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Li Y, Zhi W, Haoxu D, Qing W, Ling C, Ping Y, Dongmei H. Effects of electroacupuncture on the expression of hypothalamic neuropeptide Y and ghrelin in pubertal rats with polycystic ovary syndrome. PLoS One 2022; 17:e0259609. [PMID: 35704659 PMCID: PMC9200359 DOI: 10.1371/journal.pone.0259609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 06/01/2022] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Polycystic ovary syndrome often starts in puberty, and its pathogenesis is not clear. This study aimed to explore the pathogenesis of pubertal polycystic ovary syndrome (PCOS) and assess the therapeutic effect of electroacupuncture on pubertal PCOS. METHODS Dihydrotestosterone (DHT) was used to induce rat models of pubertal PCOS. pubertal rats with PCOS were randomly divided into a model group (M), an electroacupuncture group (EA), and a sham acupuncture group (SA). Age-matched normal rats were regarded as normal controls (N). Rats were treated with EA or SA five times a week for 25 minutes during their 6th-7th week. At the end of the experiment, we observed any changes in ovarian morphology; detected levels of metabolic indices in serum, the hypothalamus and pancreas. RESULTS EA significantly improved estrous cycle disorders and the ovarian polycystic morphology in pubertal rats with PCOS, but SA only improved disorders of the estrous cycle. The serum levels of insulin, neuropeptide Y(NPY) and fasting blood glucose(FBG) increased significantly (both p < 0.01), while the serum levels of ghrelin(GHRL) decreased in the model group (p < 0.01). After treatment with EA, the levels of NPY (p < 0.01) and FBG (p < 0.05) went into decrease, whereas the levels of GHRL (p < 0.05) and insulin (p < 0.01) increased. There was few differences in the hypothalamic expression of galanin (GAL), galanin-like peptide (GALP) and ghrelin receptor(GHSR) between the four groups. The upregulation of NPY mRNA and neuropeptide Y2 receptor(NPY2R) mRNA and the downregulation of GHRL protein and mRNA in the hypothalamus, and the increased expression of NPY and NPY2R as well as the decreased expression of GHRL in the arcuate nucleus (ARC) can be rescued by EA. But, surprisingly, SA seem to make no difference to the levels of FBG and insulin, and the protein expression of ghrelin in the hypothalamus and ARC. Co-expression of kisspeptin and GHSR, and co-expression of gonadotrophin releasing hormone(GnRH) and NPY2R were observed in ARC. No differences were found between groups in protein of GAL, GALP and GHRL expression in the pancreas. Neither EA nor SA can attenuate the upregulated kisspeptin protein expression in the pancreas of PCOS model rats. CONCLUSIONS EA and SA improved the symptoms of pubertal PCOS rats, and the mechanism might be associated with regulating hypothalamic NPY and ghrelin levels.
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Affiliation(s)
- Yang Li
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Wang Zhi
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Haoxu
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Wang Qing
- Department of Rehabilitation Center of Wuhan Puren Hospital, Affiliated Hospital of Wuhan University of Science and Technology, Wuhan, China
| | - Cheng Ling
- Department of Acupuncture and Moxibustion, East Hospital, Tongji University, Shanghai, China
| | - Yi Ping
- Department of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
| | - Huang Dongmei
- Institute of Integrated Traditional Chinese and Western Medicine, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China
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Protective and Healing Effects of Ghrelin and Risk of Cancer in the Digestive System. Int J Mol Sci 2021; 22:ijms221910571. [PMID: 34638910 PMCID: PMC8509076 DOI: 10.3390/ijms221910571] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 09/24/2021] [Accepted: 09/27/2021] [Indexed: 01/19/2023] Open
Abstract
Ghrelin is an endogenous ligand for the ghrelin receptor, previously known as the growth hormone secretagogue receptor. This hormone is mainly produced by endocrine cells present in the gastric mucosa. The ghrelin-producing cells are also present in other organs of the body, mainly in the digestive system, but in much smaller amount. Ghrelin exhibits a broad spectrum of physiological effects, such as stimulation of growth hormone secretion, gastric secretion, gastrointestinal motility, and food intake, as well as regulation of glucose homeostasis and bone formation, and inhibition of inflammatory processes. This review summarizes the recent findings concerning animal and human data showing protective and therapeutic effects of ghrelin in the gut, and also presents the role of growth hormone and insulin-like growth factor-1 in these effects. In addition, the current data on the possible influence of ghrelin on the carcinogenesis, its importance in predicting the risk of developing gastrointestinal malignances, as well as the potential usefulness of ghrelin in the treatment of cancer, have been presented.
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Ceron-Romero N, Taofeek N, Thomas A, Vroonland E, Sanmartin K, Verghese M, Heinen E, Vizcarra JA. Capromorelin, a ghrelin receptor agonist, increases feed intake and body weight gain in broiler chickens (Gallus gallus domesticus). Poult Sci 2021; 100:101204. [PMID: 34182219 PMCID: PMC8250453 DOI: 10.1016/j.psj.2021.101204] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 03/24/2021] [Accepted: 04/05/2021] [Indexed: 11/27/2022] Open
Abstract
Ghrelin is a hormone that induces orexigenic effects in mammals. However, in avian species, there is scant and conflictive results on the effect of ghrelin on feed intake (FI). Therefore, we evaluated the effect of a ghrelin receptor agonist (capromorelin) on FI, ADG, water intake (WI), animal behavior and concentrations of ghrelin, glucose, growth hormone (GH) and insulin in broiler chickens. One-day-old male broilers were reared as recommended by the industry. At 4 wk of age (experimental day 0; D0), birds were blocked by weight and randomly assigned to 3 treatments in 2 identical trials. Control birds received a vehicle control solution containing 0 mg/kgBW/d of capromorelin. Birds in treatments 2 and 3 received capromorelin at target doses of 6 or 12 mg/kgBW/d of capromorelin (n = 27). FI and WI were measured 3 times a day at 0700 h (Period 1; P1), 1200 h (P2) and 1700 h (P3), while BW was recorded daily. Blood samples were collected on D-1 and D5. Bird behavior (pecking, sitting and standing) was evaluated for 9 h on D2. Data were analyzed using a randomized complete block design with repeated measures over time. Orthogonal polynomial contrasts were used to determine linear and quadratic effects of increasing levels of capromorelin. Polynomial contrasts showed that capromorelin doses linearly increased FI (P = 0.002) and ADG (P = 0.019). There were no treatment, day or treatment x d interactions on glucose, ghrelin and GH concentrations. However, there was a treatment x d interaction (P = 0.041) on insulin concentrations. Concentrations of insulin were higher on D5 for the 0 and 12 mg/kgBW/d treatments as compared with D-1. Polynomial contrasts showed that capromorelin doses linearly increased number of pecks/h (P = 0.018). Per hour FI and WI was higher during P1 (i.e., 0700-1200) as compared to P2 and P3 (P < 0.001). Our observations suggest that capromorelin linearly increases feed intake; thus, the same effect of that reported in mammalian species.
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Affiliation(s)
- N Ceron-Romero
- Food and Animal Sciences, Alabama A&M University, Normal, AL 35762, USA
| | - N Taofeek
- Food and Animal Sciences, Alabama A&M University, Normal, AL 35762, USA
| | - A Thomas
- Food and Animal Sciences, Alabama A&M University, Normal, AL 35762, USA
| | - E Vroonland
- Food and Animal Sciences, Alabama A&M University, Normal, AL 35762, USA
| | - K Sanmartin
- Food and Animal Sciences, Alabama A&M University, Normal, AL 35762, USA
| | - M Verghese
- Food and Animal Sciences, Alabama A&M University, Normal, AL 35762, USA
| | - E Heinen
- Elanco Animal Health, Greenfield, IN 46140, USA
| | - J A Vizcarra
- Food and Animal Sciences, Alabama A&M University, Normal, AL 35762, USA.
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Mika K, Szafarz M, Sapa J, Kotańska M. Influence of betahistine repeated administration on a weight gain and selected metabolic parameters in the model of excessive eating in rats. Biomed Pharmacother 2021; 141:111892. [PMID: 34229247 DOI: 10.1016/j.biopha.2021.111892] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/24/2021] [Accepted: 06/28/2021] [Indexed: 01/02/2023] Open
Abstract
It is important to search for a promising therapeutic target or small molecules that can control excessive eating since limiting the intake of foods, especially tasty ones, could be effective in the treatment or prevention of obesity. Some studies indicate betahistine as an unique drug having the ability to ameliorate, for example, antipsychotic-induced weight gain. This study aimed to determine whether repeated administration of betahistine (histamine H1R agonist and H3R antagonist) could be beneficial in reducing the intake of tasty foods or the body's response to overeating via mechanisms such as by influencing the levels of hormones involved in the regulation of food intake or the levels of selected metabolic parameters. Studies were performed in the excessive eating model in rats, which perfectly illustrates the harmful high-caloric intake from freely available tasty products rich in sugar and fat. Our results indicated that repeated administration of betahistine to rats caused lower gain of body mass compared to the control rats fed palatable feed. Interestingly, betahistine treatment increased the consumption of cheese, which is a source of histamine. Although betahistine did not prevent the development of metabolic disorders, such as reduced glucose tolerance, in test animals, it significantly increased the level of high-density lipoprotein cholesterol, which could certainly be considered beneficial. Further studies should be conducted to investigate the effect of repeated administration of betahistine on satiety, gastrointestinal disorders, and the preference for histamine-containing foods.
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Affiliation(s)
- Kamil Mika
- Department of Pharmacological Screening, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Cracow, Poland
| | - Małgorzata Szafarz
- Department of Pharmacokinetics and Physical Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland
| | - Jacek Sapa
- Department of Pharmacological Screening, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Cracow, Poland
| | - Magdalena Kotańska
- Department of Pharmacological Screening, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Cracow, Poland.
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The endocannabinoid system: Novel targets for treating cancer induced bone pain. Biomed Pharmacother 2019; 120:109504. [PMID: 31627091 DOI: 10.1016/j.biopha.2019.109504] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2019] [Revised: 09/16/2019] [Accepted: 09/26/2019] [Indexed: 02/08/2023] Open
Abstract
Treating Cancer-induced bone pain (CIBP) continues to be a major clinical challenge and underlying mechanisms of CIBP remain unclear. Recently, emerging body of evidence suggested the endocannabinoid system (ECS) may play essential roles in CIBP. Here, we summarized the current understanding of the antinociceptive mechanisms of endocannabinoids in CIBP and discussed the beneficial effects of endocannabinoid for CIBP treatment. Targeting non-selective cannabinoid 1 receptors or selective cannabinoid 2 receptors, and modulation of peripheral AEA and 2-AG, as well as the inhibition the function of fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have produced analgesic effects in animal models of CIBP. Management of ECS therefore appears to be a promising way for the treatment of CIBP in terms of efficacy and safety. Further clinical studies are encouraged to confirm the possible translation to humans of the very promising results already obtained in the preclinical studies.
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Stempniewicz A, Ceranowicz P, Warzecha Z. Potential Therapeutic Effects of Gut Hormones, Ghrelin and Obestatin in Oral Mucositis. Int J Mol Sci 2019; 20:ijms20071534. [PMID: 30934722 PMCID: PMC6479885 DOI: 10.3390/ijms20071534] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Revised: 03/15/2019] [Accepted: 03/19/2019] [Indexed: 12/16/2022] Open
Abstract
Chemotherapy and/or head and neck radiotherapy are frequently associated with oral mucositis. Oral pain, odynophagia and dysphagia, opioid use, weight loss, dehydration, systemic infection, hospitalization and introduction of a feeding tube should be mentioned as the main determinated effect of oral mucositis. Oral mucositis leads to a decreased quality of life and an increase in treatment costs. Moreover, oral mucositis is a life-threatening disease. In addition to its own direct life-threatening consequences, it can also lead to a reduced survival due to the discontinuation or dose reduction of anti-neoplasm therapy. There are numerous strategies for the prevention or treatment of oral mucositis; however, their effectiveness is limited and does not correspond to expectations. This review is focused on the ghrelin and obestatin as potentially useful candidates for the prevention and treatment of chemo- or/and radiotherapy-induced oral mucositis.
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Affiliation(s)
- Agnieszka Stempniewicz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Grzegórzecka 16 St., 31-531 Krakow, Poland.
| | - Piotr Ceranowicz
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Grzegórzecka 16 St., 31-531 Krakow, Poland.
| | - Zygmunt Warzecha
- Department of Physiology, Faculty of Medicine, Jagiellonian University Medical College, Grzegórzecka 16 St., 31-531 Krakow, Poland.
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Improvement of Adipose Macrophage Polarization in High Fat Diet-Induced Obese GHSR Knockout Mice. BIOMED RESEARCH INTERNATIONAL 2018; 2018:4924325. [PMID: 30112394 PMCID: PMC6077514 DOI: 10.1155/2018/4924325] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Revised: 05/06/2018] [Accepted: 05/28/2018] [Indexed: 12/16/2022]
Abstract
Purpose Adipose tissue inflammation is the key linking obesity to insulin resistance. Over 50% of the interstitial cells in adipose tissue are macrophages, which produce inflammatory cytokines and therefore play an important role in the progression of insulin resistance. Within this classification view, macrophage biology is driven by two polarization phenotypes, M1 (proinflammatory) and M2 (anti-inflammatory). The unique functional receptor of ghrelin, growth hormone secretagogue receptor (GHSR), is a classic seven-transmembrane G protein-coupled receptor that is linked to multiple intracellular signaling pathways. Knockout of GHSR improves the obesity and glucose metabolic disorders, suggesting a crucial role of ghrelin activity in insulin resistance. Here, we discussed whether macrophage polarization phenotypes in adipose tissue were changed in GHSR knockout (GHSR-/-) mice. Methods GHSR-/- mice were fed with normal chow diet (NCD) or high fat diet (HFD). Markers of different macrophage polarization phenotypes were detected by real-time RT-PCR. Results The size of adipocytes decreased and interstitial cells, especially infiltrated macrophages, reduced in epididymal adipose tissue of GHSR-/- mice fed with HFD. Compared with wild type mice, the mRNA levels of inflammatory adipokines such as resistin, IL-6, and PAI-1 were significantly lower in epididymal adipose tissue of GHSR-/- mice, whereas anti-inflammatory adipokine, adiponectin, was significantly higher. M1 markers, MCP-1, TNF-α, and iNOS, were significantly lower in epididymal adipose tissue of GHSR-/- mice, whereas M2 markers, Arg-1, Mgl-1, were Mrc1, were significantly higher. Conclusion The GHSR-/- mice fed with HFD showed suppressed adipose inflammation, reduced macrophage infiltration, and enhanced M2 polarization of macrophages in adipose tissue, which improved insulin sensitivity.
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Zhou M, Liu J, Qi Y, Wang M, Wang Y, Zhao F, Hao Y, Zhao D. The association between Helicobacter pylori seropositivity and risk of new-onset diabetes: a prospective cohort study. Diabetologia 2018; 61:300-307. [PMID: 29085991 PMCID: PMC6448956 DOI: 10.1007/s00125-017-4465-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2017] [Accepted: 08/31/2017] [Indexed: 12/30/2022]
Abstract
AIMS/HYPOTHESIS Previous studies have suggested a possible connection between Helicobacter pylori (H. pylori) infection and diabetes risk. However, prospective studies examining direct associations between these two factors are relatively lacking. In this prospective cohort study, we aimed to evaluate the association between H. pylori infection and risk of developing diabetes. METHODS We performed a population-based prospective study, recruiting participants aged 45-74 years and without diabetes from the Chinese Multi-provincial Cohort Study in 2002, with a 10 year follow-up to investigate development of diabetes. H. pylori serostatus was determined by measuring serum H. pylori antibodies. H. pylori seropositivity was defined as the antibody concentration ≥ 10 U/ml. To examine the association between H. pylori seropositivity and diabetes risk, modified Poisson regression was performed. RESULTS Of 2085 participants without diabetes, 1208 (57.9%) were H. pylori seropositive in 2002. After multivariate adjustment of possible diabetes risk factors, H. pylori seropositivity was associated with lower risk of diabetes (RR 0.78 [95% CI 0.63, 0.97], p = 0.022). Of the 1275 participants with H. pylori antibody measurements in both 2002 and 2007, 677 (53.1%) were persistently seropositive. A lower risk of diabetes was also observed in participants with persistent H. pylori seropositivity (RR 0.61 [95% CI 0.41, 0.93], p = 0.020), compared with those persistently seronegative. CONCLUSIONS/INTERPRETATION H. pylori seropositivity was associated with lower risk of diabetes in this prospective cohort study. Extrapolation of these results and the mechanism underlying the observed association require further investigation.
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Affiliation(s)
- Mengge Zhou
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Jing Liu
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Yue Qi
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Miao Wang
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Ying Wang
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Fan Zhao
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Yongchen Hao
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China
| | - Dong Zhao
- Department of Epidemiology, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung and Blood Vessel Diseases, the Key Laboratory of Remodelling-Related Cardiovascular Diseases, Ministry of Education, No. 2 Anzhen Road, Chaoyang District, Beijing, 100029, China.
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Chen VP, Gao Y, Geng L, Brimijoin S. Butyrylcholinesterase regulates central ghrelin signaling and has an impact on food intake and glucose homeostasis. Int J Obes (Lond) 2017; 41:1413-1419. [PMID: 28529331 PMCID: PMC5585042 DOI: 10.1038/ijo.2017.123] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 04/21/2017] [Accepted: 05/03/2017] [Indexed: 12/13/2022]
Abstract
Background: Ghrelin is the only orexigenic hormone known to stimulate food intake and promote obesity and insulin resistance. We recently showed that plasma ghrelin is controlled by butyrylcholinesterase (BChE), which has a strong impact on feeding and weight gain. BChE knockout (KO) mice are prone to obesity on high-fat diet, but hepatic BChE gene transfer rescues normal food intake and obesity resistance. However, these mice lack brain BChE and still develop hyperinsulinemia and insulin resistance, suggesting essential interactions between BChE and ghrelin within the brain. Methods: To test the hypothesis we used four experimental groups: (1) untreated wild-type mice, (2) BChE KO mice with LUC delivered by adeno-associated virus (AAV) in combined intravenous (i.v.) and intracerebral (i.c.) injections, (3) KO mice given AAV for mouse BChE (i.v. only) and (4) KO mice given the same vector both i.v. and i.c. All mice ate a 45% calorie high-fat diet from the age of 1 month. Body weight, body composition, daily caloric intake and serum parameters were monitored throughout, and glucose tolerance and insulin tolerance tests were performed at intervals. Results: Circulating ghrelin levels dropped substantially in the KO mice after i.v. AAV–BChE delivery, which led to normal food intake and healthy body weight. BChE KO mice that received AAV–BChE through i.v. and i.c. combined treatments not only resisted weight gain on high-fat diet but also retained normal glucose and insulin tolerance. Conclusions: These data indicate a central role for BChE in regulating both insulin and glucose homeostasis. BChE gene transfer could be a useful therapy for complications linked to diet-induced obesity and insulin resistance.
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Affiliation(s)
- V P Chen
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - Y Gao
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - L Geng
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
| | - S Brimijoin
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55905, USA
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Stawerska R, Smyczyńska J, Hilczer M, Lewiński A. Relationship between IGF-I Concentration and Metabolic Profile in Children with Growth Hormone Deficiency: The Influence of Children's Nutritional State as well as the Ghrelin, Leptin, Adiponectin, and Resistin Serum Concentrations. Int J Endocrinol 2017; 2017:5713249. [PMID: 28596789 PMCID: PMC5449754 DOI: 10.1155/2017/5713249] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2017] [Accepted: 04/13/2017] [Indexed: 01/19/2023] Open
Abstract
BACKGROUND Some, however not all, children with growth hormone deficiency (GHD) reveal a tendency towards metabolic disorders. Insulin-like growth factor I (IGF-I) is the main mediator of GH anabolic effects. OBJECTIVE The aim of the study was to compare ghrelin, adiponectin, leptin, resistin, lipid, glucose, and insulin concentrations in GHD children, depending on the IGF-I bioavailability. METHODS The analysis comprised 26 children with GHD, aged 5.7-15.3 yrs. Fasting serum concentrations of IGF-I, IGFBP-3, ghrelin, leptin, adiponectin, resistin, lipids, glucose, and insulin were measured. The GHD children were divided into two subgroups: (1) with lower IGF-I/IGFBP-3 molar ratio and (2) with higher IGF-I/IGFBP-3 molar ratio. The control group consisted of 39 healthy children, aged 5.1-16.6 yrs, of normal height and body mass. RESULTS GHD children with lower IGF-I/IGFBP-3 molar ratio were found to have a significantly lower body mass and insulin and triglyceride concentrations, as well as significantly higher ghrelin and adiponectin concentrations than GHD children with higher IGF-I/IGFBP-3. CONCLUSIONS A better metabolic profile characterised GHD children with low IGF-I bioavailability. This phenomenon may be the result of high adiponectin and ghrelin concentrations in those children and their influence on adipose tissue, glucose uptake, and orexigenic axis.
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Affiliation(s)
- Renata Stawerska
- Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital-Research Institute, Rzgowska Street 281/289, 93-338 Lodz, Poland
| | - Joanna Smyczyńska
- Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital-Research Institute, Rzgowska Street 281/289, 93-338 Lodz, Poland
| | - Maciej Hilczer
- Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital-Research Institute, Rzgowska Street 281/289, 93-338 Lodz, Poland
- Department of Pediatric Endocrinology, Medical University of Lodz, Rzgowska Street 281/289, 93-338 Lodz, Poland
| | - Andrzej Lewiński
- Department of Endocrinology and Metabolic Diseases, Polish Mother's Memorial Hospital-Research Institute, Rzgowska Street 281/289, 93-338 Lodz, Poland
- Department of Endocrinology and Metabolic Diseases, Medical University of Lodz, Rzgowska Street 281/289, 93-338 Lodz, Poland
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Clarifying the Ghrelin System's Ability to Regulate Feeding Behaviours Despite Enigmatic Spatial Separation of the GHSR and Its Endogenous Ligand. Int J Mol Sci 2017; 18:ijms18040859. [PMID: 28422060 PMCID: PMC5412441 DOI: 10.3390/ijms18040859] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/04/2017] [Accepted: 04/11/2017] [Indexed: 12/23/2022] Open
Abstract
Ghrelin is a hormone predominantly produced in and secreted from the stomach. Ghrelin is involved in many physiological processes including feeding, the stress response, and in modulating learning, memory and motivational processes. Ghrelin does this by binding to its receptor, the growth hormone secretagogue receptor (GHSR), a receptor found in relatively high concentrations in hypothalamic and mesolimbic brain regions. While the feeding and metabolic effects of ghrelin can be explained by the effects of this hormone on regions of the brain that have a more permeable blood brain barrier (BBB), ghrelin produced within the periphery demonstrates a limited ability to reach extrahypothalamic regions where GHSRs are expressed. Therefore, one of the most pressing unanswered questions plaguing ghrelin research is how GHSRs, distributed in brain regions protected by the BBB, are activated despite ghrelin’s predominant peripheral production and poor ability to transverse the BBB. This manuscript will describe how peripheral ghrelin activates central GHSRs to encourage feeding, and how central ghrelin synthesis and ghrelin independent activation of GHSRs may also contribute to the modulation of feeding behaviours.
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Blanco AM, Bertucci JI, Ramesh N, Delgado MJ, Valenciano AI, Unniappan S. Ghrelin Facilitates GLUT2-, SGLT1- and SGLT2-mediated Intestinal Glucose Transport in Goldfish (Carassius auratus). Sci Rep 2017; 7:45024. [PMID: 28338019 PMCID: PMC5364492 DOI: 10.1038/srep45024] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 02/17/2017] [Indexed: 12/13/2022] Open
Abstract
Glucose homeostasis is an important biological process that involves a variety of regulatory mechanisms. This study aimed to determine whether ghrelin, a multifunctional gut-brain hormone, modulates intestinal glucose transport in goldfish (Carassius auratus). Three intestinal glucose transporters, the facilitative glucose transporter 2 (GLUT2), and the sodium/glucose co-transporters 1 (SGLT1) and 2 (SGLT2), were studied. Immunostaining of intestinal sections found colocalization of ghrelin and GLUT2 and SGLT2 in mucosal cells. Some cells containing GLUT2, SGLT1 and SGLT2 coexpressed the ghrelin/growth hormone secretagogue receptor 1a (GHS-R1a). Intraperitoneal glucose administration led to a significant increase in serum ghrelin levels, as well as an upregulation of intestinal preproghrelin, ghrelin O-acyltransferase and ghs-r1 expression. In vivo and in vitro ghrelin treatment caused a concentration- and time-dependent modulation (mainly stimulatory) of GLUT2, SGLT1 and SGLT2. These effects were abolished by the GHS-R1a antagonist [D-Lys3]-GHRP-6 and the phospholipase C inhibitor U73122, suggesting that ghrelin actions on glucose transporters are mediated by GHS-R1a via the PLC/PKC signaling pathway. Finally, ghrelin stimulated the translocation of GLUT2 into the plasma membrane of goldfish primary intestinal cells. Overall, data reported here indicate an important role for ghrelin in the modulation of glucoregulatory machinery and glucose homeostasis in fish.
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Affiliation(s)
- Ayelén Melisa Blanco
- Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain.,Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Juan Ignacio Bertucci
- Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.,Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico Chascomús, Buenos Aires, Argentina
| | - Naresh Ramesh
- Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - María Jesús Delgado
- Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain
| | - Ana Isabel Valenciano
- Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, Madrid, Spain
| | - Suraj Unniappan
- Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
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Blanco AM, Bertucci JI, Sánchez-Bretaño A, Delgado MJ, Valenciano AI, Unniappan S. Ghrelin modulates gene and protein expression of digestive enzymes in the intestine and hepatopancreas of goldfish (Carassius auratus) via the GHS-R1a: Possible roles of PLC/PKC and AC/PKA intracellular signaling pathways. Mol Cell Endocrinol 2017; 442:165-181. [PMID: 28042022 DOI: 10.1016/j.mce.2016.12.027] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 12/28/2016] [Accepted: 12/28/2016] [Indexed: 12/13/2022]
Abstract
Ghrelin, a multifunctional gut-brain hormone, is involved in the regulation of gastric functions in mammals. This study aimed to determine whether ghrelin modulates digestive enzymes in goldfish (Carassius auratus). Immunofluorescence microscopy found colocalization of ghrelin, GHS-R1a and the digestive enzymes sucrase-isomaltase, aminopeptidase A, trypsin and lipoprotein lipase in intestinal and hepatopancreatic cells. In vitro ghrelin treatment in intestinal and hepatopancreas explant culture led to a concentration- and time-dependent modulation (mainly stimulatory) of most of the digestive enzymes tested. The ghrelin-induced upregulations of digestive enzyme expression were all abolished by preincubation with the GHS-R1a ghrelin receptor antagonist [D-Lys3]-GHRP-6, and most of them by the phospholipase C inhibitor U73122 or the protein kinase A inhibitor H89. This indicates that ghrelin effects on digestive enzymes are mediated by GHS-R1a, partly by triggering the PLC/PKC and AC/PKA intracellular signaling pathways. These data suggest a role for ghrelin on digestive processes in fish.
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Affiliation(s)
- Ayelén Melisa Blanco
- Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, S7N 5B4 Saskatoon, Saskatchewan, Canada; Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, José Antonio Nováis 12, 28040 Madrid, Spain.
| | - Juan Ignacio Bertucci
- Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, S7N 5B4 Saskatoon, Saskatchewan, Canada; Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico Chascomús, Avenida Intendente Marinos Km. 8,2, 7130 Chascomús, Buenos Aires, Argentina.
| | - Aída Sánchez-Bretaño
- Department of Pharmacology and Toxicology, and Neuroscience Institute, Morehouse School of Medicine, 720 Westview Drive, GA 30310 Atlanta, GA, United States.
| | - María Jesús Delgado
- Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, José Antonio Nováis 12, 28040 Madrid, Spain.
| | - Ana Isabel Valenciano
- Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, José Antonio Nováis 12, 28040 Madrid, Spain.
| | - Suraj Unniappan
- Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, S7N 5B4 Saskatoon, Saskatchewan, Canada.
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McGovern-Gooch KR, Mahajani NS, Garagozzo A, Schramm AJ, Hannah LG, Sieburg MA, Chisholm JD, Hougland JL. Synthetic Triterpenoid Inhibition of Human Ghrelin O-Acyltransferase: The Involvement of a Functionally Required Cysteine Provides Mechanistic Insight into Ghrelin Acylation. Biochemistry 2017; 56:919-931. [PMID: 28134508 DOI: 10.1021/acs.biochem.6b01008] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The peptide hormone ghrelin plays a key role in regulating hunger and energy balance within the body. Ghrelin signaling presents a promising and unexploited target for development of small molecule therapeutics for treatment of obesity, diabetes, and other health conditions. Inhibition of ghrelin O-acyltransferase (GOAT), which catalyzes an essential octanoylation step in ghrelin maturation, offers a potential avenue for controlling ghrelin signaling. Through screening a small molecule library, we have identified a class of synthetic triterpenoids that efficiently inhibit ghrelin acylation by the human isoform of GOAT (hGOAT). These compounds function as covalent reversible inhibitors of hGOAT, providing the first evidence of the involvement of a nucleophilic cysteine residue in substrate acylation by a MBOAT family acyltransferase. Surprisingly, the mouse form of GOAT does not exhibit susceptibility to cysteine-modifying electrophiles, revealing an important distinction in the activity and behavior between these closely related GOAT isoforms. This study establishes these compounds as potent small molecule inhibitors of ghrelin acylation and provides a foundation for the development of novel hGOAT inhibitors as therapeutics targeting diabetes and obesity.
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Affiliation(s)
| | - Nivedita S Mahajani
- Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States
| | - Ariana Garagozzo
- Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States
| | - Anthony J Schramm
- Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States
| | - Lauren G Hannah
- Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States
| | - Michelle A Sieburg
- Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States
| | - John D Chisholm
- Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States
| | - James L Hougland
- Department of Chemistry, Syracuse University , Syracuse, New York 13244, United States
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15
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Bertucci JI, Blanco AM, Canosa LF, Unniappan S. Glucose, amino acids and fatty acids directly regulate ghrelin and NUCB2/nesfatin-1 in the intestine and hepatopancreas of goldfish (Carassius auratus) in vitro. Comp Biochem Physiol A Mol Integr Physiol 2017; 206:24-35. [PMID: 28089858 DOI: 10.1016/j.cbpa.2017.01.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 01/10/2017] [Accepted: 01/11/2017] [Indexed: 02/07/2023]
Abstract
Ghrelin and nesfatin-1 are two peptidyl hormones primarily involved in food intake regulation. We previously reported that the amount of dietary carbohydrates, protein and lipids modulates the expression of these peptides in goldfish in vivo. In the present work, we aimed to characterize the effects of single nutrients on ghrelin and nesfatin-1 in the intestine and hepatopancreas. First, immunolocalization of ghrelin and NUCB2/nesfatin-1 in goldfish hepatopancreas cells was studied by immunohistochemistry. Second, the effects of 2 and 4hour-long exposures of cultured intestine and hepatopancreas sections to glucose, l-tryptophan, oleic acid, linolenic acid (LNA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on ghrelin and nesfatin-1 gene and protein expression were studied. Co-localization of ghrelin and NUCB2/nesfatin-1 in the cytoplasm of goldfish hepatocytes was found. Exposure to glucose led to an upregulation of preproghrelin and a downregulation of nucb2/nesfatin-1 in the intestine. l-Tryptophan mainly decreased the expression of both peptides in the intestine and hepatopancreas. Fatty acids, in general, downregulated NUCB2/nesfatin-1 in the intestine, but only the longer and highly unsaturated fatty acids inhibited preproghrelin. EPA exposure led to a decrease in preproghrelin, and an increase in nucb2/nesfatin-1 expression in hepatopancreas after 2h. These results show that macronutrients exert a dose- and time-dependent, direct regulation of ghrelin and nesfatin-1 in the intestine and hepatopancreas, and suggest a role for these hormones in the digestive process and nutrient metabolism.
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Affiliation(s)
- Juan Ignacio Bertucci
- Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico Chascomús, Av. Intendente Marino Km 8.2, CC 164 (7130) Chascomús, Prov. de Buenos Aires, Argentina.
| | - Ayelén Melisa Blanco
- Departamento de Fisiología (Fisiología Animal II), Facultad de Biología, Universidad Complutense de Madrid, Calle José Antonio Nováis 12, 28040 Madrid, Spain.
| | - Luis Fabián Canosa
- Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico Chascomús, Av. Intendente Marino Km 8.2, CC 164 (7130) Chascomús, Prov. de Buenos Aires, Argentina.
| | - Suraj Unniappan
- Laboratory of Integrative Neuroendocrinology, Department of Veterinary Biomedical Sciences, Western College of Veterinary Medicine, University of Saskatchewan, 52 Campus Drive, Saskatoon, Saskatchewan S7N 5B4, Canada.
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16
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Development of novel ligands for peptide GPCRs. Curr Opin Pharmacol 2016; 31:57-62. [DOI: 10.1016/j.coph.2016.08.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/02/2016] [Accepted: 08/12/2016] [Indexed: 12/11/2022]
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17
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Miller DW, Prosser Z, Chee EYW, Hansen CF, Dunshea FR, Mullan BP, Pluske JR. Dietary stimulation of the endogenous somatotropic axis in weaner and grower-finisher pigs using medium chain triglycerides and cysteamine hydrochloride. J Anim Sci Biotechnol 2016; 7:61. [PMID: 27777763 PMCID: PMC5069931 DOI: 10.1186/s40104-016-0121-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Accepted: 10/01/2016] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Three experiments were conducted to examine the overall hypothesis that addition of medium chain triglycerides (MCT) and cysteamine hydrochloride (CSH) into the diets of young and growing pigs would stimulate the endogenous somatotropic axis to improve growth and performance. RESULTS In Experiment 1, weaner pigs were given either a 5 d dietary supplement of 5 % MCT (n = 8) or a control diet (n = 8). MCT increased the plasma concentration of growth hormone (GH; P < 0.05) and the GH secretagogue, ghrelin (P < 0.05). Additionally, the MCT treatment reduced scouring (P < 0.05), maintained villous height in the small intestine (P < 0.05) and stabilised daily weight gain (P < 0.05), compared to the controls. Experiment 2 compared the effects of 4 levels (0, 1, 3 and 6 % v/v) of MCT supplementation in grower-finisher male pigs, of approximately 35 kg live weight (n = 15 per treatment). Blood samples taken after 7 wk of treatment showed that the MCT supplementation increased circulating ghrelin (P < 0.001), GH (P < 0.01) and insulin (P < 0.05) concentrations in a dose-dependent manner. Daily weight gain, feed intake and feed conversion ratio were not affected by the MCT diets. In Experiment 3, 64 female pigs of approximately 60 kg live weight were allocated to one of three dietary treatments: control (n = 20); 6 % MCT (n = 21); and 70 mg/kg CSH (n = 21). After 3 wk of supplementation, the MCT treated pigs had a higher plasma concentration of ghrelin compared to the control and CSH pigs (P < 0.05). Plasma concentrations of GH and weight were not affected by any of the dietary treatments. CONCLUSIONS Evidence is provided in Experiment 1 to support the use of dietary MCT supplements, perhaps acting via stimulation of somatotropic endocrine pathways, to minimise weaning-associated disorders such as slowing of growth and diarrhoea. In Experiments 2 and 3, although there was no effect on weight gain or feed conversion ratio in either experiment, MCT and CSH increased endocrine components of the somatotropic axis.
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Affiliation(s)
- David W. Miller
- School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA 6150 Australia
| | - Zoe Prosser
- School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA 6150 Australia
| | - Edward Y. W. Chee
- School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA 6150 Australia
| | - Christian F. Hansen
- Department of Large Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Groennegaardsvej 2, 1870 Frederiksberg C, Denmark
| | - Frank R. Dunshea
- Melbourne School of Land and Environment, University of Melbourne, Parkville, VIC 3051 Australia
| | - Bruce P. Mullan
- Department of Agriculture and Food Western Australia, Bentley Delivery Center, Locked Bag 4, Bentley, WA 6983 Australia
| | - John R. Pluske
- School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA 6150 Australia
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18
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Kunath N, Müller NCJ, Tonon M, Konrad BN, Pawlowski M, Kopczak A, Elbau I, Uhr M, Kühn S, Repantis D, Ohla K, Müller TD, Fernández G, Tschöp M, Czisch M, Steiger A, Dresler M. Ghrelin modulates encoding-related brain function without enhancing memory formation in humans. Neuroimage 2016; 142:465-473. [PMID: 27402596 DOI: 10.1016/j.neuroimage.2016.07.016] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 06/07/2016] [Accepted: 07/06/2016] [Indexed: 01/24/2023] Open
Abstract
Ghrelin regulates energy homeostasis in various species and enhances memory in rodent models. In humans, the role of ghrelin in cognitive processes has yet to be characterized. Here we show in a double-blind randomized crossover design that acute administration of ghrelin alters encoding-related brain activity, however does not enhance memory formation in humans. Twenty-one healthy young male participants had to memorize food- and non-food-related words presented on a background of a virtual navigational route while undergoing fMRI recordings. After acute ghrelin administration, we observed decreased post-encoding resting state fMRI connectivity between the caudate nucleus and the insula, amygdala, and orbitofrontal cortex. In addition, brain activity related to subsequent memory performance was modulated by ghrelin. On the next day, however, no differences were found in free word recall or cued location-word association recall between conditions; and ghrelin's effects on brain activity or functional connectivity were unrelated to memory performance. Further, ghrelin had no effect on a cognitive test battery comprising tests for working memory, fluid reasoning, creativity, mental speed, and attention. In conclusion, in contrast to studies with animal models, we did not find any evidence for the potential of ghrelin acting as a short-term cognitive enhancer in humans.
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Affiliation(s)
- N Kunath
- Max Planck Institute of Psychiatry, Munich, Germany
| | - N C J Müller
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - M Tonon
- Max Planck Institute of Psychiatry, Munich, Germany
| | - B N Konrad
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - M Pawlowski
- Max Planck Institute of Psychiatry, Munich, Germany
| | - A Kopczak
- Max Planck Institute of Psychiatry, Munich, Germany
| | - I Elbau
- Max Planck Institute of Psychiatry, Munich, Germany
| | - M Uhr
- Max Planck Institute of Psychiatry, Munich, Germany
| | - S Kühn
- Max Planck Institute for Human Development, Berlin, Germany
| | - D Repantis
- Charité - Universitätsmedizin Berlin, Department of Psychiatry and Psychotherapy, CBF, Berlin, Germany
| | - K Ohla
- German Institute for Human Nutrition, Potsdam-Rehbrücke, Germany
| | - T D Müller
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, Munich, Germany; Department of Medicine, Technische Universität München, Munich, Germany
| | - G Fernández
- Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - M Tschöp
- Institute for Diabetes and Obesity, Helmholtz Zentrum München, Munich, Germany; Department of Medicine, Technische Universität München, Munich, Germany
| | - M Czisch
- Max Planck Institute of Psychiatry, Munich, Germany
| | - A Steiger
- Max Planck Institute of Psychiatry, Munich, Germany
| | - M Dresler
- Max Planck Institute of Psychiatry, Munich, Germany; Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
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19
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Navarro G, Aguinaga D, Angelats E, Medrano M, Moreno E, Mallol J, Cortés A, Canela EI, Casadó V, McCormick PJ, Lluís C, Ferré S. A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons. J Biol Chem 2016; 291:13048-62. [PMID: 27129257 DOI: 10.1074/jbc.m116.715144] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2016] [Indexed: 01/01/2023] Open
Abstract
The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling.
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Affiliation(s)
- Gemma Navarro
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain,
| | - David Aguinaga
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Edgar Angelats
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Mireia Medrano
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Estefanía Moreno
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Josefa Mallol
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Antonio Cortés
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Enric I Canela
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Vicent Casadó
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Peter J McCormick
- the School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, United Kingdom, and
| | - Carme Lluís
- From the Department of Biochemistry and Molecular Biology, Faculty of Biology, University of Barcelona and Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, 08028 Barcelona, Spain
| | - Sergi Ferré
- the Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224
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20
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Ngernsoungnern A, Ngernsoungnern P. Localization of ghrelin-like peptide in the gastrointestinal tract of the golden apple snail (Pomacea canaliculata) and changing of its concentration during fasting. Acta Histochem 2016; 118:244-51. [PMID: 26850996 DOI: 10.1016/j.acthis.2016.01.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 01/22/2016] [Accepted: 01/22/2016] [Indexed: 12/13/2022]
Abstract
Ghrelin is an endogenous hormone detected in the gastrointestinal tracts (GI) of various species. In the present study, ghrelin-like peptide (ghrelin-LP) was identified in the GI tract of the golden apple snail, Pomacea canaliculata. Using immunohistochemistry, the result revealed an immunoreactivity (-ir) of ghrelin-LP in regions of the GI tract. The ghrelin-LP-ir was observed in both opened-type and closed-type cells of the esophagus, stomach, and small and large intestines. The highest density of ghrelin-LP immunoreactive cells was found in the esophagus and the least density was detected in the stomach. The highest percentages of the opened-type and closed-type cells were present in the esophagus and small intestine, respectively. In immunoblotting, the molecular weight of ghrelin-LP was related to the human ghrelin peptide (∼13kDa). Moreover, the concentration of ghrelin-LP was significantly higher in snails that were fasted for 24h compared with fed snails. The concentration decreased after refeeding. The present study could be useful for understanding the physiological role of ghrelin-LP in mollusk species.
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Affiliation(s)
- Apichart Ngernsoungnern
- School of Anatomy, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand
| | - Piyada Ngernsoungnern
- School of Anatomy, Institute of Science, Suranaree University of Technology, Nakhon Ratchasima 30000, Thailand.
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21
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Kim HS, Lee MK. β-Cell regeneration through the transdifferentiation of pancreatic cells: Pancreatic progenitor cells in the pancreas. J Diabetes Investig 2016; 7:286-96. [PMID: 27330712 PMCID: PMC4847880 DOI: 10.1111/jdi.12475] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 12/27/2015] [Accepted: 01/04/2016] [Indexed: 12/17/2022] Open
Abstract
Pancreatic progenitor cell research has been in the spotlight, as these cells have the potential to replace pancreatic β‐cells for the treatment of type 1 and 2 diabetic patients with the absence or reduction of pancreatic β‐cells. During the past few decades, the successful treatment of diabetes through transplantation of the whole pancreas or isolated islets has nearly been achieved. However, novel sources of pancreatic islets or insulin‐producing cells are required to provide sufficient amounts of donor tissues. To overcome this limitation, the use of pancreatic progenitor cells is gaining more attention. In particular, pancreatic exocrine cells, such as duct epithelial cells and acinar cells, are attractive candidates for β‐cell regeneration because of their differentiation potential and pancreatic lineage characteristics. It has been assumed that β‐cell neogenesis from pancreatic progenitor cells could occur in pancreatic ducts in the postnatal stage. Several studies have shown that insulin‐producing cells can arise in the duct tissue of the adult pancreas. Acinar cells also might have the potential to differentiate into insulin‐producing cells. The present review summarizes recent progress in research on the transdifferentiation of pancreatic exocrine cells into insulin‐producing cells, especially duct and acinar cells.
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Affiliation(s)
- Hyo-Sup Kim
- Division of Endocrinology and Metabolism Department of Medicine Sungkyunkwan University School of Medicine Samsung Biomedical Research Institute Samsung Medical Center Seoul Korea
| | - Moon-Kyu Lee
- Division of Endocrinology and Metabolism Department of Medicine Sungkyunkwan University School of Medicine Samsung Biomedical Research Institute Samsung Medical Center Seoul Korea
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Cowan E, Kumar P, Burch KJ, Grieve DJ, Green BD, Graham SF. Treatment of lean and diet-induced obesity (DIO) mice with a novel stable obestatin analogue alters plasma metabolite levels as detected by untargeted LC-MS metabolomics. Metabolomics 2016; 12:124. [PMID: 27471436 PMCID: PMC4932145 DOI: 10.1007/s11306-016-1063-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/04/2015] [Accepted: 03/31/2016] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Obestatin is a controversial gastrointestinal peptide purported to have metabolic actions. OBJECTIVES This study investigated whether treatment with a stable obestatin analogue (PEG-OB(Cys10, Cys13)) changed plasma metabolite levels firstly in lean and subsequently in diet-induced obesity (DIO) C57BL6/J mice. METHODS Untargeted LC-HRMS metabolomics experiments were carried out in ESI + mode with plasma extracts from both groups of animals. Data were normalised, multivariate and univariate statistical analysis performed and metabolites of interest putatively identified. RESULTS In lean mice, 39 metabolites were significantly changed by obestatin treatment and the majority of these were increased, including various C16 and C18 moieties of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and monoacylglycerol, along with vitamin A, vitamin D3, tyrosine, acetylcarnitine and 2α-(hydroxymethyl)-5α-androstane-3β,17β-diol. Decreased concentrations of glycolithocholic acid, 3-dehydroteasterone and various phospholipids were observed. In DIO mice, 25 metabolites were significantly affected and strikingly, the magnitudes of changes here were generally much greater in DIO mice than in lean mice, and in contrast, the majority of metabolite changes were decreases. Four metabolites affected in both groups included glycolithocholic acid, and three different long-chain (C18) phospholipid molecules (phosphatidylethanolamine, platelet activating factor (PAF), and monoacylglycerol). Metabolites exclusively affected in DIO mice included various phosphatidylcholines, lysophosphatidylcholines and fatty acyls, as well as creatine and oxidised glutathione. CONCLUSION This investigation demonstrates that obestatin treatment affects phospholipid turnover and influences lipid homeostasis, whilst providing convincing evidence that obestatin may be acting to ameliorate diet-induced impairments in lipid metabolism, and it may influence steroid, bile acid, PAF and glutathione metabolism.
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Affiliation(s)
- Elaine Cowan
- />Institute for Global Food Security, Queen’s University of Belfast, Belfast, BT9 5BN Northern Ireland, UK
| | - Praveen Kumar
- />Beaumont Research Institute, 3811 W. 13 Mile Road, Royal Oak, MI 48073 USA
| | - Kerry J. Burch
- />Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University of Belfast, Belfast, BT9 7AE Northern Ireland, UK
| | - David J. Grieve
- />Wellcome-Wolfson Institute for Experimental Medicine, Queen’s University of Belfast, Belfast, BT9 7AE Northern Ireland, UK
| | - Brian D. Green
- />Institute for Global Food Security, Queen’s University of Belfast, Belfast, BT9 5BN Northern Ireland, UK
| | - Stewart F. Graham
- />Beaumont Research Institute, 3811 W. 13 Mile Road, Royal Oak, MI 48073 USA
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Jiang FX, Morahan G. Multipotent pancreas progenitors: Inconclusive but pivotal topic. World J Stem Cells 2015; 7:1251-1261. [PMID: 26730269 PMCID: PMC4691693 DOI: 10.4252/wjsc.v7.i11.1251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/20/2015] [Accepted: 11/11/2015] [Indexed: 02/07/2023] Open
Abstract
The establishment of multipotent pancreas progenitors (MPP) should have a significant impact not only on the ontology of the pancreas, but also for the translational research of glucose-responding endocrine β-cells. Deficiency of the latter may lead to the pandemic type 1 or type 2 diabetes mellitus, a metabolic disorder. An ideal treatment of which would potentially be the replacement of destroyed or failed β-cells, by restoring function of endogenous pancreatic endocrine cells or by transplantation of donor islets or in vitro generated insulin-secreting cells. Thus, considerable research efforts have been devoted to identify MPP candidates in the pre- and post-natal pancreas for the endogenous neogenesis or regeneration of endocrine insulin-secreting cells. In order to advance this inconclusive but critical field, we here review the emerging concepts, recent literature and newest developments of potential MPP and propose measures that would assist its forward progression.
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Ghrelin receptor in Japanese fire belly newt, Cynops pyrrhogaster. Comp Biochem Physiol B Biochem Mol Biol 2015; 189:15-22. [DOI: 10.1016/j.cbpb.2015.07.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Revised: 06/19/2015] [Accepted: 07/03/2015] [Indexed: 12/20/2022]
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Ruiz-Tovar J, Llavero C, Ortega I, Diez M, Zubiaga L, Calpena R. La neuroestimulación eléctrica percutánea del dermatoma T7 mejora el perfil glucémico en pacientes obesos y diabéticos tipo 2. Estudio clínico aleatorizado. Cir Esp 2015; 93:460-5. [DOI: 10.1016/j.ciresp.2014.06.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2014] [Revised: 05/20/2014] [Accepted: 06/21/2014] [Indexed: 11/25/2022]
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Kunath N, van Groen T, Allison DB, Kumar A, Dozier-Sharpe M, Kadish I. Ghrelin agonist does not foster insulin resistance but improves cognition in an Alzheimer's disease mouse model. Sci Rep 2015; 5:11452. [PMID: 26090621 PMCID: PMC4473679 DOI: 10.1038/srep11452] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2015] [Accepted: 05/15/2015] [Indexed: 12/24/2022] Open
Abstract
The orexigenic hormone ghrelin, a potential antagonist of the insulin system, ensures sufficient serum glucose in times of fasting. In the race for new therapeutics for diabetes, one focus of study has been antagonizing the ghrelin system in order to improve glucose tolerance. We provide evidence for a differential role of a ghrelin agonist on glucose homeostasis in an Alzheimer’s disease mouse model fed a high–glycemic index diet as a constant challenge for glucose homeostasis. The ghrelin agonist impaired glucose tolerance immediately after administration but not in the long term. At the same time, the ghrelin agonist improved spatial learning in the mice, raised their activity levels, and reduced their body weight and fat mass. Immunoassay results showed a beneficial impact of long-term treatment on insulin signaling pathways in hippocampal tissue. The present results suggest that ghrelin might improve cognition in Alzheimer’s disease via a central nervous system mechanism involving insulin signaling.
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Affiliation(s)
- Nicolas Kunath
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham AL, USA.,Department of Clinical Research, Max-Planck-Institute of Psychiatry, Munich, Germany
| | - Thomas van Groen
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham AL, USA
| | - David B Allison
- Office of Energetics; Nutrition Obesity Research Center; Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ashish Kumar
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham AL, USA
| | - Monique Dozier-Sharpe
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham AL, USA
| | - Inga Kadish
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham AL, USA
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A new class of ghrelin O-acyltransferase inhibitors incorporating triazole-linked lipid mimetic groups. Bioorg Med Chem Lett 2015; 25:2800-3. [PMID: 26009163 DOI: 10.1016/j.bmcl.2015.05.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2015] [Revised: 05/04/2015] [Accepted: 05/06/2015] [Indexed: 02/06/2023]
Abstract
Inhibitors of ghrelin O-acyltransferase (GOAT) have untapped potential as therapeutics targeting obesity and diabetes. We report the first examples of GOAT inhibitors incorporating a triazole linkage as a biostable isosteric replacement for the ester bond in ghrelin and amide bonds in previously reported GOAT inhibitors. These triazole-containing inhibitors exhibit sub-micromolar inhibition of the human isoform of GOAT (hGOAT), and provide a foundation for rapid future chemical diversification and optimization of hGOAT inhibitors.
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Benso A, Gramaglia E, Olivetti I, Tomelini M, Belcastro S, Calvi E, Dotta A, St-Pierre D, Ghigo E, Broglio F. Acute effects of acylated ghrelin on salbutamol-induced metabolic actions in humans. Endocrine 2015; 48:937-41. [PMID: 25012253 DOI: 10.1007/s12020-014-0343-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2014] [Accepted: 06/18/2014] [Indexed: 10/25/2022]
Abstract
The aim of this study is to describe a potential modulatory effect of acute acylated ghrelin (AG) administration on the glucose, insulin, and free fatty acids (FFA) responses to salbutamol (SALBU). Six healthy young male volunteers underwent the following four testing sessions in random order at least 7 days apart: (a) acute AG administration (1.0 μg/kg i.v. as bolus at 0'); (b) SALBU infusion (0.06 μg/kg/min i.v. from -15' to +45'); (c) SALBU infusion+AG; and (d) isotonic saline infusion. Blood samples for glucose, insulin, and FFA levels were collected every 15 min. As expected, with respect to saline, SALBU infusion induced a remarkable increase in glucose (10.8±5.6 mmol/l×min; P<0.05), insulin (2436.8±556.9 pmol/l×min; P<0.05), and FFA (18.9±4.5 mmol/l×min; P<0.01) levels. A significant increase in glucose (7.4±3.9 mmol/l×min; P<0.05) and FFA levels (10.0±2.8 mmol/l×min; P<0.01) without significant variations in insulin levels were recorded after AG administration. Interestingly, the hyperglycemic effect of AG appeared to be significantly potentiated during SALBU infusion (26.7±4.8 mmol/l×min; P<0.05). On the other hand, the stimulatory effect of SALBU on insulin and FFA was not significantly modified by AG administration. The results of this study show that acute AG administration has a synergic effect with β2-adrenergic receptor activation by SALBU on blood glucose increase, suggesting that their pharmacological hyperglycemic action takes place via different mechanisms. On the other hand, AG has a negligible influence on the other pharmacological metabolic effects of SALBU infusion.
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Affiliation(s)
- A Benso
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Turin, A.O. Città della Salute e della Scienza - Molinette, Corso Dogliotti 14, 10126, Turin, Italy
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Wittekind DA, Kluge M. Ghrelin in psychiatric disorders - A review. Psychoneuroendocrinology 2015; 52:176-94. [PMID: 25459900 DOI: 10.1016/j.psyneuen.2014.11.013] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 11/13/2014] [Accepted: 11/13/2014] [Indexed: 12/21/2022]
Abstract
Ghrelin is a 28-amino-acid peptide hormone, first described in 1999 and broadly expressed in the organism. As the only known orexigenic hormone secreted in the periphery, it increases hunger and appetite, promoting food intake. Ghrelin has also been shown to be involved in various physiological processes being regulated in the central nervous system such as sleep, mood, memory and reward. Accordingly, it has been implicated in a series of psychiatric disorders, making it subject of increasing investigation, with knowledge rapidly accumulating. This review aims at providing a concise yet comprehensive overview of the role of ghrelin in psychiatric disorders. Ghrelin was consistently shown to exert neuroprotective and memory-enhancing effects and alleviated psychopathology in animal models of dementia. Few human studies show a disruption of the ghrelin system in dementia. It was also shown to play a crucial role in the pathophysiology of addictive disorders, promoting drug reward, enhancing drug seeking behavior and increasing craving in both animals and humans. Ghrelin's exact role in depression and anxiety is still being debated, as it was shown to both promote and alleviate depressive and anxiety-behavior in animal studies, with an overweight of evidence suggesting antidepressant effects. Not surprisingly, the ghrelin system is also implicated in eating disorders, however its exact role remains to be elucidated. Its widespread involvement has made the ghrelin system a promising target for future therapies, with encouraging findings in recent literature.
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Affiliation(s)
| | - Michael Kluge
- Department of Psychiatry and Psychotherapy, University of Leipzig, Leipzig, Germany
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30
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Khatib MN, Gaidhane S, Gaidhane AM, Simkhada P, Zahiruddin QS. Ghrelin O Acyl Transferase (GOAT) as a Novel Metabolic Regulatory Enzyme. J Clin Diagn Res 2015; 9:LE01-5. [PMID: 25859472 PMCID: PMC4378754 DOI: 10.7860/jcdr/2015/9787.5514] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 12/06/2014] [Indexed: 01/12/2023]
Abstract
BACKGROUND Obesity and Type 2 Diabetes Mellitus (T2DM) presents a growing threat to the global health. Evidences highlight an important role of ghrelin as a key regulator of glucose metabolism. The physiological functions of ghrelin are mediated by enzyme ghrelin-O-acyltransferase (GOAT) which is capable of generating the active form of this metabolic hormone. However, its exact mechanism of action and influence on energy balance and glucose metabolism is yet to be explored. OBJECTIVES To review the physiological role of GOAT in the regulation of energy balance and glucose metabolism and explore the potential therapeutic avenues of modulators of GOAT to counter the progression of obesity and T2DM. METHODS Publications were sought through electronic searches. The bibliographies of all papers, book, chapters and editorials were scanned and hand searches were also conducted for journals, and conference proceedings. CONCLUSION GOAT peptide modulates the insulin secretion as well as insulin sensitivity. Modulators of GOAT signaling like inhibitors of GOAT increases insulin secretion, enhance peripheral insulin sensitivity and thus counters obesity and T2DM. Modulators of GOAT can be a probable therapy for modifying food intake and for countering obesity and T2DM.
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Affiliation(s)
- Mahalaqua Nazli Khatib
- Professor, Department of Physiology, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Shilpa Gaidhane
- Associate Professor, Department of Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Abhay M. Gaidhane
- Professor, Department of Community Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
| | - Padam Simkhada
- Senior Lecturer in International Health ScHARR, University of Sheffield, UK and Centre for public Health Liverpool Johns Moores University, Liverpool, UK
| | - Quazi Syed Zahiruddin
- Professor, Department of Community Medicine, JN Medical College, Datta Meghe Institute of Medical Sciences, Wardha, Maharashtra, India
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Tereshchenko IV, Kamenskikh YA, Kayushev PE. The concurrence of diabetes mellitus and gallstone disease. TERAPEVT ARKH 2015. [DOI: 10.17116/terarkh20158710105-109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Abstract
PURPOSE OF REVIEW To discuss recent research on the role of ghrelin in the regulation of carbohydrate and lipid metabolism in the context of its wider role in regulating energy balance. RECENT FINDINGS Ghrelin possesses a range of centrally and peripherally mediated metabolic actions influencing insulin glucose homeostasis and fatty acid metabolism and appetite. Although acyl ghrelin was previously thought to be the active hormone, recent evidence suggests that des-acyl ghrelin also possesses activity, and the enzyme ghrelin-O-acyl transferase regulates their interconversion. In partnership with insulin and leptin, ghrelin defends against energy deficit by enhancing hunger, conserving carbohydrate and promoting fat oxidation. In the postprandial state, it contributes to satiety, energy storage and favours glucose oxidation. New research suggests a range of new roles including addictive behaviours, cardiovascular protection, neuroprotection and regeneration and perhaps the ageing process. SUMMARY Ghrelin functions primarily as a short-term metabolic switch at the onset of fasting, gearing the fuel economy away from glucose uptake, conserving glucose for vital functions, favouring fatty acid oxidation and triggering food-seeking behaviour. The ghrelin system is a potential target for a range of pharmacological interventions, but its pleiotropic nature makes selective treatments challenging.
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Affiliation(s)
- Jonathan Pinkney
- Centre for Clinical Trials and Population Studies, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom
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Abstract
Diabetes mellitus is caused by absolute (type 1) or relative (type 2) deficiency of insulin-secreting islet β cells. An ideal treatment of diabetes would, therefore, be to replace the lost or deficient β cells, by transplantation of donated islets or differentiated endocrine cells or by regeneration of endogenous islet cells. Due to their ability of unlimited proliferation and differentiation into all functional lineages in our body, including β cells, embryonic stem cells and induced pluripotent stem cells are ideally placed as cell sources for a diabetic transplantation therapy. Unfortunately, the inability to generate functional differentiated islet cells from pluripotent stem cells and the poor availability of donor islets have severely restricted the broad clinical use of the replacement therapy. Therefore, endogenous sources that can be directed to becoming insulin-secreting cells are actively sought after. In particular, any cell types in the developing or adult pancreas that may act as pancreatic stem cells (PSC) would provide an alternative renewable source for endogenous regeneration. In this review, we will summarize the latest progress and knowledge of such PSC, and discuss ways that facilitate the future development of this often controversial, but crucial research.
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Affiliation(s)
- Fang-Xu Jiang
- 1 Islet Cell Development Program, Harry Perkins Institute of Medical Research, and Centre for Medical Research, The University of Western Australia , Perth, Australia
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Perret J, De Vriese C, Delporte C. Polymorphisms for ghrelin with consequences on satiety and metabolic alterations. Curr Opin Clin Nutr Metab Care 2014; 17:306-11. [PMID: 24870813 DOI: 10.1097/mco.0000000000000072] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE OF REVIEW To understand the current trend of ghrelin genetic variations on the control of satiety, eating behaviours, obesity, and metabolic alterations, and its development over the last 18 months. RECENT FINDINGS Several polymorphisms of the ghrelin gene, its receptor gene and ghrelin's acylating enzyme, ghrelin O-acyl transferase, have been identified and studied over the last decade in relation to control of satiety, obesity, eating behaviours, metabolic syndrome, glucose homeostasis, and type 2 diabetes. However, the effects described are either small or nonsignificant and often subjected to contradictory conclusions between studies. In the last 18 months, several of these areas of investigations have been revisited under more controlled conditions or have been subjected to meta-analysis. SUMMARY The effects of ghrelin gene polymorphism, is a complex area of investigation, due to ghrelin's interplay with a host of various factors part of an integrative network. However, taken together, results suggest that there are no or nonsignificant effects of the common genetic variants. A better understanding of the network, probably by a systems biology type approach, will be necessary to assign the exact role played by gene polymorphism of the component of the ghrelin axis.
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Affiliation(s)
- Jason Perret
- aLaboratory of Pathophysiological and Nutritional Biochemistry bLaboratory of Pharmaceutics and Biopharmaceutics, Université Libre de Bruxelles, Brussels, Belgium
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Abstract
Although the stomach is often perceived as a crude, food-grinding, muscular bag, scientific breakthroughs have shown us that in the case of the stomach there is more than meets the eye. The endocrine function of the stomach is mainly exerted through the actions of ghrelin, an acylated peptide hormone that is the first known and so far most extensively studied endogenous orexigenic substance. The satiety-hunger balance is kept in check by many anorexigenic gut hormones among which is the deacylated form of ghrelin--desacyl ghrelin. The interplay of gut hormones affects the brain directly, as most gut hormones cross the blood-brain barrier and bind to their respective receptors in the central nervous system. Other hormones like obestatin and nesfatin are secreted from the stomach along with ghrelin, yet their physiological function is to be elucidated. The importance of the satiety-hunger balance can be seen in its most typical derangement--obesity. Some studies imply that ghrelin, along with other gut hormones, plays an important part in the pathophysiology of obesity. More importantly, it seems that the mechanisms by which bariatric surgery procedures induce weight loss are primarily based on changing the gut hormone levels, including ghrelin. If proven, ghrelin antagonists could be the renaissance of pharmacological obesity treatment.
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Affiliation(s)
- Davor Štimac
- Department of Gastroenterology, Clinical Hospital Centre Rijeka, School of Medicine, University of Rijeka, Rijeka, Croatia
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El-Sabagh M, Taniguchi D, Sugino T, Obitsu T, Taniguchi K. Effect of glucagon-like peptide-1 and ghrelin on liver metabolites in steers. ANIMAL PRODUCTION SCIENCE 2014. [DOI: 10.1071/an14363] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Glucagon-like peptide 1 (GLP-1) and ghrelin have opposite regulatory effects on glucose metabolism in non-ruminants. However, mechanisms by which GLP-1 and ghrelin regulate nutrient partitioning, particularly in the liver, have been much less demonstrated in ruminants. A novel metabolomic method based on capillary electrophoresis time-of-flight mass spectrometry (CE-TOFMS) combined with multivariate statistical analysis was applied to address the GLP-1 and ghrelin-induced metabolic changes in the liver of steers. Three Holstein steers (400 ± 5.0 kg LW) fed a maintenance diet according to Japanese feeding standards were randomly assigned to three treatments (GLP-1, ghrelin and saline) in a 3 × 3 Latin square design with one week apart. Liver biopsies were taken 30 min after a single injection (1.0 μg/kg LW) of GLP-1 or ghrelin, and analysed for metabolites by Agilent CE-TOFMS system. Also, blood samples were collected for plasma hormones analysis. Results indicated that 20 and 10 liver metabolites were altered (P < 0.05) by GLP-1 and ghrelin, respectively. Pathway analysis showed that GLP-1 is involved in biochemical pathways related to glycolysis/gluconeogenesis, lipogenesis and lipid export from the liver, oxidative stress defence and protein turnover. Ghrelin was shown to be involved in pathways related to glycolysis, protein anabolism and phospholipid biosynthesis. However, plasma concentrations of insulin, growth hormone and glucagon did not differ between treatments. These results imply that GLP-1 and ghrelin are involved in multibiochemical pathways that go beyond simply regulating glucose metabolism. In addition, the effects of GLP-1 and ghrelin may potentially be independent of insulin and growth hormone, respectively.
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Gesmundo I, Gallo D, Favaro E, Ghigo E, Granata R. Obestatin: a new metabolic player in the pancreas and white adipose tissue. IUBMB Life 2013; 65:976-82. [PMID: 24217898 DOI: 10.1002/iub.1226] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2013] [Revised: 10/10/2013] [Accepted: 10/11/2013] [Indexed: 01/14/2023]
Abstract
Obestatin is a 23 amino acid amidated peptide, member of the preproghrelin gene-derived peptides. Initially, obestatin was reported to exert opposite effects to those of ghrelin on food intake and body weight gain, through interaction with GPR39; however, these findings are still strongly debated and obestatin biological role remains largely unknown. Interestingly, binding of obestatin to the glucagon-like peptide 1 receptor has been recently suggested. Despite being a controversial peptide, recent findings have clearly indicated that obestatin is indeed a multifunctional peptide, exerting a variety of effects, such as stimulation of cell proliferation, survival and differentiation, influence on glucose and lipid metabolism, as well as anti-inflammatory and cardioprotective actions. Its positive effects on glucose and lipid metabolism candidate this peptide as a potential therapeutic tool in pathological conditions such as insulin resistance and diabetes.
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Affiliation(s)
- Iacopo Gesmundo
- Division of Endocrinology, Diabetology and Metabolism, Department of Medical Sciences, University of Torino, Torino, Italy
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