scholarly journals Ghrelin, Des-Acyl Ghrelin, and Obestatin: Regulatory Roles on the Gastrointestinal Motility

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Mineko Fujimiya ◽  
Akihiro Asakawa ◽  
Koji Ataka ◽  
Chih-Yen Chen ◽  
Ikuo Kato ◽  
...  
Keyword(s):  
Gastrointestinal Motility ◽  
Inhibitory Effects ◽  
Conscious Rat ◽  
Afferent Pathways ◽  
Fed State ◽  
Fasted State ◽  
Vagal Afferent ◽  
Acyl Ghrelin ◽  
The Brain

Ghrelin, des-acyl ghrelin, and obestatin are derived from a common prohormone, preproghrelin by posttranslational processing, originating from endocrine cells in the stomach. To examine the regulatory roles of these peptides, we applied the manometric measurement of gastrointestinal motility in freely moving conscious rat or mouse model. Ghrelin exerts stimulatory effects on the motility of antrum and duodenum in both fed and fasted state of animals. Des-acyl ghrelin exerts inhibitory effects on the motility of antrum but not on the motility of duodenum in the fasted state of animals. Obestatin exerts inhibitory effects on the motility of antrum and duodenum in the fed state but not in the fasted state of animals. NPY Y2 and Y4 receptors in the brain may mediate the action of ghrelin, CRF type 2 receptor in the brain may mediate the action of des-acyl ghrelin, whereas CRF type 1 and type 2 receptors in the brain may mediate the action of obestatin. Vagal afferent pathways might be involved in the action of ghrelin, but not involved in the action of des-acyl ghrelin, whereas vagal afferent pathways might be partially involved in the action of obestatin.

scholarly journals Liver-expressed antimicrobial peptide 2 antagonizes the effect of ghrelin in rodents

2020 ◽  
Vol 244 (1) ◽  
pp. 13-23 ◽  
Author(s):  
Md Nurul Islam ◽  
Yuichiro Mita ◽  
Keisuke Maruyama ◽  
Ryota Tanida ◽  
Weidong Zhang ◽  
...  
Keyword(s):  
Food Intake ◽  
Body Temperature ◽  
Antimicrobial Peptide ◽  
Ampk Activation ◽  
Inhibitory Effects ◽  
Gh Secretion ◽  
Hypothalamic Nuclei ◽  
Acyl Ghrelin ◽  
Blood Glucose Elevation ◽  
The Brain

Ghrelin, a stomach-derived peptide, promotes feeding and growth hormone (GH) secretion. A recent study identified liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inhibitor of ghrelin-induced GH secretion, but the effect of LEAP2 in the brain remained unknown. In this study, we showed that intracerebroventricular (i.c.v.) administration of LEAP2 to rats suppressed central ghrelin functions including Fos expression in the hypothalamic nuclei, promotion of food intake, blood glucose elevation, and body temperature reduction. LEAP2 did not inhibit neuropeptide Y (NPY)-induced food intake or des-acyl ghrelin-induced reduction in body temperature, indicating that the inhibitory effects of LEAP2 were specific for GHSR. Plasma LEAP2 levels varied according to feeding status and seemed to be dependent on the hepatic Leap2 expression. Furthermore, ghrelin suppressed the expression of hepatic Leap2 via AMPK activation. Together, these results reveal that LEAP2 inhibits central ghrelin functions and crosstalk between liver and stomach.

Obestatin inhibits motor activity in the antrum and duodenum in the fed state of conscious rats

2008 ◽  
Vol 294 (5) ◽  
pp. G1210-G1218 ◽  
Author(s):  
Koji Ataka ◽  
Akio Inui ◽  
Akihiro Asakawa ◽  
Ikuo Kato ◽  
Mineko Fujimiya
Keyword(s):  
Motor Activity ◽  
Immunohistochemical Analysis ◽  
Phase Iii ◽  
Fed State ◽  
Conscious Rats ◽  
Duodenal Motility ◽  
Gastroduodenal Motility ◽  
The Brain

Obestatin is a novel peptide encoded by the ghrelin precursor gene; however, its effects on gastrointestinal motility remain controversial. Here we have examined the effects of obestatin on fed and fasted motor activities in the stomach and duodenum of freely moving conscious rats. We examined the effects of intravenous (IV) injection of obestatin on the percentage motor index (%MI) and phase III-like contractions in the antrum and duodenum. The brain mechanism mediating the action of obestatin on gastroduodenal motility and the involvement of vagal afferent pathway were also examined. Between 30 and 90 min after IV injection, obestatin decreased the %MI in the antrum and prolonged the time taken to return to fasted motility in the duodenum in fed rats given 3 g of chow after 18 h of fasting. Immunohistochemical analysis demonstrated that corticotropin-releasing factor- and urocortin-2-containing neurons in the paraventricular nucleus in the hypothalamus were activated by IV injection of obestatin. Intracerebroventricular injection of CRF type 1 and type 2 receptor antagonists prevented the effects of obestatin on gastroduodenal motility. Capsaicin treatment blocked the effects of obestatin on duodenal motility but not on antral motility. Obestatin failed to antagonize ghrelin-induced stimulation of gastroduodenal motility. These results suggest that, in the fed state, obestatin inhibits motor activity in the antrum and duodenum and that CRF type 1 and type 2 receptors in the brain might be involved in these effects of obestatin on gastroduodenal motility.

scholarly journals Synergistic Effects of Milk-Derived Exosomes and Galactose on α-Synuclein Pathology in Parkinson’s Disease and Type 2 Diabetes Mellitus

2021 ◽  
Vol 22 (3) ◽  
pp. 1059
Author(s):  
Bodo C. Melnik
Keyword(s):  
Oxidative Stress ◽  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Dopaminergic Neurons ◽  
Vagal Nerve ◽  
Β Cells ◽  
Pancreatic Β Cells ◽  
The Brain

Epidemiological studies associate milk consumption with an increased risk of Parkinson’s disease (PD) and type 2 diabetes mellitus (T2D). PD is an α-synucleinopathy associated with mitochondrial dysfunction, oxidative stress, deficient lysosomal clearance of α-synuclein (α-syn) and aggregation of misfolded α-syn. In T2D, α-syn promotes co-aggregation with islet amyloid polypeptide in pancreatic β-cells. Prion-like vagal nerve-mediated propagation of exosomal α-syn from the gut to the brain and pancreatic islets apparently link both pathologies. Exosomes are critical transmitters of α-syn from cell to cell especially under conditions of compromised autophagy. This review provides translational evidence that milk exosomes (MEX) disturb α-syn homeostasis. MEX are taken up by intestinal epithelial cells and accumulate in the brain after oral administration to mice. The potential uptake of MEX miRNA-148a and miRNA-21 by enteroendocrine cells in the gut, dopaminergic neurons in substantia nigra and pancreatic β-cells may enhance miRNA-148a/DNMT1-dependent overexpression of α-syn and impair miRNA-148a/PPARGC1A- and miRNA-21/LAMP2A-dependent autophagy driving both diseases. MiRNA-148a- and galactose-induced mitochondrial oxidative stress activate c-Abl-mediated aggregation of α-syn which is exported by exosome release. Via the vagal nerve and/or systemic exosomes, toxic α-syn may spread to dopaminergic neurons and pancreatic β-cells linking the pathogenesis of PD and T2D.

scholarly journals Development of [18F]LU14 for PET Imaging of Cannabinoid Receptor Type 2 in the Brain

2021 ◽  
Vol 22 (15) ◽  
pp. 8051
Author(s):  
Rodrigo Teodoro ◽  
Daniel Gündel ◽  
Winnie Deuther-Conrad ◽  
Lea Ueberham ◽  
Magali Toussaint ◽  
...  
Keyword(s):  
Cannabinoid Receptors ◽  
Cannabinoid Receptor ◽  
Biological Evaluation ◽  
Emission Tomography ◽  
Tailored Therapy ◽  
Positron Emission ◽  
Cannabinoid Receptor Type 2 ◽  
Attractive Therapeutic Target ◽  
The Brain

Cannabinoid receptors type 2 (CB2R) represent an attractive therapeutic target for neurodegenerative diseases and cancer. Aiming at the development of a positron emission tomography (PET) radiotracer to monitor receptor density and/or occupancy during a CB2R-tailored therapy, we herein describe the radiosynthesis of cis-[18F]1-(4-fluorobutyl-N-((1s,4s)-4-methylcyclohexyl)-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide ([18F]LU14) starting from the corresponding mesylate precursor. The first biological evaluation revealed that [18F]LU14 is a highly affine CB2R radioligand with >80% intact tracer in the brain at 30 min p.i. Its further evaluation by PET in a well-established rat model of CB2R overexpression demonstrated its ability to selectively image the CB2R in the brain and its potential as a tracer to further investigate disease-related changes in CB2R expression.

scholarly journals Targeting the Incretin/Glucagon System With Triagonists to Treat Diabetes

2018 ◽  
Vol 39 (5) ◽  
pp. 719-738 ◽  
Author(s):  
Megan E Capozzi ◽  
Richard D DiMarchi ◽  
Matthias H Tschöp ◽  
Brian Finan ◽  
Jonathan E Campbell
Keyword(s):  
Metabolic Disease ◽  
Type 2 Diabetes ◽  
Bariatric Surgery ◽  
Drug Class ◽  
Clinical Findings ◽  
Metabolic Dysfunction ◽  
Multiple Receptors ◽  
Insulinotropic Peptide ◽  
The Brain

Abstract Glucagonlike peptide 1 (GLP-1) receptor agonists have been efficacious for the treatment of type 2 diabetes due to their ability to reduce weight and attenuate hyperglycemia. However, the activity of glucagonlike peptide 1 receptor–directed strategies is submaximal, and the only potent, sustainable treatment of metabolic dysfunction is bariatric surgery, necessitating the development of unique therapeutics. GLP-1 is structurally related to glucagon and glucose-dependent insulinotropic peptide (GIP), allowing for the development of intermixed, unimolecular peptides with activity at each of their respective receptors. In this review, we discuss the range of tissue targets and added benefits afforded by the inclusion of each of GIP and glucagon. We discuss considerations for the development of sequence-intermixed dual agonists and triagonists, highlighting the importance of evaluating balanced signaling at the targeted receptors. Several multireceptor agonist peptides have been developed and evaluated, and the key preclinical and clinical findings are reviewed in detail. The biological activity of these multireceptor agonists are founded in the success of GLP-1-directed strategies; by including GIP and glucagon components, these multireceptor agonists are thought to enhance GLP-1’s activities by broadening the tissue targets and synergizing at tissues that express multiple receptors, such at the brain and pancreatic isletβ cells. The development and utility of balanced, unimolecular multireceptor agonists provide both a useful tool for querying the actions of incretins and glucagon during metabolic disease and a unique drug class to treat type 2 diabetes with unprecedented efficacy.

scholarly journals The angiotensin II type 2 receptor in the brain

2009 ◽  
Vol 11 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Masatsugu Horiuchi ◽  
Masaki Mogi ◽  
Masaru Iwai
Keyword(s):  
Angiotensin Ii ◽  
The Brain

scholarly journals Thyroid Hormone and the Neuroglia: Both Source and Target

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Petra Mohácsik ◽  
Anikó Zeöld ◽  
Antonio C. Bianco ◽  
Balázs Gereben
Keyword(s):  
Thyroid Hormone ◽  
Cell Function ◽  
Hormone Regulation ◽  
Mediobasal Hypothalamus ◽  
Iodothyronine Deiodinase ◽  
Neuronal Gene ◽  
Health And Disease ◽  
And Function ◽  
The Brain

Thyroid hormone plays a crucial role in the development and function of the nervous system. In order to bind to its nuclear receptor and regulate gene transcription thyroxine needs to be activated in the brain. This activation occurs via conversion of thyroxine to T3, which is catalyzed by the type 2 iodothyronine deiodinase (D2) in glial cells, in astrocytes, and tanycytes in the mediobasal hypothalamus. We discuss how thyroid hormone affects glial cell function followed by an overview on the fine-tuned regulation of T3 generation by D2 in different glial subtypes. Recent evidence on the direct paracrine impact of glial D2 on neuronal gene expression underlines the importance of glial-neuronal interaction in thyroid hormone regulation as a major regulatory pathway in the brain in health and disease.

scholarly journals The Effect of Long-Term Intranasal Serotonin Treatment on Metabolic Parameters and Hormonal Signaling in Rats with High-Fat Diet/Low-Dose Streptozotocin-Induced Type 2 Diabetes

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Kira V. Derkach ◽  
Vera M. Bondareva ◽  
Oxana V. Chistyakova ◽  
Lev M. Berstein ◽  
Alexander O. Shpakov
Keyword(s):  
Type 2 Diabetes ◽  
High Fat Diet ◽  
Low Dose ◽  
Diabetic Rats ◽  
Brain Serotonin ◽  
Serotonin Level ◽  
High Fat ◽  
Brain Serotonin Level ◽  
The Brain

In the last years the treatment of type 2 diabetes mellitus (DM2) was carried out using regulators of the brain signaling systems. In DM2 the level of the brain serotonin is reduced. So far, the effect of the increase of the brain serotonin level on DM2-induced metabolic and hormonal abnormalities has been studied scarcely. The present work was undertaken with the aim of filling this gap. DM2 was induced in male rats by 150-day high-fat diet and the treatment with low dose of streptozotocin (25 mg/kg) on the 70th day of experiment. From the 90th day, diabetic rats received for two months intranasal serotonin (IS) at a daily dose of 20 μg/rat. The IS treatment of diabetic rats decreased the body weight, and improved glucose tolerance, insulin-induced glucose utilization, and lipid metabolism. Besides, it restored hormonal regulation of adenylyl cyclase (AC) activity in the hypothalamus and normalized AC stimulation byβ-adrenergic agonists in the myocardium. In nondiabetic rats the same treatment induced metabolic and hormonal alterations, some of which were similar to those in DM2 but expressed to a lesser extent. In conclusion, the elevation of the brain serotonin level may be regarded as an effective approach to treat DM2 and its complications.

Duodenal acid-induced gastric relaxation is mediated by multiple pathways

1999 ◽  
Vol 276 (6) ◽  
pp. G1501-G1506 ◽  
Author(s):  
Yuan-Xu Lu ◽  
Chung Owyang
Keyword(s):  
Gastric Motility ◽  
No Reduction ◽  
Direct Action ◽  
Intragastric Pressure ◽  
Afferent Pathways ◽  
Serotonin Antagonist ◽  
Intraduodenal Infusion ◽  
Rate Dependent ◽  
Vagal Afferent

In this study, we used an in vivo anesthetized rat model to investigate the mechanisms responsible for duodenal acid-induced inhibition of gastric motility. Intraduodenal infusion of HCl produced a rate-dependent decrease in intragastric pressure. Infusion of HCl at 2 ml/h produced a physiological plasma secretin level and elicited a decrease in intragastric pressure of 3.0 ± 0.2 cmH20. Infusion of rabbit secretin antiserum reduced the acid-induced inhibition of gastric motility by 85 ± 5%, suggesting mediation mainly by endogenous secretin. Administration of the cholecystokinin (CCK)-A antagonist MK-329 caused only a modest 10 ± 3% reduction in gastric relaxation, whereas the serotonin antagonist ICS-205930 had no effect. In contrast, immunoneutralization with the secretin antibody caused only a 15% reduction in the relaxation evoked by a higher rate of HCl infusion (3 ml/h), whereas MK-329 and ICS-205930 caused a 20 ± 4% reduction and no reduction, respectively. Bilateral truncal vagotomy or perivagal application of capsaicin completely abolished gastric relaxation in response to low rates (1–2 ml/h) of 0.1 N HCl infusion but only partially affected gastric relaxation in response to a higher infusion rate (3 ml/h). These observations indicate that multiple pathways mediate the duodenal acid-induced inhibition of gastric motility. At low rates of HCl infusion, gastric relaxation is mediated primarily by endogenous secretin, which acts through vagal afferent pathways. At higher rates of HCl infusion, gastric relaxation is mediated by endogenous secretin, CCK, and possibly by the direct action of HCl on vagal afferent pathways or yet unidentified neuropathways.

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