The role of gut endocrine cells in control of metabolism and appetite

ABSTRACT Activating signal cointegrator 2 (ASC-2) is a transcriptional coactivator of many nuclear receptors (NRs) and other transcription factors and contains two NR-interacting LXXLL motifs (NR boxes). In the pancreas, ASC-2 is expressed only in the endocrine cells of the islets of Langerhans, but not in the exocrine cells. Thus, we examined the potential role of ASC-2 in insulin secretion from pancreatic β-cells. Overexpressed ASC-2 increased glucose-elicited insulin secretion, whereas insulin secretion was decreased in islets from ASC-2+/− mice. DN1 and DN2 are two dominant-negative fragments of ASC-2 that contain NR boxes 1 and 2, respectively, and block the interactions of cognate NRs with the endogenous ASC-2. Primary rat islets ectopically expressing DN1 or DN2 exhibited decreased insulin secretion. Furthermore, relative to the wild type, ASC-2+/− mice showed reduced islet mass and number, which correlated with increased apoptosis and decreased proliferation of ASC-2+/− islets. These results suggest that ASC-2 regulates insulin secretion and β-cell survival and that the regulatory role of ASC-2 in insulin secretion appears to involve, at least in part, its interaction with NRs via its two NR boxes.

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Bitter stimuli induce Ca2+ signaling and CCK release in enteroendocrine STC-1 cells: role of L-type voltage-sensitive Ca2+ channels

AJP Cell Physiology ◽

10.1152/ajpcell.00003.2006 ◽

2006 ◽

Vol 291 (4) ◽

pp. C726-C739 ◽

Cited By ~ 141

Author(s):

Monica C. Chen ◽

S. Vincent Wu ◽

Joseph R. Reeve ◽

Enrique Rozengurt

Keyword(s):

Endocrine Cells ◽

Bitter Taste ◽

Dependent Manner ◽

Gi Tract ◽

Intracellular Ca ◽

Α Subunits ◽

Ca2 Channels ◽

Cck Release

We previously demonstrated the expression of bitter taste receptors of the type 2 family (T2R) and the α-subunits of the G protein gustducin (Gαgust) in the rodent gastrointestinal (GI) tract and in GI endocrine cells. In this study, we characterized mechanisms of Ca2+ fluxes induced by two distinct T2R ligands: denatonium benzoate (DB) and phenylthiocarbamide (PTC), in mouse enteroendocrine cell line STC-1. Both DB and PTC induced a marked increase in intracellular [Ca2+] ([Ca2+]i) in a dose- and time-dependent manner. Chelating extracellular Ca2+ with EGTA blocked the increase in [Ca2+]i induced by either DB or PTC but, in contrast, did not prevent the effect induced by bombesin. Thapsigargin blocked the transient increase in [Ca2+]i induced by bombesin, but did not attenuate the [Ca2+]i increase elicited by DB or PTC. These results indicate that Ca2+ influx mediates the increase in [Ca2+]i induced by DB and PTC in STC-1 cells. Preincubation with the L-type voltage-sensitive Ca2+ channel (L-type VSCC) blockers nitrendipine or diltiazem for 30 min inhibited the increase in [Ca2+]i elicited by DB or PTC. Furthermore, exposure to the L-type VSCCs opener BAY K 8644 potentiated the increase in [Ca2+]i induced by DB and PTC. Stimulation with DB also induced a marked increase in the release of cholecystokinin from STC-1 cells, an effect also abrogated by prior exposure to EGTA or L-type VSCC blockers. Collectively, our results demonstrate that bitter tastants increase [Ca2+]i and cholecystokinin release through Ca2+ influx mediated by the opening of L-type VSCCs in enteroendocrine STC-1 cells.

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The effect of pancreatic mesenchyme on the differentiation of endocrine cells from gastric endoderm

Development ◽

10.1242/dev.100.4.661 ◽

1987 ◽

Vol 100 (4) ◽

pp. 661-671 ◽

Cited By ~ 1

Author(s):

B. Kramer ◽

A. Andrew ◽

B.B. Rawdon ◽

P. Becker

Keyword(s):

Endocrine Cell ◽

Endocrine Cells ◽

Cell Types ◽

The Other ◽

Chick Embryos ◽

Cell Type ◽

Pancreatic Insulin ◽

Somatostatin Cells ◽

Regional Specificity ◽

Gut Endocrine Cells

To determine whether mesenchyme plays a part in the differentiation of gut endocrine cells, proventricular endoderm from 4- to 5-day chick or quail embryos was associated with mesenchyme from the dorsal pancreatic bud of chick embryos of the same age. The combinations were grown on the chorioallantoic membranes of host chick embryos until they reached a total incubation age of 21 days. Proventricular or pancreatic endoderm of the appropriate age and species reassociated with its own mesenchyme provided the controls. Morphogenesis in the experimental grafts corresponded closely to that in proventricular controls, i.e. the pancreatic mesenchyme supported the development of proventricular glands from proventricular endoderm. Insulin, glucagon and somatostatin cells and cells with pancreatic polypeptide-like immunoreactivity differentiated in the pancreatic controls. The latter three endocrine cell types, together with neurotensin and bombesin/gastrin-releasing polypeptide (GRP) cells, developed in proventricular controls and experimental grafts. The proportions of the major types common to proventriculus and pancreas (somatostatin and glucagon cells) were in general similar when experimental grafts were compared with proventricular controls but different when experimental and pancreatic control grafts were compared. Hence pancreatic mesenchyme did not materially affect the proportions of these three cell types in experimental grafts, induced no specific pancreatic (insulin) cell type and allowed the differentiation of the characteristic proventricular endocrine cell types, neurotensin and bombesin/GRP cells. However, an important finding was a significant reduction in the proportion of bombesin/GRP cells, attributable in part to a decrease in their number and in part to an increase in the numbers of endocrine cells of the other types. This indicates that mesenchyme may well play a part in determining the regional specificity of populations of gut endocrine cells.

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The distribution of endocrine cell progenitors in the gut of chick embryos

Development ◽

10.1242/dev.82.1.131 ◽

1984 ◽

Vol 82 (1) ◽

pp. 131-145

Author(s):

B. B. Rawdon ◽

Beverley Kramer ◽

Ann Andrew

Keyword(s):

Gastrointestinal Tract ◽

Progenitor Cells ◽

Digestive Tract ◽

Pancreatic Polypeptide ◽

Endocrine Cell ◽

Endocrine Cells ◽

Chick Embryos ◽

Intact Embryo ◽

Pancreatic Endocrine Cells ◽

Gut Endocrine Cells

The aim of this experiment was to find out whether or not, at early stages of development, progenitors of the various types of gut endocrine cells are localized to one or more specific regions of the gastrointestinal tract. Transverse strips of blastoderm two to four somites in length were excised between the levels of somites 5 and 27 in chick embryos at 5- to 24-somite stages and were cultured as chorioallantoic grafts. The distribution of endocrine cells in the grafts revealed confined localization of progenitor cells only in the case of insulinimmunoreactive cells. Theprogenitors of cells with somatostatin-, pancreatic polypeptide-, glucagon-, secretin-, gastrin/CCK-, motilin-, neurotensin- and serotonin-like immunoreactivity were distributed along the length of the presumptive gut at the time of explantation; indeed, in many cases they were more widespread than are their differentiated progeny in normal gut of the same age. This finding indicates that conditions in grafts must differ from those that operate in the intact embryo. Also it may explain the occurrence of ectopic gut or pancreatic endocrine cells in tumours of the digestive tract.

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REST is a major negative regulator of endocrine differentiation during pancreas organogenesis

10.1101/2021.03.17.435876 ◽

2021 ◽

Author(s):

Meritxell Rovira ◽

Goutham Atla ◽

Miguel Angel Maestro ◽

Vane Grau ◽

Javier García-Hurtado ◽

...

Keyword(s):

Endocrine Cells ◽

Negative Regulator ◽

Β Cell ◽

Knock Out ◽

Endocrine Differentiation ◽

Conditional Allele ◽

Embryonic Pancreas ◽

Pancreatic Endocrine Cells ◽

Knock Out Mice

SUMMARYUnderstanding genomic regulatory mechanisms of pancreas differentiation is relevant to the pathophysiology of diabetes mellitus, and to the development of replacement therapies. Numerous transcription factors promote β cell differentiation, although less is known about negative regulators. Earlier epigenomic studies suggested that the transcriptional repressor REST could be a suppressor of endocrine gene programs in the embryonic pancreas. However, pancreaticRestknock-out mice failed to show increased numbers of endocrine cells, suggesting that REST is not a major regulator of endocrine differentiation. Using a different conditional allele that enables profound REST inactivation, we now observe a marked increase in the formation of pancreatic endocrine cells. REST inhibition also promoted endocrinogenesis in zebrafish and mouse early postnatal ducts, and induced β-cell specific genes in human adult duct-derived organoids. Finally, we define REST genomic programs that suppress pancreatic endocrine differentiation. These results establish a crucial role of REST as a negative regulator of pancreatic endocrine differentiation.

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Co-localisation of substance P-, bombesin-and peptide histidine isoleucine (PHI)-like peptides in gut endocrine cells of the dogfish Scyliorhinus stellaris

Anatomy and Embryology ◽

10.1007/bf00315702 ◽

1989 ◽

Vol 179 (6) ◽

pp. 605-614 ◽

Cited By ~ 17

Author(s):

V. Cimini ◽

S. Noorden ◽

J. M. Polak

Keyword(s):

Substance P ◽

Endocrine Cells ◽

Gut Endocrine Cells

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Gut chemosensing: Interactions between gut endocrine cells and visceral afferents

Autonomic Neuroscience ◽

10.1016/j.autneu.2009.07.007 ◽

2010 ◽

Vol 153 (1-2) ◽

pp. 41-46 ◽

Cited By ~ 119

Author(s):

Helen E. Raybould

Keyword(s):

Endocrine Cells ◽

Visceral Afferents ◽

Gut Endocrine Cells

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Follistatin regulates the relative proportions of endocrine versus exocrine tissue during pancreatic development

Development ◽

10.1242/dev.125.6.1017 ◽

1998 ◽

Vol 125 (6) ◽

pp. 1017-1024 ◽

Cited By ~ 8

Author(s):

F. Miralles ◽

P. Czernichow ◽

R. Scharfmann

Keyword(s):

Endocrine Cells ◽

Glucose Transporter ◽

Inductive Effect ◽

Secretory Granules ◽

Pancreatic Development ◽

Soluble Factors ◽

Repressive Effect ◽

Development In Vitro

In this study, we have investigated the role of the embryonic mesenchyme in the development of the pancreas. We have compared the development in vitro of E12.5 rat pancreatic rudiments grown in the presence or absence of mesenchyme. When the E12.5 pancreatic epithelial rudiment is cultured in the presence of its surrounding mesenchyme, both morphogenesis and cytodifferentiation of the exocrine component of the pancreas are completely achieved, while only a few immature endocrine cells develop. The pancreatic rudiments grown in the absence of mesenchyme develop in a completely different way; the exocrine tissue develops poorly and fails to undergo acinar morphogenesis, while the endocrine tissue develops actively. Four times more insulin-positive cells develop after removal of the mesenchyme than in the cultures performed in the presence of mesenchyme. Moreover, the insulin-expressing cells developed in the mesenchyme-depleted rudiments appear mature since they do not coexpress glucagon, express the glucose transporter Glut-2 and express Rab3A, a molecule associated with the secretory granules. Moreover, these endocrine cells are able to associate and form true islets. Both the inductive effect of the mesenchyme on the proper development of the exocrine tissue and its repressive effect on the development of the endocrine cells are mediated by soluble factors. Follistatin, which is expressed by E12.5 pancreatic mesenchyme, can mimic both inductive and repressive effects of the mesenchyme. Follistatin could thus represent one of the mesenchymal factors required for the development of the exocrine tissue while exerting a repressive role on the differentiation of the endocrine cells.

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III. Endocrine cell recognition of luminal nutrients

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.1999.277.6.g1103 ◽

1999 ◽

Vol 277 (6) ◽

pp. G1103-G1107 ◽

Cited By ~ 28

Author(s):

Alison M. J. Buchan

Keyword(s):

Epithelial Cell ◽

Endocrine Cells ◽

Hormone Secretion ◽

Cell Recognition ◽

Cell Type ◽

Distal Small Intestine ◽

Extrinsic Innervation ◽

Different Response ◽

Outstanding Question

The profile of hormone secretion from the gastrointestinal tract on food ingestion depends to a great extent on the composition of the meal. High levels of protein result in a quantitatively and qualitatively different response compared with a meal rich in fats. The outstanding question is whether this differential response is driven by the ability of gastroenteric endocrine cells to directly sense the contents of the lumen via apical microvilli. Alternative effectors would include activation of the intrinsic and extrinsic innervation or other epithelial cell populations. The data available indicate that the role of the gastrointestinal innervation is relatively limited and is probably a major factor only in the postprandial responses of hormones released from endocrine cells in the distal small intestine. However, whether nutrients directly stimulate gastroenteric endocrine cells or another epithelial cell type has yet to be established.

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Morphogenesis of the islets of Langerhans is guided by extra-endocrine Slit2/3 signals

Molecular and Cellular Biology ◽

10.1128/mcb.00451-20 ◽

2020 ◽

pp. MCB.00451-20

Author(s):

Jennifer M. Gilbert ◽

Melissa T. Adams ◽

Nadav Sharon ◽

Hariharan Jayaraaman ◽

Barak Blum

Keyword(s):

Axon Guidance ◽

Islets Of Langerhans ◽

Endocrine Cells ◽

Β Cells ◽

Robo Receptors ◽

Correct Function ◽

Cell Positioning ◽

Spatial Architecture ◽

Endocrine Tissues

The spatial architecture of the islets of Langerhans is vitally important for their correct function, and alterations in islet morphogenesis often result in diabetes mellitus. We have previously reported that Roundabout (Robo) receptors are required for proper islet morphogenesis. As part of the Slit-Robo signaling pathway, Robo receptors function in conjunction with Slit ligands to mediate axon guidance, cell migration, and cell positioning in development. However, the role of Slit ligands in islet morphogenesis has not yet been determined. Here we report that Slit ligands are expressed in overlapping and distinct patterns in both endocrine and non-endocrine tissues in late pancreas development. We show that function of either Slit2 or Slit3, which are predominantly expressed in the pancreatic mesenchyme, is required and sufficient for islet morphogenesis, while Slit1, which is predominantly expressed in the β-cells, is dispensable for islet morphogenesis. We further show that Slit functions as a repellent signal to β-cells. These data suggest that clustering of endocrine cells during islet morphogenesis is guided, at least in part, by repelling Slit2/3 signals from the pancreatic mesenchyme.

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