scholarly journals L-Cell Expression of Melanocortin-4-Receptor Is Marginal in Most of the Small Intestine in Mice and Humans and Direct Stimulation of Small Intestinal Melanocortin-4-Receptors in Mice and Rats Does Not Affect GLP-1 Secretion

2021 ◽  
Vol 12 ◽  
Author(s):  
Rune E. Kuhre ◽  
Ida M. Modvig ◽  
Sara L. Jepsen ◽  
Hüsün S. Kizilkaya ◽  
Cecilie Bæch-Laursen ◽  
...  
Keyword(s):  
Small Intestine ◽  
Partial Agonist ◽  
Plasma Concentrations ◽  
Lower Half ◽  
Direct Stimulation ◽  
Molecular Sensors ◽  
L Cells ◽  
L Cell ◽  
Melanocortin 4 Receptor ◽  
Cell Expression

The molecular sensors underlying nutrient-stimulated GLP-1 secretion are currently being investigated. Peripheral administration of melanocortin-4 receptor (MC4R) agonists have been reported to increase GLP-1 plasma concentrations in mice and humans but it is unknown whether this effect results from a direct effect on the GLP-1 secreting L-cells in the intestine, from other effects in the intestine or from extra-intestinal effects. We investigated L-cell expression of MC4R in mouse and human L-cells by reanalyzing publicly available RNA sequencing databases (mouse and human) and by RT-qPCR (mouse), and assessed whether administration of MC4R agonists to a physiologically relevant gut model, isolated perfused mouse and rat small intestine, would stimulate GLP-1 secretion or potentiate glucose-stimulated secretion. L-cell MC4R expression was low in mouse duodenum and hardly detectable in the ileum and MC4R expression was hardly detectable in human L-cells. In isolated perfused mouse and rat intestine, neither intra-luminal nor intra-arterial administration of NDP-alpha-MSH, a potent MC4R agonist, had any effect on GLP-1 secretion (P ≥0.98, n = 5–6) from the upper or lower-half of the small intestine in mice or in the lower half in rats. Furthermore, HS014—an often used MC4R antagonist, which we found to be a partial agonist—did not affect the glucose-induced GLP-1 response in the rat, P = 0.62, n = 6). Studies on transfected COS7-cells confirmed bioactivity of the used compounds and that concentrations employed were well within in the effective range. Our combined data therefore suggest that MC4R-activated GLP-1 secretion in rodents either exclusively occurs in the colon or involves extra-intestinal signaling.

scholarly journals Intra-Amniotic Administration of l-Glutamine Promotes Intestinal Maturation And Enteroendocrine Stimulation In Chick Embryos

2021 ◽  
Author(s):  
Naama Reicher ◽  
Tal Melkman-Zehavi ◽  
Jonathan Dayan ◽  
Zehava Uni
Keyword(s):  
Small Intestine ◽  
Cell Signaling ◽  
Mrna Expression ◽  
Chick Embryos ◽  
L Cells ◽  
Functional Maturation ◽  
Intestinal Maturation ◽  
L Cell ◽  
Before And After ◽  
Signaling Components

Abstract Initial nutritional stimulation is a key driving force for small intestinal maturation, and is mediated by enteroendocrine L-cells signaling. In chick embryos, administration of specific nutrients into the amniotic fluid stimulates early development of the small intestine. In this study, we examined the effects of intra-amniotic administration of l-glutamine (Gln) on enterocyte morphological and functional maturation and L-cell signaling before and after hatch. Gln stimulation at embryonic day 17 caused an increase in enterocyte and microvilli dimensions by 10 and 20%, respectively, within 48h. Post-hatch, enterocytes and microvilli were 20% longer in Gln-treated chicks. Correspondingly, mRNA expression of brush border nutrient transporters PepT-1 and SGLT-1 and tight junction proteins TJP-1, TJP-2 and Occludin was significantly upregulated before and after hatch (P<0.05) in Gln-treated chicks. We then evaluated the effects of Gln stimulation on enteroendocrine signaling by locating L-cells in the developing jejunum and observed significant increases in mRNA expression of L-cell signaling components GLP-2R, IGF-1 and IGF-1R before and after hatch, in response to Gln stimulation (P<0.05). Our findings link primary nutrient stimulation of L-cells to enterocyte morphological and functional maturation and provide a model for investigating the effects of specific nutrients on enteroendocrine signaling in the developing small intestine.

Generation and Maintenance of Immune Interferon-Producing Cells Induced by Allogeneic Stimulation in Mice

1980 ◽  
Vol 29 (2) ◽  
pp. 383-389
Author(s):  
Yasuhiko Ito ◽  
Hiizu Aoki ◽  
Yoshinobu Kimura ◽  
Michiko Takano ◽  
Koichiro Maeno ◽  
...  
Keyword(s):  
Tissue Distribution ◽  
Culture Fluid ◽  
Suppressive Effect ◽  
Interferon Production ◽  
Spleen Cells ◽  
Immune Interferon ◽  
L Cells ◽  
L Cell ◽  
Interferon Activity ◽  
Allogeneic Stimulation

When spleen cells derived from C57BL/6 mice immunized with L cells 7 days previously were cocultured with antigenic cells, immune interferon appeared in the culture fluid. We analyzed the tissue distribution of the immune interferon-producing cells (IIPC) which appeared in various lymphoid organs after allogeneic stimulation. Although fluid from cocultures of L-cell-sensitized thymocytes and L-cells could not detect interferon activity consistently, small numbers of IIPC could be detected by using the enumeration method of IIPC. The generation, maintenance, and nature of IIPC emerging in the spleen were different depending on how the host mice were immunized. Multiple antigenic stimulations were more effective and induced longer-lasting immune interferon production than a single stimulation. IIPC induced by a single stimulation appeared to be sensitive to cortisone, vinblastine, and cyclophosphamide and were relatively short lived. In contrast, IIPC induced by multiple stimulations seemed to be partially resistant to these drugs and long lived. When mice were immunized with intact L-cells, carrageenan, a known antimacrophage agent, had no effect on immune interferon production. However, when mice were immunized with solubilized L-cell antigen, this drug displayed a suppressive effect on immune interferon production.

Increased fluid absorption and cell volume in isolated rabbit proximal straight tubules after in vivo DOCA administration

1981 ◽  
Vol 241 (5) ◽  
pp. F502-F508 ◽  
Author(s):  
M. A. Knepper ◽  
M. B. Burg
Keyword(s):  
Proximal Tubule ◽  
Cell Volume ◽  
Fluid Transport ◽  
Sodium Intake ◽  
Plasma Concentrations ◽  
Dietary Sodium ◽  
Fluid Absorption ◽  
Direct Stimulation ◽  
Stimulation Of

To investigate whether mineralocorticoids affect the intrinsic capacity of the proximal tubule to absorb sodium and fluid, rabbits were chronically treated a number of ways to systematically vary plasma concentrations of mineralocorticoid hormones. The rate of fluid absorption and tubule dimensions were measured in superficial S2 segments from these rabbits. Chronic administration of deoxycorticosterone acetate (DOCA) was associated with a 67% increase in fluid absorption and a 29% increase in cell volume per unit tubule length. However, neither adrenalectomy nor low sodium diet significantly affected either fluid absorption or cell volume. Furthermore, marked dietary sodium restriction prevented the response to DOCA. We conclude that the DOCA-induced increases in fluid absorption and cell volume do not result from a direct stimulation of the proximal tubular cells by the steroid but more likely are responses to systemic effects of DOCA administration that are dependent on the level of sodium intake. Thus, we find no evidence for a direct mineralocorticoid stimulation of sodium and fluid transport by the S2 portion of the proximal tubule.

scholarly journals Investigating Intestinal Glucagon After Roux-en-Y Gastric Bypass Surgery

2019 ◽  
Vol 104 (12) ◽  
pp. 6403-6416 ◽  
Author(s):  
Tina Jorsal ◽  
Nicolai J Wewer Albrechtsen ◽  
Marie M Christensen ◽  
Brynjulf Mortensen ◽  
Erik Wandall ◽  
...  
Keyword(s):  
Gastric Bypass ◽  
Small Intestine ◽  
Gastric Bypass Surgery ◽  
Plasma Concentrations ◽  
University Hospital ◽  
Morbidly Obese ◽  
Mucosal Biopsy ◽  
Cross Sectional ◽  
Biopsy Specimens ◽  
Before And After

Abstract Context After Roux-en-Y gastric bypass (RYGB) surgery, postprandial plasma glucagon concentrations have been reported to increase. This occurs despite concomitant improved glucose tolerance and increased circulating plasma concentrations of insulin and the glucagon-inhibiting hormone glucagon-like peptide 1 (GLP-1). Objective To investigate whether RYGB-induced hyperglucagonemia may be derived from the gut. Design and Setting Substudy of a prospective cross-sectional study at a university hospital in Copenhagen, Denmark. Participants Morbidly obese individuals undergoing RYGB (n = 8) with or without type 2 diabetes. Interventions Three months before and after RYGB, participants underwent upper enteroscopy with retrieval of gastrointestinal mucosal biopsy specimens. Mixed-meal tests were performed 1 week and 3 months before and after RYGB. Main Outcome Measures The 29–amino acid glucagon concentrations in plasma and in mucosal gastrointestinal biopsy specimens were assessed using mass spectrometry–validated immunoassays, and a new monoclonal antibody reacting with immunoreactive glucagon was used for immunohistochemistry. Results Postprandial plasma concentrations of glucagon after RYGB were increased. Expression of the glucagon gene in the small intestine increased after surgery. Glucagon was identified in the small-intestine biopsy specimens obtained after, but not before, RYGB. Immunohistochemically, mucosal biopsy specimens from the small intestine harbored cells costained for GLP-1 and immunoreactive glucagon. Conclusion Increased concentrations of glucagon were observed in small-intestine biopsy specimens and postprandially in plasma after RYGB. The small intestine harbored cells immunohistochemically costaining for GLP-1 and glucagon-like immunoreactivity after RYGB. Glucagon derived from small-intestine enteroendocrine l cells may contribute to postprandial plasma concentrations of glucagon after RYGB.

scholarly journals Use of immobilized lactoperoxidase to label L cell proteins involved in adhesion to polystyrene.

1980 ◽  
Vol 85 (2) ◽  
pp. 402-413 ◽  
Author(s):  
N W Chin ◽  
K W Lanks
Keyword(s):  
Molecular Weight ◽  
Tissue Culture ◽  
Broad Spectrum ◽  
Peptide Mapping ◽  
Limited Proteolysis ◽  
Functional Association ◽  
One Dimensional ◽  
L Cells ◽  
L Cell ◽  
10 Nm Filaments

Proteins involved in the attachment of murine L cells to polystyrene have been identified by a technique designed to iodinate only those macromolecules coming into closet apposition to the substratum. Whereas soluble lactoperoxidase (LPO) catalyzes the radioiodination of a broad spectrum of polypeptides, the same enzyme immobilized on polystyrene tissue culture flasks discriminately labels 55,000 and 42,000 mol wt polypeptides that adhere tightly to the substratum after the cells are removed. One-dimensional peptide mapping following limited proteolysis showed that the labeled 55,000 mol wt polypeptide is similar to a component of comparable molecular weight present in the detergent-extracted cytoskeleton. The functional association of two cytoskeletal structures, presumably 10-nm filaments and actin, is discussed, and alternative explanations for their susceptibility to iodination by immobilized LPO are presented.

scholarly journals The Protective Role of Hydrogen Sulfide Against Obesity-Associated Cellular Stress in Blood Glucose Regulation

Antioxidants ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 1038
Author(s):  
Ania Mezouari ◽  
Radhika Nangia ◽  
Jeffrey Gagnon
Keyword(s):  
Oxidative Stress ◽  
Hydrogen Sulfide ◽  
Blood Glucose ◽  
Cell Function ◽  
Fasting Blood Glucose ◽  
Protective Role ◽  
Oral Glucose ◽  
Chow Diet ◽  
L Cells ◽  
L Cell

Circulating palmitic acid (PA) is increased in obesity and causes metabolic stress, leading to diabetes. This includes the impairment of the glucoregulatory hormone glucagon-like peptide-1 (GLP-1) secreted from intestinal L-cells. Recently, the anti-inflammatory gasotransmitter hydrogen sulfide (H2S) has been implicated in the enhancement of GLP-1 secretion. We hypothesized that H2S can reduce the oxidative stress caused by palmitate and play a protective role in L-cell function. This study was conducted on both human and mouse L-cells and a mouse model of Western diet (WD)-induced obesity. PA-induced L-cell stress was assessed using DCF-DA. H2S was delivered using the donor GYY4137. C57BL/6 mice were fed either chow diet or PA-enriched WD for 20 weeks with ongoing measurements of glycemia and GLP-1 secretion. In both L-cell models, we demonstrated that PA caused an increase in reactive oxygen species (ROS). This ROS induction was partially blocked by the H2S administration. In mice, the WD elevated body weight in both sexes and elevated fasting blood glucose and lipid peroxidation in males. Additionally, a single GYY4137 injection improved oral glucose tolerance in WD-fed male mice and also enhanced glucose-stimulated GLP-1 release. To conclude, H2S reduces oxidative stress in GLP-1 cells and can improve glucose clearance in mice.

GLP-1 secretion is enhanced directly in the ileum but indirectly in the duodenum by a newly identified potent stimulator, zein hydrolysate, in rats

2009 ◽  
Vol 297 (4) ◽  
pp. G663-G671 ◽  
Author(s):  
Tohru Hira ◽  
Taisuke Mochida ◽  
Kyoko Miyashita ◽  
Hiroshi Hara
Keyword(s):  
Small Intestine ◽  
Sampling Method ◽  
Rat Intestine ◽  
Mesenteric Vein ◽  
L Cells ◽  
Corn Protein ◽  
Before And After ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Dose Dependent

Glucagon-like peptide-1 (GLP-1) is released from enteroendocrine cells (L cells) in response to food ingestion. The mechanism by which dietary peptides stimulate GLP-1 secretion in the gut is unknown. In the present study, we found that a hydrolysate prepared from zein, a major corn protein [zein hydrolysate (ZeinH)], strongly stimulates GLP-1 secretion in enteroendocrine GLUTag cells. Stimulatory mechanisms of GLP-1 secretion induced by ZeinH were investigated in the rat small intestine under anesthesia. Blood was collected through a portal catheter before and after ZeinH administration into different sites of the small intestine. The duodenal, jejunal, and ileal administration of ZeinH induced dose-dependent increases in portal GLP-1 concentration. GLP-1 secretion in response to the ileal administration of ZeinH was higher than that in the duodenal or jejunal administration. Capsaicin treatment on esophageal vagal trunks abolished the GLP-1 secretion induced by duodenal ZeinH but did not affect the secretion induced by jejunal or ileal ZeinH. These results suggest that ZeinH in the jejunum or ileum directly stimulates GLP-1 secretion but duodenal ZeinH indirectly stimulates GLP-1 secretion via the vagal afferent nerve. A direct blood sampling method from the duodenal vein and ileal mesenteric vein revealed that ZeinH administered into the ligated duodenal loop enhanced GLP-1 concentration in the ileal mesenteric vein but not in the duodenal vein. This confirmed that ZeinH in the duodenum induces GLP-1 secretion from L cells located in the ileum by an indirect mechanism. These results indicate that a potent GLP-1-releasing peptide, ZeinH, induces GLP-1 secretion by direct and indirect mechanisms in the rat intestine.

scholarly journals Protein Kinase Cζ Is Required for Oleic Acid-Induced Secretion of Glucagon-Like Peptide-1 by Intestinal Endocrine L Cells

Endocrinology ◽  
2007 ◽  
Vol 148 (3) ◽  
pp. 1089-1098 ◽  
Author(s):  
Roman Iakoubov ◽  
Angelo Izzo ◽  
Andrea Yeung ◽  
Catharine I. Whiteside ◽  
Patricia L. Brubaker
Keyword(s):  
Oleic Acid ◽  
Protein Kinase ◽  
Monounsaturated Fatty Acids ◽  
L Cells ◽  
L Cell ◽  
Rna Transfection ◽  
Pkc Isoforms ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1 ◽  
Long Chain

Long-chain, monounsaturated fatty acids (FAs) stimulate secretion of the incretin hormone, glucagon-like peptide-1 (GLP-1) from the intestinal L cell. Because the atypical protein kinase C (PKC), PKCζ, is involved in FA signaling in many cells, the role of PKCζ in FA-induced GLP-1 secretion was investigated, using the murine GLUTag L cell line and primary rat intestinal L cells. GLUTag cells expressed mRNA for several PKC isoforms, including PKCζ, and PKCζ protein was localized throughout the cytoplasm in GLUTag and primary L cells as well as normal mouse and rat L cells. Treatment with oleic acid (150–1000 μm) for 2 h increased GLP-1 secretion (P &lt; 0.001), and this was abrogated by the PKCζ inhibitor ZI (P &lt; 0.05) and PKCζ small interfering RNA transfection (P &lt; 0.05) but not inhibition of classical/novel PKC isoforms. Although most PKCζ was localized in the particulate compartment of GLUTag cells, oleate treatment did not alter PKCζ levels or activity in this cell fraction. GLUTag cells expressed mRNA for the Gq-coupled FA receptor GPR120; however, oleic acid did not induce any changes in Akt, MAPK, or calcium, and pretreatment with LY294002 and PD98059 to inhibit phosphatidylinositol 3-kinase and MAPK, respectively, did not prevent the effects of oleic acid. Finally, GLUTag cells also released GLP-1 in response to arachidonic acid (P &lt; 0.001) but were not affected by other long-chain FAs. These findings demonstrate that PKCζ is required for oleic acid-induced GLP-1 secretion. This enzyme may therefore serve as a therapeutic target to enhance GLP-1 release in type 2 diabetes.

Effects of intra-arterial arginine-vasopressin infusions on peripheral blood flows in conscious dogs

1986 ◽  
Vol 71 (6) ◽  
pp. 713-721 ◽  
Author(s):  
Jean-Francois Liard
Keyword(s):  
Skeletal Muscle ◽  
Blood Flow ◽  
Small Intestine ◽  
Arginine Vasopressin ◽  
Muscle Blood Flow ◽  
Plasma Concentrations ◽  
Abdominal Fat ◽  
Conscious Dogs ◽  
Bone Blood Flow ◽  
Blood Flows

1. We reported in an earlier study that intravenous infusions of arginine-vasopressin (AVP), 220 pg min−1 kg−1 for 1 h, substantially reduced blood flow to the skin, skeletal muscle, pancreas, colon, small intestine, abdominal fat and myocardium [1] in conscious dogs. In the present study, we infused AVP directly into the artery supplying these organs and tissues in order to determine the relative contribution of local versus systemic mechanisms in the vascular resistance changes previously observed. 2. Regional blood flows were measured with radioactive microspheres in conscious, chronically instrumented dogs before and during intra-arterial infusions of AVP administered into the left axillary artery (n = 6), the left coronary artery (n = 6), and the cranial mesenteric artery (n = 6). The infusion rates were calculated to increase local, target organ plasma concentrations of AVP to the levels reached in our previous study while minimizing systemic changes. 3. Left axillary AVP artery infusion significantly reduced skin and compact bone blood flow, but had no effect on skeletal muscle blood flow. Intra-coronary AVP infusion had no effect on myocardial blood flow nor on cardiac output. Intramesenteric AVP infusion had no effect on blood flow to the colon, small intestine and abdominal fat, but significantly reduced blood flow to those areas of the pancreas which received blood from the cannulated artery. 4. Measurements in a limited number of dogs indicated that the local axillary and mesenteric venous levels of AVP were similar when the hormone was infused systemically at a rate of 220 pg min−1 kg−1 or intra-arterially at a lower rate. 5. These findings suggest that the increase in resistance measured in the skeletal muscle, small intestine, colon and abdominal fat after systemic administration of small amounts of AVP results in large part from indirect mechanisms. Direct vasoconstrictor effects of AVP at these plasma concentrations appear limited to the skin, the pancreas and the compact bones.

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