to be therapeutically useful in obesity.
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Affiliation(s)
- Javier Lugilde
- Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (J.L.); (S.C.); (D.B.); (J.C.); (R.N.)
| | - Sabela Casado
- Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (J.L.); (S.C.); (D.B.); (J.C.); (R.N.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Daniel Beiroa
- Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (J.L.); (S.C.); (D.B.); (J.C.); (R.N.)
| | - Juan Cuñarro
- Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (J.L.); (S.C.); (D.B.); (J.C.); (R.N.)
| | - Montserrat Garcia-Lavandeira
- Neoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; (M.G.-L.); (C.V.Á.)
| | - Clara V. Álvarez
- Neoplasia & Endocrine Differentiation P0L5, Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), University of Santiago de Compostela (USC), 15782 Santiago de Compostela, Spain; (M.G.-L.); (C.V.Á.)
| | - Rubén Nogueiras
- Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (J.L.); (S.C.); (D.B.); (J.C.); (R.N.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
| | - Carlos Diéguez
- Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (J.L.); (S.C.); (D.B.); (J.C.); (R.N.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
- Correspondence: (C.D.); (S.T.)
| | - Sulay Tovar
- Departamento de Fisioloxía and Centro de Investigación en Medicina Molecular (CIMUS), Instituto de Investigaciones Sanitarias de Santiago de Compostela (IDIS), Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain; (J.L.); (S.C.); (D.B.); (J.C.); (R.N.)
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), 15706 Santiago de Compostela, Spain
- Correspondence: (C.D.); (S.T.)
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Liang Y, Yu R, He R, Sun L, Luo C, Feng L, Chen H, Yin Y, Zhang W. Lower ghrelin levels does not impact the metabolic benefit induced by Roux-en-Y gastric bypass. Front Endocrinol (Lausanne) 2022; 13:891379. [PMID: 36082078 PMCID: PMC9445200 DOI: 10.3389/fendo.2022.891379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 08/01/2022] [Indexed: 01/19/2023] Open
Abstract
OBJECTIVE Roux-en-Y gastric bypass is an effective intervention for metabolic disorder. We aim to elucidate whether ghrelin contributes to weight reduction, and glycemic and lipid control after Roux-en-Y gastric bypass (RYGB). DESIGN Four-week-old WT and Ghrl-TSC1-/- mice were fed high fat diet for 12 weeks before surgery, and continued to be on the same diet for 3 weeks after surgery. Body weight, food intake, glycemic and lipid metabolism were analyzed before and after surgery. RESULTS Gastric and circulating ghrelin was significantly increased in mice with RYGB surgery. Hypoghrelinemia elicited by deletion of TSC1 to activate mTOR signaling in gastric X/A like cells demonstrated no effect on weight reduction, glycemic and lipid control induced by Roux-en-Y gastric bypass surgery. CONCLUSION Lower ghrelin levels does not impact the metabolic benefit induced by Roux-en-Y gastric bypass.
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Affiliation(s)
- Yuan Liang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Ruili Yu
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- Department of Pathology, Henan Provincial People’s Hospital; People’s Hospital of Zhengzhou University, Zhengzhou, China
| | - Rui He
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China
| | - Lijun Sun
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Chao Luo
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Lu Feng
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Hong Chen
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
| | - Yue Yin
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- *Correspondence: Yue Yin,
| | - Weizhen Zhang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, and Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Peking University, Beijing, China
- Department of Surgery, University of Michigan Medical Center, Ann Arbor, MI, United States
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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.
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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
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22
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Peris-Sampedro F, Le May MV, Stoltenborg I, Schéle E, Dickson SL. A skeleton in the cupboard in ghrelin research: Where are the skinny dwarfs? J Neuroendocrinol 2021; 33:e13025. [PMID: 34427011 DOI: 10.1111/jne.13025] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 07/09/2021] [Accepted: 08/05/2021] [Indexed: 12/15/2022]
Abstract
Based on studies delivering ghrelin or ghrelin receptor agonists, we have learned a great deal about the importance of the brain ghrelin signalling system for a wide range of physiological processes that include feeding behaviours, growth hormone secretion and glucose homeostasis. Because these processes can be considered as essential to life, the question arises as to why mouse models of depleted ghrelin signalling are not all skinny dwarfs with a host of behavioural and metabolic problems. Here, we provide a systematic detailed review of the phenotype of mice with deficient ghrelin signalling to help better understand the relevance and importance of the brain ghrelin signalling system, with a particular emphasis on those questions that remain unanswered.
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Affiliation(s)
- Fiona Peris-Sampedro
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Marie V Le May
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Iris Stoltenborg
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Erik Schéle
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
| | - Suzanne L Dickson
- Department of Physiology/Endocrine, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
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23
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Shankar K, Takemi S, Gupta D, Varshney S, Mani BK, Osborne-Lawrence S, Metzger NP, Richard CP, Berglund ED, Zigman JM. Ghrelin cell-expressed insulin receptors mediate meal- and obesity-induced declines in plasma ghrelin. JCI Insight 2021; 6:e146983. [PMID: 34473648 PMCID: PMC8492315 DOI: 10.1172/jci.insight.146983] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 08/04/2021] [Indexed: 01/20/2023] Open
Abstract
Mechanisms underlying postprandial and obesity-associated plasma ghrelin reductions are incompletely understood. Here, using ghrelin cell-selective insulin receptor-KO (GhIRKO) mice, we tested the impact of insulin, acting via ghrelin cell-expressed insulin receptors (IRs), to suppress ghrelin secretion. Insulin reduced ghrelin secretion from cultured gastric mucosal cells of control mice but not from those of GhIRKO mice. Acute insulin challenge and insulin infusion during both hyperinsulinemic-hypoglycemic clamps and hyperinsulinemic-euglycemic clamps lowered plasma ghrelin in control mice but not GhIRKO mice. Thus, ghrelin cell-expressed IRs are required for insulin-mediated reductions in plasma ghrelin. Furthermore, interventions that naturally raise insulin (glucose gavage, refeeding following fasting, and chronic high-fat diet) also lowered plasma ghrelin only in control mice - not GhIRKO mice. Thus, meal- and obesity-associated increases in insulin, acting via ghrelin cell-expressed IRs, represent a major, direct negative modulator of ghrelin secretion in vivo, as opposed to ingested or metabolized macronutrients. Refed GhIRKO mice exhibited reduced plasma insulin, highlighting ghrelin's actions to inhibit insulin release via a feedback loop. Moreover, GhIRKO mice required reduced glucose infusion rates during hyperinsulinemic-hypoglycemic clamps, suggesting that suppressed ghrelin release resulting from direct insulin action on ghrelin cells usually limits ghrelin's full potential to protect against insulin-induced hypoglycemia.
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Affiliation(s)
- Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Shota Takemi
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, Sakuraku, Saitama, Japan
| | - Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Salil Varshney
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Bharath K. Mani
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Nathan P. Metzger
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Corine P. Richard
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Eric D. Berglund
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
| | - Jeffrey M. Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, Texas, USA
- Division of Endocrinology, Department of Internal Medicine, and
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, Texas, USA
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Wang L, Shi C, Yan H, Xia M, Zhu X, Sun X, Yang X, Jiao H, Wu H, Lou W, Chang X, Gao X, Bian H. Acute Effects of Sleeve Gastrectomy on Glucose Variability, Glucose Metabolism, and Ghrelin Response. Obes Surg 2021; 31:4005-4014. [PMID: 34240316 DOI: 10.1007/s11695-021-05534-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 02/06/2023]
Abstract
PURPOSE This study aims to examine the changes of glucose metabolism, glucose variability (GV), and ghrelin secretion within 1 week following SG in Chinese patients with obesity. MATERIALS AND METHODS Forty-nine patients with obesity (15 with type 2 diabetes) were enrolled to undergo SG. Within 1 week before and after surgery, liquid meal tests were performed in all subjects, and continuous glucose monitoring (CGM) was performed in diabetic patients. Blood samples were collected at 0, 15, 30, 45, 60, 120, and 180 min for glucose, C-peptide, insulin, and ghrelin analysis in liquid meal test. Mean amplitude of glucose excursions (MAGE), standard deviations (SD), and percent time-in-range (%TIR) determined by CGM were analyzed. RESULTS Both in diabetic and non-diabetic groups, significant decrease was observed in glucose, insulin, C-peptide, and ghrelin. Homeostasis model assessment-insulin resistance and liver fat content was decreased. In diabetic group, MAGE and SD were decreased significantly, and the percent time-in-range was higher. The decrease in blood glucose was positively correlated with the decrease in ghrelin concentration in non-diabetic group. CONCLUSION Within 1 week after SG, both glucose metabolism and glucose variability were improved significantly. Suppression of ghrelin secretion postoperatively might be a driver of this early improved glycemia homeostasis.
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Affiliation(s)
- Liu Wang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
- Second Affiliated Hospital of Army Military Medical University, Chongqing, 400037, China
| | - Chenye Shi
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
- Department of General surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hongmei Yan
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Mingfeng Xia
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Xiaopeng Zhu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Xiaoyang Sun
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Xinyu Yang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
| | - Huan Jiao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
- Department of General surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Haifu Wu
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
- Department of General surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wenhui Lou
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China
- Department of General surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Xinxia Chang
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China.
| | - Xin Gao
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China.
| | - Hua Bian
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
- Fudan Institute for Metabolic Disease, Fudan University, Shanghai, 200032, China.
- Department of Endocrinology and Metabolism, Wusong Branch of Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
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25
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Ouerghi N, Feki M, Bragazzi NL, Knechtle B, Hill L, Nikolaidis PT, Bouassida A. Ghrelin Response to Acute and Chronic Exercise: Insights and Implications from a Systematic Review of the Literature. Sports Med 2021; 51:2389-2410. [PMID: 34374968 PMCID: PMC8514378 DOI: 10.1007/s40279-021-01518-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/05/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Ghrelin is a peptide hormone predominantly produced by the stomach. It exerts a wide range of functions including stimulating growth hormone release and regulating appetite, food intake, and glucose and lipid metabolism. Since physical exercise affects all these aspects, a particular interest is accorded to the relationship between ghrelin and exercise. This systematic review aimed to summarize the current available data on the topic for a better understanding of the relationship. METHODS An extensive computerized search was performed in the PubMed and SPORTDiscus databases for retrieving relevant articles. The search contained the following keywords: ghrelin, appetite-related peptides, gastrointestinal peptides, gastrointestinal hormones, exercise, acute exercise, chronic exercise, training, and physical activity. Studies investigating the effects of acute/chronic exercise on circulating forms of ghrelin were included. RESULTS The initial search identified 840 articles. After screening, 80 articles were included. Despite a heterogeneity of studies and a variability of the findings, the review suggests that acute exercise suppresses acyl ghrelin production regardless of the participants and the exercise characteristics. Long- and very long-term exercise training programs mostly resulted in increased total and des-acyl ghrelin production. The increase is more noticeable in overweight/obese individuals, and is most likely due to weight loss resulting from the training program. CONCLUSION The review suggests that exercise may impact ghrelin production. While the precise mechanisms are unclear, the effects are likely due to blood flow redistribution and weight loss for acute and chronic exercise, respectively. These changes are expected to be metabolically beneficial. Further research is needed for a better understanding of the relationship between ghrelin and exercise.
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Affiliation(s)
- Nejmeddine Ouerghi
- High Institute of Sport and Physical Education of Kef, UR13JS01, University of Jendouba, 7100, Kef, Tunisia.,Faculty of Medicine of Tunis, Rabta Hospital, LR99ES11, University of Tunis El Manar, 1007, Tunis, Tunisia
| | - Moncef Feki
- Faculty of Medicine of Tunis, Rabta Hospital, LR99ES11, University of Tunis El Manar, 1007, Tunis, Tunisia
| | - Nicola Luigi Bragazzi
- Postgraduate School of Public Health, Department of Health Sciences (DISSAL), University of Genoa, 16132, Genoa, Italy
| | - Beat Knechtle
- Medbase St. Gallen Am Vadianplatz, Vadianstrasse 26, 9001, St. Gallen, Switzerland. .,Institute of Primary Care, University of Zurich, Zurich, Switzerland.
| | - Lee Hill
- Division of Gastroenterology and Nutrition, Department of Pediatrics, McMaster University, Hamilton, L8S 4L8, Canada
| | | | - Anissa Bouassida
- High Institute of Sport and Physical Education of Kef, UR13JS01, University of Jendouba, 7100, Kef, Tunisia
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β Cell GHS-R Regulates Insulin Secretion and Sensitivity. Int J Mol Sci 2021; 22:ijms22083950. [PMID: 33920473 PMCID: PMC8069226 DOI: 10.3390/ijms22083950] [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] [Received: 03/16/2021] [Revised: 04/09/2021] [Accepted: 04/09/2021] [Indexed: 12/14/2022] Open
Abstract
Growth hormone secretagogue receptor (GHS-R) is widely known to regulate food intake and adiposity, but its role in glucose homeostasis is unclear. In this study, we investigated the expression of GHS-R in mouse pancreatic islets and its role in glycemic regulation. We used Ghsr-IRES-tauGFP mice, with Green Fluorescent Protein (GFP) as a surrogate for GHS-R, to demonstrate the GFP co-localization with insulin and glucagon expression in pancreatic islets, confirming GHS-R expression in β and α cells. We then generated β-cell-specific GHSR-deleted mice with MIP-Cre/ERT and validated that GHS-R suppression was restricted to the pancreatic islets. MIP-Cre/ERT;Ghsrf/f mice showed normal energy homeostasis with similar body weight, body composition, and indirect calorimetry profile. Interestingly, MIP-Cre/ERT;Ghsrf/f mice exhibited an impressive phenotype in glucose homeostasis. Compared to controls, MIP-Cre/ERT;Ghsrf/f mice showed lower fasting blood glucose and insulin; reduced first-phase insulin secretion during a glucose tolerance test (GTT) and glucose-stimulated insulin secretion (GSIS) test in vivo. The isolated pancreatic islets of MIP-Cre/ERT;Ghsrf/f mice also showed reduced insulin secretion during GSIS ex vivo. Further, MIP-Cre/ERT;Ghsrf/f mice exhibited improved insulin sensitivity during insulin tolerance tests (ITT). Overall, our results confirmed GHS-R expression in pancreatic β and α cells; GHS-R cell-autonomously regulated GSIS and modulated systemic insulin sensitivity. In conclusion, β cell GHS-R was an important regulator of glucose homeostasis, and GHS-R antagonists may have therapeutic potential for Type 2 Diabetes.
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Subba R, Sandhir R, Singh SP, Mallick BN, Mondal AC. Pathophysiology linking depression and type 2 diabetes: Psychotherapy, physical exercise, and fecal microbiome transplantation as damage control. Eur J Neurosci 2021; 53:2870-2900. [PMID: 33529409 DOI: 10.1111/ejn.15136] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2020] [Revised: 01/10/2021] [Accepted: 01/28/2021] [Indexed: 02/06/2023]
Abstract
Diabetes increases the likelihood of developing depression and vice versa. Research on this bidirectional association has somewhat managed to delineate the interplay among implicated physiological processes. Still, further exploration is required in this context. This review addresses the comorbidity by investigating suspected common pathophysiological mechanisms. One such factor is psychological stress which disturbs the hypothalamic-pituitary-adrenal axis causing hormonal imbalance. This includes elevated cortisol levels, a common biomarker of both depression and diabetes. Disrupted insulin signaling drives the hampered neurotransmission of serotonin, dopamine, and norepinephrine. Also, adipokine hormones such as adiponectin, leptin, and resistin and the orexigenic hormone, ghrelin, are involved in both depression and T2DM. This disarray further interferes with physiological processes encompassing sleep, the gut-brain axis, metabolism, and mood stability. Behavioral coping mechanisms, such as unhealthy eating, mediate disturbed glucose homeostasis, and neuroinflammation. This is intricately linked to oxidative stress, redox imbalance, and mitochondrial dysfunction. However, interventions such as psychotherapy, physical exercise, fecal microbiota transplantation, and insulin-sensitizing agents can help to manage the distressing condition. The possibility of glucagon-like peptide 1 possessing a therapeutic role has also been discussed. Nonetheless, there stands an urgent need for unraveling new correlating targets and biological markers for efficient treatment.
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Affiliation(s)
- Rhea Subba
- School of Life Sciences, Jawaharlal Nehru University, New Delhi, India
| | - Rajat Sandhir
- Dept. of Biochemistry, Panjab University, Chandigarh, Punjab, India
| | - Surya Pratap Singh
- Dept. of Biochemistry, Banaras Hindu University, Varanasi, Uttar Pradesh, India
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[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.
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Reich N, Hölscher C. Acylated Ghrelin as a Multi-Targeted Therapy for Alzheimer's and Parkinson's Disease. Front Neurosci 2020; 14:614828. [PMID: 33381011 PMCID: PMC7767977 DOI: 10.3389/fnins.2020.614828] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 11/27/2020] [Indexed: 12/13/2022] Open
Abstract
Much thought has been given to the impact of Amyloid Beta, Tau and Alpha-Synuclein in the development of Alzheimer's disease (AD) and Parkinson's disease (PD), yet the clinical failures of the recent decades indicate that there are further pathological mechanisms at work. Indeed, besides amyloids, AD and PD are characterized by the culminative interplay of oxidative stress, mitochondrial dysfunction and hyperfission, defective autophagy and mitophagy, systemic inflammation, BBB and vascular damage, demyelination, cerebral insulin resistance, the loss of dopamine production in PD, impaired neurogenesis and, of course, widespread axonal, synaptic and neuronal degeneration that leads to cognitive and motor impediments. Interestingly, the acylated form of the hormone ghrelin has shown the potential to ameliorate the latter pathologic changes, although some studies indicate a few complications that need to be considered in the long-term administration of the hormone. As such, this review will illustrate the wide-ranging neuroprotective properties of acylated ghrelin and critically evaluate the hormone's therapeutic benefits for the treatment of AD and PD.
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Affiliation(s)
- Niklas Reich
- Biomedical & Life Sciences Division, Lancaster University, Lancaster, United Kingdom
| | - Christian Hölscher
- Neurology Department, A Second Hospital, Shanxi Medical University, Taiyuan, China.,Research and Experimental Center, Henan University of Chinese Medicine, Zhengzhou, China
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"A LEAP 2 conclusions? Targeting the ghrelin system to treat obesity and diabetes". Mol Metab 2020; 46:101128. [PMID: 33246141 PMCID: PMC8085568 DOI: 10.1016/j.molmet.2020.101128] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2020] [Revised: 11/15/2020] [Accepted: 11/20/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The hormone ghrelin stimulates food intake, promotes adiposity, increases body weight, and elevates blood glucose. Consequently, alterations in plasma ghrelin levels and the functioning of other components of the broader ghrelin system have been proposed as potential contributors to obesity and diabetes. Furthermore, targeting the ghrelin system has been proposed as a novel therapeutic strategy for obesity and diabetes. SCOPE OF REVIEW The current review focuses on the potential for targeting ghrelin and other proteins comprising the ghrelin system as a treatment for obesity and diabetes. The main components of the ghrelin system are introduced. Data supporting a role for the endogenous ghrelin system in the development of obesity and diabetes along with data that seemingly refute such a role are outlined. An argument for further research into the development of ghrelin system-targeted therapeutic agents is delineated. Also, an evidence-based discussion of potential factors and contexts that might influence the efficacy of this class of therapeutics is provided. MAJOR CONCLUSIONS It would not be a "leap to" conclusions to suggest that agents which target the ghrelin system - including those that lower acyl-ghrelin levels, raise LEAP2 levels, block GHSR activity, and/or raise desacyl-ghrelin signaling - could represent efficacious novel treatments for obesity and diabetes.
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31
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de la Nuez Veulens A, Rodríguez Fernández RE, Álvarez Ginarte YM, Montero Cabrera LA. In silico strategy for detailing the binding modes of a novel family of peptides proven as ghrelin receptor agonists. J Mol Model 2020; 26:294. [PMID: 33015729 DOI: 10.1007/s00894-020-04553-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 09/17/2020] [Indexed: 11/26/2022]
Abstract
Ghrelin is a peptide hormone involved in multiple functions, including growth hormone release stimulation, food intake regulation, and metabolic and cytoprotective effect. A novel family of peptides with internal cycles was designed as ghrelin analogs and the biological activity of two of them (A228 and A233) was experimentally studied in-depth. In this work, an in silico strategy was developed for describing and assessing the binding modes of A228 and A233 to GHS-R1a (ghrelin receptor) comparing it with ghrelin and GHRP-6 peptides. Several reported structures of different G protein coupled receptors were used as templates, to obtain a good quality model of GHS-R1a. The best model was selected by preliminary molecular docking with ghrelin and GHRP-6. Docking was used to estimate peptide orientations in the binding site of the best model, observing a superposition of its N-terminal and its first aromatic residue. To test the complex stability in time, the C-terminal fragments of each peptide were added and the complexes were inserted a 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) membrane, performing a molecular dynamic simulation for 100 ns using the CHARMM36 force field. Despite of the structural differences, the studied peptides share a common binding mode; the N-terminal interacts with E124 and the aromatic residue close to it, with the aromatic cluster (F279, F309, and F312). A preliminary pharmacophore model, consisting in a positive charged amine and an aromatic ring at an approximate distance of 0.79 nm, can be proposed. The results here described could represent a step forward in the efficient search of new ghrelin analogs.
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Affiliation(s)
| | | | - Yoanna M Álvarez Ginarte
- Laboratory of Theoretical and Computational Chemistry, Faculty of Chemistry, University of Havana, Havana, Cuba
| | - Luis A Montero Cabrera
- Laboratory of Theoretical and Computational Chemistry, Faculty of Chemistry, University of Havana, Havana, Cuba.
- Department of Chemistry, Johns Hopkins University, Baltimore, MD, USA.
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Mani BK, Osborne-Lawrence S, Metzger N, Zigman JM. Lowering oxidative stress in ghrelin cells stimulates ghrelin secretion. Am J Physiol Endocrinol Metab 2020; 319:E330-E337. [PMID: 32543942 PMCID: PMC7473909 DOI: 10.1152/ajpendo.00119.2020] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Ghrelin is a predominantly stomach-derived peptide hormone with many actions including regulation of food intake, body weight, and blood glucose. Plasma ghrelin levels are robustly regulated by feeding status, with its levels increasing upon caloric restriction and decreasing after food intake. At least some of this regulation might be due to direct responsiveness of ghrelin cells to changes in circulating nutrients, including glucose. Indeed, oral and parental glucose administration to humans and mice lower plasma ghrelin. Also, dissociated mouse gastric mucosal cell preparations, which contain ghrelin cells, decrease ghrelin secretion when cultured in high ambient glucose. Here, we used primary cultures of mouse gastric mucosal cells in combination with an array of pharmacological tools to examine the potential role of changed intracellular oxidative stress in glucose-restricted ghrelin secretion. The antioxidants resveratrol, SRT1720, and curcumin all markedly increased ghrelin secretion. Furthermore, three different selective activators of Nuclear factor erythroid-derived-2-like 2 (Nrf2), a master regulator of the antioxidative cellular response to oxidative stress, increased ghrelin secretion. These antioxidant compounds blocked the inhibitory effects of glucose on ghrelin secretion. Therefore, we conclude that lowering oxidative stress within ghrelin cells stimulates ghrelin secretion and blocks the direct effects of glucose on ghrelin cells to inhibit ghrelin secretion.
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Affiliation(s)
- Bharath K Mani
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Nathan Metzger
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Jeffrey M Zigman
- Center for Hypothalamic Research and Division of Endocrinology, Department of Internal Medicine and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas
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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.
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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.
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Rivera-León EA, Llamas-Covarrubias MA, Sánchez-Enríquez S, Martínez-López E, González-Hita M, Llamas-Covarrubias IM. Leu72Met polymorphism of GHRL gene decreases susceptibility to type 2 diabetes mellitus in a Mexican population. BMC Endocr Disord 2020; 20:109. [PMID: 32698854 PMCID: PMC7374978 DOI: 10.1186/s12902-020-00596-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 07/14/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Type 2 diabetes mellitus (T2D) is the most frequent type of diabetes. It has a multifactorial etiology, affecting millions of people worldwide. Ghrelin gene (GHRL) encodes the ghrelin peptide, which promotes food intake, induces body weight and adipogenesis. Several single nucleotide polymorphisms (SNPs) in GHRL gene have been associated with metabolic diseases. A protective effect of the Leu72Met (rs696217) polymorphism has been described for T2D in some populations, but this effect seems to depend on the ethnicity of the patients studied. METHODS The aim of this study was to investigate the association between the GHRL Leu72Met (rs696217) SNP with the development of T2D and serum ghrelin levels in a Western Mexican population. We performed a case-control study in which we included 284 subjects (159 with previous T2D diagnosis and 125 control subjects (CS)). Leu72Met SNP was genotyped by using PCR-RFLPs technique. Serum ghrelin levels were measured using a commercial enzyme immunoassay. Genotypic and allelic distributions were compared using Chi square test. Student T-test and Mann-Whitney U test were used to compare quantitative variables. Odds ratio (OR) was used to evaluate the association between alleles or genotypes and T2D. Multiple and logistic regression models were performed for adjustment. A two-tailed p-value ≤0.05 was considered statistically significant. RESULTS Leu72Leu genotype was more frequent among T2D compared to CS (p < 0.05). After adjusting for age and body composition, there was a significant protective effect of the 72Met allele for T2D development (OR 0.40 IC 95% 0.23-0.70; p ≤ 0.001). Fasting serum ghrelin levels were lower in T2D than CS (p ≤ 0.0001) irrespective of age, body weight and BMI. No associations were found between genotypes and ghrelin serum levels in our population. CONCLUSIONS The GHRL 72Met allele decreases susceptibility for T2D development in a Western Mexican population. Serum ghrelin levels are lower in T2D independently of Leu72Met polymorphism genotype.
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Affiliation(s)
- Edgar Alfonso Rivera-León
- Departamento de Biología Molecular y Genómica, Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, CUCS, Postal adress: Sierra Mojada 950, Colonia Independencia, CP, 44340 Guadalajara, Jalisco Mexico
| | - Mara Anaís Llamas-Covarrubias
- Departamento de Biología Molecular y Genómica, Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, CUCS, Postal adress: Sierra Mojada 950, Colonia Independencia, CP, 44340 Guadalajara, Jalisco Mexico
| | - Sergio Sánchez-Enríquez
- Departamento de Clínicas, Universidad de Guadalajara, Centro Universitario de los Altos, Tepatitlán de Morelos, Jalisco Mexico
| | - Erika Martínez-López
- Departamento de Biología Molecular y Genómica, Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, CUCS, Postal adress: Sierra Mojada 950, Colonia Independencia, CP, 44340 Guadalajara, Jalisco Mexico
| | - Mercedes González-Hita
- Departamento de Biología Molecular y Genómica, Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, CUCS, Postal adress: Sierra Mojada 950, Colonia Independencia, CP, 44340 Guadalajara, Jalisco Mexico
| | - Iris Monserrat Llamas-Covarrubias
- Departamento de Biología Molecular y Genómica, Universidad de Guadalajara, Centro Universitario de Ciencias de la Salud, CUCS, Postal adress: Sierra Mojada 950, Colonia Independencia, CP, 44340 Guadalajara, Jalisco Mexico
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Wu Y, Zhou A, Tang L, Lei Y, Tang B, Zhang L. Bile Acids: Key Regulators and Novel Treatment Targets for Type 2 Diabetes. J Diabetes Res 2020; 2020:6138438. [PMID: 32733968 PMCID: PMC7383344 DOI: 10.1155/2020/6138438] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 06/29/2020] [Accepted: 07/04/2020] [Indexed: 02/08/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and unclear pathogenesis, is a serious menace to human health. Bile acids are the end products of cholesterol catabolism and play an important role in maintaining cholesterol homeostasis. Furthermore, increasing studies suggest that bile acids may regulate glucose tolerance, insulin sensitivity, and energy metabolism, suggesting that bile acids may represent a potential therapeutic target for T2DM. This study summarizes the metabolism of bile acids and, more importantly, changes in their concentrations, constitution, and receptors in diabetes. Furthermore, we provide an overview of the mechanisms underlying the role of bile acids in glucose and lipid metabolism, as well as the occurrence and development of T2DM. Bile acid-targeted therapy may represent a valid approach for T2DM treatment.
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Affiliation(s)
- Yingjie Wu
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou 510030, China
| | - An Zhou
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Li Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Yuanyuan Lei
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Bo Tang
- Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China
| | - Linjing Zhang
- Department of Nuclear Medicine, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
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Tuero C, Valenti V, Rotellar F, Landecho MF, Cienfuegos JA, Frühbeck G. Revisiting the Ghrelin Changes Following Bariatric and Metabolic Surgery. Obes Surg 2020; 30:2763-2780. [PMID: 32323063 DOI: 10.1007/s11695-020-04601-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Since the description of ghrelin in 1999, several studies have dug into the effects of this hormone and its relationship with bariatric surgery. While some aspects are still unresolved, a clear connection between ghrelin and the changes after metabolic surgery have been established. Besides weight loss, a significant amelioration in obesity-related comorbidities following surgery has also been reported. These changes in patients occur in the early postoperative period, before the weight loss appears, so that amelioration may be mainly due to hormonal changes. The purpose of this review is to go through the current body of knowledge of ghrelin's physiology, as well as to update and clarify the changes that take place in ghrelin concentrations following bariatric/metabolic surgery together with their potential consolidation to outcomes.
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Affiliation(s)
- Carlota Tuero
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain.
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain.
| | - Victor Valenti
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain
| | - Fernando Rotellar
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain
| | - Manuel F Landecho
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Internal Medicine, General Health Check-up unit, Clínica Universidad de Navarra, Pamplona, Spain
| | - Javier A Cienfuegos
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain
- Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain
| | - Gema Frühbeck
- Obesity Area, Clínica Universidad de Navarra, Avenida Pio XII 36, 31008, Pamplona, Navarra, Spain.
- CIBEROBN, Instituto de Salud Carlos III, Pamplona, Navarra, Spain.
- Obesity and Adipobiology Group, IdiSNA, Pamplona, Spain.
- Department of Endocrinology and Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
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Abstract
Ghrelin is a key signal driving energy seeking and storage in order to reverse energy deficit. In line with this view, the metabolic status of an organism predicts sensitivity to ghrelin, with fasting increasing and obesity decreasing ghrelin sensitivity. However, the mechanism responsible for controlling this sensitivity is unknown. In this issue of the JCI, Mani and colleagues show that plasma levels of plasma liver-enriched antimicrobial peptide-2 (LEAP2), a recently identified hormone that antagonizes the ghrelin receptor, are inversely correlated with those of plasma acyl-ghrelin under conditions of both energy deficit and energy surplus in mice and humans. Their results show that a fall in plasma LEAP2 during energy deficit facilitates the actions of acyl-ghrelin, whereas increased LEAP2 in obesity suppresses the actions of acyl-ghrelin. This important discovery helps reshape our understanding of ghrelin function and may provide a new approach to aiding weight maintenance after diet-induced weight loss.
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Sovetkina A, Nadir R, Fung JNM, Nadjarpour A, Beddoe B. The Physiological Role of Ghrelin in the Regulation of Energy and Glucose Homeostasis. Cureus 2020; 12:e7941. [PMID: 32499981 PMCID: PMC7266561 DOI: 10.7759/cureus.7941] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Ghrelin is a peptide hormone that is primarily released from the stomach. It is best known for its role in appetite initiation. However, evidence also suggests that ghrelin may play a much wider role in energy homeostasis and glucose metabolism. It is known that exogenous ghrelin exerts an orexigenic signal via growth hormone secretagogue receptors in the arcuate nucleus of the hypothalamus. However, blocking ghrelin signalling in the arcuate nucleus does not decrease feeding. Evidence now proposes that an alternative pathway for ghrelin’s action is via the vagus nerve. Furthermore, it has been suggested that ghrelin signalling is an important physiological regulator of body adiposity and energy storage. Ghrelin also seems to be important in controlling glucose metabolism through action in the pancreatic islets of Langerhans, representing a promising novel therapeutic target in diabetes treatment. Despite these findings, further research in humans is required before ghrelin can be indicated as a therapeutic target in obesity or diabetes. This review summarises the current literature concerning ghrelin’s physiological roles in energy and glucose homeostasis.
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Affiliation(s)
| | - Rans Nadir
- Faculty of Medicine, Imperial College London, London, GBR
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Wu R, Xiao D, Shan X, Dong Y, Tao WW. Rapid and Prolonged Antidepressant-like Effect of Crocin Is Associated with GHSR-Mediated Hippocampal Plasticity-related Proteins in Mice Exposed to Prenatal Stress. ACS Chem Neurosci 2020; 11:1159-1170. [PMID: 32203651 DOI: 10.1021/acschemneuro.0c00022] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Prenatal stress (PNS) has a prolonged and adverse effect on offspring, leading to a significantly increased vulnerability to developing depression in their later life. Traditional therapies have delayed onset and limited efficacy; thus, it remains an urgent need to find novel medications with fast-onset and high-efficacy potentials. Crocin, with its structure clearly examined, has shown antidepressant-like effects. However, few studies extensively investigated its effect especially in mice exposed to PNS. Using an established PNS model, we tested whether crocin could have a rapid and persistent antidepressant-like effect in PNS mice. Growth hormone secretagogue receptor (GHSR) and phosphoinositide 3-kinase (PI3K) inhibitors were used to test their effects in antidepressant-like effect of crocin. Hippocampal GHSR-PI3K signaling was examined both in PNS mice treated with a single dose of crocin and in combination of GHSR inhibitor. PNS mice showed depression-like behaviors at juvenile and adulthood, and crocin induced an instant and persistent antidepressant-like response in PNS mice in a dose-dependent manner. Moreover, crocin increased the expression of hippocampal synaptic plasticity-associated proteins through the restoration of GHSR-PI3K signaling. Inhibitions of both GHSR and PI3K abolished the effect of crocin in alleviating depressive-like behaviors. More importantly, GHSR inhibitor JMV2959 blocked the enhanced expression of hippocampal plasticity-related proteins induced by crocin. The present study demonstrated that crocin induced a fast-onset and prolonged antidepressant effect in PNS mice and suggested that GHSR-PI3K signaling may play a key role in crocin's effect at least partially by a restoration of hippocampal synaptic plasticity-associated proteins.
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Affiliation(s)
- Ruyan Wu
- School of Medicine, Yangzhou University, Yangzhou 225000, China
- Department of Pharmacology and Toxicology, University at Buffalo, Buffalo 14203, New York, United States
| | - Dong Xiao
- Key Laboratory of Integrative Biomedicine for Brain Diseases, School of Basic Biomedical Science, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Xin Shan
- Key Laboratory of Integrative Biomedicine for Brain Diseases, School of Basic Biomedical Science, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yu Dong
- Key Laboratory of Integrative Biomedicine for Brain Diseases, School of Basic Biomedical Science, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei-Wei Tao
- Key Laboratory of Integrative Biomedicine for Brain Diseases, School of Basic Biomedical Science, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Fernandez-Ranvier G, Meknat A, Guevara DE, Alenazi N, Ruiz H, Ritondale O, Alsanea O, Kini S, Herron D. The Role of Bariatric Surgery in Patients with Obesity and Type 1 Diabetes Mellitus. Bariatr Surg Pract Patient Care 2020. [DOI: 10.1089/bari.2019.0058] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Affiliation(s)
- Gustavo Fernandez-Ranvier
- Division of Metabolic, Endocrine and Minimally Invasive Surgery, Department of Surgery, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Aryan Meknat
- Division of Metabolic, Endocrine and Minimally Invasive Surgery, Department of Surgery, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Daniela E. Guevara
- Division of Metabolic, Endocrine and Minimally Invasive Surgery, Department of Surgery, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Naif Alenazi
- Department of Surgery, Prince Mohammed Bin Abdulaziz Hospital, Riyadh, Saudi Arabia
| | - Hugo Ruiz
- Division of Metabolic and Bariatric Surgery, Department of Surgery, Hospital Alejandro Posadas, El Palomar, Buenos Aires, Argentina
| | - Otto Ritondale
- Division of Metabolic and Bariatric Surgery, Department of Surgery, Hospital Alejandro Posadas, El Palomar, Buenos Aires, Argentina
| | | | - Subhash Kini
- Division of Metabolic, Endocrine and Minimally Invasive Surgery, Department of Surgery, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Daniel Herron
- Division of Metabolic, Endocrine and Minimally Invasive Surgery, Department of Surgery, Mount Sinai Hospital, Icahn School of Medicine at Mount Sinai, New York, New York
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Hartig SM, Cox AR. Paracrine signaling in islet function and survival. J Mol Med (Berl) 2020; 98:451-467. [PMID: 32067063 DOI: 10.1007/s00109-020-01887-x] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2019] [Revised: 02/05/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023]
Abstract
The pancreatic islet is a dense cellular network comprised of several cell types with endocrine function vital in the control of glucose homeostasis, metabolism, and feeding behavior. Within the islet, endocrine hormones also form an intricate paracrine network with supportive cells (endothelial, neuronal, immune) and secondary signaling molecules regulating cellular function and survival. Modulation of these signals has potential consequences for diabetes development, progression, and therapeutic intervention. Beta cell loss, reduced endogenous insulin secretion, and dysregulated glucagon secretion are hallmark features of both type 1 and 2 diabetes that not only impact systemic regulation of glucose, but also contribute to the function and survival of cells within the islet. Advancing research and technology have revealed new islet biology (cellular identity and transcriptomes) and identified previously unrecognized paracrine signals and mechanisms (somatostatin and ghrelin paracrine actions), while shifting prior views of intraislet communication. This review will summarize the paracrine signals regulating islet endocrine function and survival, the disruption and dysfunction that occur in diabetes, and potential therapeutic targets to preserve beta cell mass and function.
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Affiliation(s)
- Sean M Hartig
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA
| | - Aaron R Cox
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
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Shankar K, Gupta D, Mani BK, Findley BG, Lord CC, Osborne-Lawrence S, Metzger NP, Pietra C, Liu C, Berglund ED, Zigman JM. Acyl-ghrelin Is Permissive for the Normal Counterregulatory Response to Insulin-Induced Hypoglycemia. Diabetes 2020; 69:228-237. [PMID: 31685528 PMCID: PMC6971486 DOI: 10.2337/db19-0438] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Accepted: 11/01/2019] [Indexed: 02/06/2023]
Abstract
Insulin-induced hypoglycemia leads to far-ranging negative consequences in patients with diabetes. Components of the counterregulatory response (CRR) system that help minimize and reverse hypoglycemia and coordination between those components are well studied but not yet fully characterized. Here, we tested the hypothesis that acyl-ghrelin, a hormone that defends against hypoglycemia in a preclinical starvation model, is permissive for the normal CRR to insulin-induced hypoglycemia. Ghrelin knockout (KO) mice and wild-type (WT) littermates underwent an insulin bolus-induced hypoglycemia test and a low-dose hyperinsulinemic-hypoglycemic clamp procedure. Clamps also were performed in ghrelin-KO mice and C57BL/6N mice administered the growth hormone secretagogue receptor agonist HM01 or vehicle. Results show that hypoglycemia, as induced by an insulin bolus, was more pronounced and prolonged in ghrelin-KO mice, supporting previous studies suggesting increased insulin sensitivity upon ghrelin deletion. Furthermore, during hyperinsulinemic-hypoglycemic clamps, ghrelin-KO mice required a 10-fold higher glucose infusion rate (GIR) and exhibited less robust corticosterone and growth hormone responses. Conversely, HM01 administration, which reduced the GIR required by ghrelin-KO mice during the clamps, increased plasma corticosterone and growth hormone. Thus, our data suggest that endogenously produced acyl-ghrelin not only influences insulin sensitivity but also is permissive for the normal CRR to insulin-induced hypoglycemia.
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Affiliation(s)
- Kripa Shankar
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Deepali Gupta
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Bharath K Mani
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Brianna G Findley
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Caleb C Lord
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Sherri Osborne-Lawrence
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Nathan P Metzger
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | | | - Chen Liu
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
- Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX
| | - Eric D Berglund
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
| | - Jeffrey M Zigman
- Center for Hypothalamic Research, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
- Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX
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Shankar K, Gupta D, Mani BK, Findley BG, Osborne-Lawrence S, Metzger NP, Liu C, Berglund ED, Zigman JM. Ghrelin Protects Against Insulin-Induced Hypoglycemia in a Mouse Model of Type 1 Diabetes Mellitus. Front Endocrinol (Lausanne) 2020; 11:606. [PMID: 33042003 PMCID: PMC7518392 DOI: 10.3389/fendo.2020.00606] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Accepted: 07/27/2020] [Indexed: 01/28/2023] Open
Abstract
Insulin-induced hypoglycemia is a major limiting factor in maintaining optimal blood glucose in patients with type 1 diabetes and advanced type 2 diabetes. Luckily, a counterregulatory response (1) system exists to help minimize and reverse hypoglycemia, although more studies are needed to better characterize its components. Recently, we showed that the hormone ghrelin is permissive for the normal CRR to insulin-induced hypoglycemia when assessed in mice without diabetes. Here, we tested the hypothesis that ghrelin also is protective against insulin-induced hypoglycemia in the streptozotocin (2) mouse model of type 1 diabetes. STZ-treated ghrelin-knockout (KO) (3) mice as well as STZ-treated wild-type (WT) littermates were subjected to a low-dose hyperinsulinemic-hypoglycemic clamp procedure. The STZ-treated ghrelin-KO mice required a much higher glucose infusion rate than the STZ-treated WT mice. Also, the STZ-treated ghrelin-KO mice exhibited attenuated plasma epinephrine and norepinephrine responses to the insulin-induced hypoglycemia. Taken together, our data suggest that without ghrelin, STZ-treated mice modeling type 1 diabetes are unable to mount the usual CRR to insulin-induced hypoglycemia.
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Affiliation(s)
- Kripa Shankar
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Deepali Gupta
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Bharath K. Mani
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Brianna G. Findley
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Sherri Osborne-Lawrence
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Nathan P. Metzger
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Chen Liu
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
- Department of Neuroscience, UT Southwestern Medical Center, Dallas, TX, United States
| | - Eric D. Berglund
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
| | - Jeffrey M. Zigman
- Department of Internal Medicine, Center for Hypothalamic Research, UT Southwestern Medical Center, Dallas, TX, United States
- Division of Endocrinology, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX, United States
- Department of Psychiatry, UT Southwestern Medical Center, Dallas, TX, United States
- *Correspondence: Jeffrey M. Zigman
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Akalu Y, Molla MD, Dessie G, Ayelign B. Physiological Effect of Ghrelin on Body Systems. Int J Endocrinol 2020; 2020:1385138. [PMID: 32565790 PMCID: PMC7267865 DOI: 10.1155/2020/1385138] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 02/08/2020] [Accepted: 05/13/2020] [Indexed: 02/06/2023] Open
Abstract
Ghrelin is a relatively novel multifaceted hormone that has been found to exert a plethora of physiological effects. In this review, we found/confirmed that ghrelin has effect on all body systems. It induces appetite; promotes the use of carbohydrates as a source of fuel while sparing fat; inhibits lipid oxidation and promotes lipogenesis; stimulates the gastric acid secretion and motility; improves cardiac performance; decreases blood pressure; and protects the kidneys, heart, and brain. Ghrelin is important for learning, memory, cognition, reward, sleep, taste sensation, olfaction, and sniffing. It has sympatholytic, analgesic, antimicrobial, antifibrotic, and osteogenic effects. Moreover, ghrelin makes the skeletal muscle more excitable and stimulates its regeneration following injury; delays puberty; promotes fetal lung development; decreases thyroid hormone and testosterone; stimulates release of growth hormone, prolactin, glucagon, adrenocorticotropic hormone, cortisol, vasopressin, and oxytocin; inhibits insulin release; and promotes wound healing. Ghrelin protects the body by different mechanisms including inhibition of unwanted inflammation and induction of autophagy. Having a clear understanding of the ghrelin effect in each system has therapeutic implications. Future studies are necessary to elucidate the molecular mechanisms of ghrelin actions as well as its application as a GHSR agonist to treat most common diseases in each system without any paradoxical outcomes on the other systems.
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Affiliation(s)
- Yonas Akalu
- Department of Physiology, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Meseret Derbew Molla
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Gashaw Dessie
- Department of Biochemistry, School of Medicine, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
| | - Birhanu Ayelign
- Department of Immunology and Molecular Biology, School of Biomedical and Laboratory Science, College of Medicine and Health Sciences, University of Gondar, Gondar, Ethiopia
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Mifune H, Tajiri Y, Sakai Y, Kawahara Y, Hara K, Sato T, Nishi Y, Nishi A, Mitsuzono R, Kakuma T, Kojima M. Voluntary exercise is motivated by ghrelin, possibly related to the central reward circuit. J Endocrinol 2020; 244:123-132. [PMID: 31629323 PMCID: PMC6859445 DOI: 10.1530/joe-19-0213] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 10/08/2019] [Indexed: 01/05/2023]
Abstract
We previously reported that voluntary exercise contributed to the amelioration of abnormal feeding behavior with a concomitant restoration of ghrelin production in a rat model of obesity, suggesting a possible relationship between exercise and appetite-regulating hormones. Ghrelin is known to be involved in the brain reward circuits via dopamine neurons related to motivational properties. We investigated the relevance of ghrelin as an initiator of voluntary exercise as well as feeding behavior. The plasma ghrelin concentration fluctuates throughout the day with its peak at the beginning of the dark period in the wild-type (WT) mice with voluntary exercise. Although predominant increases in wheel running activity were observed accordant to the peak of plasma ghrelin concentration in the WT mice, those were severely attenuated in the ghrelin-knockout (GKO) mice under either ad libitum or time-restricted feeding. A single injection of ghrelin receptor agonist brought about and reproduced a marked enhancement of wheel running activity, in contrast to no effect by the continuous administration of the same drug. Brain dopamine levels (DAs) were enhanced after food consumption in the WT mice under voluntary exercise. Although the acceleration of DAs were apparently blunted in the GKO mice, they were dramatically revived after the administration of ghrelin receptor agonist, suggesting the relevance of ghrelin in the reward circuit under voluntary exercise. These findings emphasize that the surge of ghrelin plays a crucial role in the formation of motivation for the initiation of voluntary exercise possibly related to the central dopamine system.
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Affiliation(s)
- Hiroharu Mifune
- Institute of Animal Experimentation, Kurume University School of Medicine, Kurume, Japan
| | - Yuji Tajiri
- Division of Endocrinology and Metabolism, Kurume University School of Medicine, Kurume, Japan
- Correspondence should be addressed to Y Tajiri:
| | - Yusuke Sakai
- Institute of Animal Experimentation, Kurume University School of Medicine, Kurume, Japan
| | - Yukie Kawahara
- Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
| | - Kento Hara
- Division of Endocrinology and Metabolism, Kurume University School of Medicine, Kurume, Japan
| | - Takahiro Sato
- Molecular Genetics, Life Science Institute, Kurume University, Kurume, Japan
| | - Yoshihiro Nishi
- Department of Physiology, Kurume University School of Medicine, Kurume, Japan
| | - Akinori Nishi
- Department of Pharmacology, Kurume University School of Medicine, Kurume, Japan
| | - Ryouichi Mitsuzono
- Department of Exercise Physiology, Institute of Health and Sports Science, Kurume University, Kurume, Japan
| | | | - Masayasu Kojima
- Molecular Genetics, Life Science Institute, Kurume University, Kurume, Japan
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Abstract
Maintenance of systemic homeostasis and the response to nutritional and environmental challenges require the coordination of multiple organs and tissues. To respond to various metabolic demands, higher organisms have developed a system of inter-organ communication through which one tissue can affect metabolic pathways in a distant tissue. Dysregulation of these lines of communication contributes to human pathologies, including obesity, diabetes, liver disease and atherosclerosis. In recent years, technical advances such as data-driven bioinformatics, proteomics and lipidomics have enabled efforts to understand the complexity of systemic metabolic cross-talk and its underlying mechanisms. Here, we provide an overview of inter-organ signals and their roles in metabolic control, and highlight recent discoveries in the field. We review peptide, small-molecule and lipid mediators secreted by metabolic tissues, as well as the role of the central nervous system in orchestrating peripheral metabolic functions. Finally, we discuss the contributions of inter-organ signalling networks to the features of metabolic syndrome.
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Affiliation(s)
- Christina Priest
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
- Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
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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: 12] [Impact Index Per Article: 2.0] [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.
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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
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Early life stress induces type 2 diabetes-like features in ageing mice. Brain Behav Immun 2019; 80:452-463. [PMID: 30981713 DOI: 10.1016/j.bbi.2019.04.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Revised: 02/22/2019] [Accepted: 04/10/2019] [Indexed: 12/31/2022] Open
Abstract
Early life stress is known to impair intestinal barrier through induction of intestinal hyperpermeability, low-grade inflammation and microbiota dysbiosis in young adult rodents. Interestingly, those features are also observed in metabolic disorders (obesity and type 2 diabetes) that appear with ageing. Based on the concept of Developmental Origins of Health and Diseases, our study aimed to investigate whether early life stress can trigger metabolic disorders in ageing mice. Maternal separation (MS) is a well-established model of early life stress in rodent. In this study, MS increased fasted blood glycemia, induced glucose intolerance and decreased insulin sensitivity in post-natal day 350 wild type C3H/HeN male mice fed a standard diet without affecting body weight. MS also triggered fecal dysbiosis favoring pathobionts and significantly decreased IL-17 and IL-22 secretion in response to anti-CD3/CD28 stimulation in small intestine lamina propria. Finally, IL-17 secretion in response to anti-CD3/CD28 stimulation was also diminished at systemic level (spleen). For the first time, we demonstrate that early life stress is a risk factor for metabolic disorders development in ageing wild type mice under normal diet.
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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.
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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
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50
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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.
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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:
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