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Single-cell mRNA sequencing of human embryonic pancreas

ABSTRACT: A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires changes in the metabolic system. Despite their central role in metabolic homeostasis, little is known about how pancreatic beta cells adjust to the new nutritional program. Our experiments show that after birth beta cells shift from amino acid- to glucose-stimulated insulin secretion that correlates with the nutritional environment of the animal. This metabolic adaptation is mediated by a transition in nutrient sensitivity of the mTORC1 pathway , which leads toresults in intermittent mTORC1 signaling activity. Disrupting nutrient sensitivity of mTORC1 in mature beta cells affects insulin secretion and reverts them to an immature functional state. Finally, manipulating nutrient sensitivity of mTORC1 in stem cell-derived beta cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrient sensing regulates beta cell function, thereby enabling a metabolic adaptation for the newborn.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147349 | GEO | 2020/05/07

REPOSITORIES: GEO

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mRNA sequencing of stem cell-derived beta cells

Project description:A drastic transition at birth, from constant maternal nutrient supply in utero to intermittent postnatal feeding, requires changes in the metabolic system. Despite their central role in metabolic homeostasis, little is known about how pancreatic beta cells adjust to the new nutritional program. Our experiments show that after birth beta cells shift from amino acid- to glucose-stimulated insulin secretion that correlates with the nutritional environment of the animal. This metabolic adaptation is mediated by a transition in nutrient sensitivity of the mTORC1 pathway , which leads toresults in intermittent mTORC1 signaling activity. Disrupting nutrient sensitivity of mTORC1 in mature beta cells affects insulin secretion and reverts them to an immature functional state. Finally, manipulating nutrient sensitivity of mTORC1 in stem cell-derived beta cells in vitro strongly enhances their glucose-responsive insulin secretion. These results reveal a mechanism by which nutrient sensing regulates beta cell function, thereby enabling a metabolic adaptation for the newborn.

2020-05-07 | GSE147347 | GEO

mRNA sequencing of stem cell-derived beta cells before and after transplantation in mice

2020-05-07 | GSE147346 | GEO

Hepatic nutrient and hormone signaling to mTORC1 instructs the postnatal metabolic zonation of the liver

Project description:The metabolic functions of the liver are organized spatially in a phenomenon known as zonation. This spatial organization of metabolic functions is linked to the differential exposure of central and portal hepatocytes to either systemic circulation or nutrient-rich blood afferent from the gastrointestinal tract, respectively. The mechanistic target of rapamycin complex 1 (mTORC1) is the central hub of a critical signaling pathway that links cellular metabolism to fluctuations in the levels of nutrients and insulin. To understand how these two signaling cues are integrated in the liver, we have generated mice with constitutive nutrient and insulin signaling to mTORC1 in hepatocytes (RragaGTP/fl; Tsc1fl/fl; Albumin-CreTg mice). Simultaneous activation of nutrient and hormone signaling to mTORC1 results in impaired establishment of the metabolic zonal identity of hepatocytes, a maturation process that takes place within the first weeks after birth. Mechanistically, a decrease in levels of the morphogenic pathway Wnt/β-catenin in hepatocytes and reduced expression of the Wnt2 ligand by liver endothelial cells after birth underlie this impaired wave of hepatocyte maturation. Lack of postnatal establishment of metabolic zonation of the liver is recapitulated in a model of constant supply of nutrients by total parenteral nutrition to neonatal pigs. Collectively, our work shows the critical role of hepatocyte sensing of fluctuations in nutrients and hormones after birth for triggering the latent metabolic zonation program.

2024-03-18 | PXD041439 | Pride

mTORC1 to AMPK Switching Underlies β-Cell Metabolic Plasticity During Maturation and Diabetes

Project description:Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). The molecular mechanisms driving this maturation of β-cell function remain incompletely understood. Here, we show that the control of cellular signaling in β-cells fundamentally switches from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this is critical for functional maturation. Moreover, AMPK is activated by the dietary transition taking place during weaning, and this in turn inhibits mTORC1 activity to drive the adult β-cell phenotype. While forcing constitutive mTORC1 signaling in adult β-cells relegates them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling is sufficient to promote β-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also show that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, is associated with a remarkable reversion of the normal AMPK-dependent adult β-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate β-cell metabolism may thus offer new targets to improve β-cell function in diabetes.

2019-06-06 | GSE132261 | GEO

A nutrient sensing transition at birth triggers glucose-stimulated insulin secretion

Project description:A nutrient sensing transition at birth triggers glucose-stimulated insulin secretion

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Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Project description:Adaptation of the islet β-cell insulin secretory response to changing insulin demand is critical for blood glucose homeostasis, yet the mechanisms underlying this adaptation are unknown. Here, we show that nutrient cues adapt insulin secretion by modulating chromatin state and transcription of genes regulating β-cell nutrient sensing and metabolism. Feeding stimulates histone acetylation at sites occupied by the chromatin-modifying enzyme Lsd1 in islets. We demonstrate that β-cell-specific deletion of Lsd1 leads to insulin hypersecretion, aberrant expression of nutrient response genes, and histone hyperacetylation, features we also observed in the db/db model of chronically increased insulin demand. Moreover, genetic variants associated with fasting glucose levels and type 2 diabetes risk are enriched at LSD1-bound sites in human islets, suggesting interindividual variation in β-cell functional adaptation in humans. These findings reveal nutrient state-dependent modulation of the islet epigenome and identify Lsd1 as a regulator of feeding-stimulated chromatin modification and adaptive insulin secretion.

2023-02-24 | GSE134901 | GEO

Neonatal beta cells lack the specialized metabolic phenotype of mature beta cells

2011-02-22 | GSE24790 | GEO

Neonatal beta cells lack the specialized metabolic phenotype of mature beta cells

Project description:Fetal and neonatal beta cells have poor glucose-induced insulin secretion and only gain robust glucose responsiveness several weeks after birth. This unresponsiveness may be due to a generalized immaturity of the metabolic pathways normally found in beta cells. Gene expression profile of neonatal (1 day old) and young adult (6 weeks old) Sprague-Dawley rat islets were evaluated and compared. Frozen sections were obtained from pancreases of neonatal (1 day old) and young adult (6 weeks old) Sprague-Dawley rats. The beta cell enriched cores of the islets were excised using laser capture microdissection. RNA was extracted, amplified and subjected to microarray analysis.

2011-02-22 | E-GEOD-24790 | biostudies-arrayexpress

Limited survival and impaired hepatic fasting metabolism of glucose, amino acids and lipids in mice with constitutive Rag GTPase signaling

Project description:The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of RagA (RagAGTP) in mice resulted in a fatal energetic crisis at birth. Herein, we have rescued neonatal lethality in RagAGTP mice and found morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months. Proteomic and metabolomic analyses of livers from RagAGTP mice revealed a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects were partially recapitulated by restricting activation of RagA to hepatocytes, and reverted by pharmacological inhibition of mTORC1. Constitutive hepatic nutrient signaling did not cause hepatocellular damage and carcinomas, unlike genetic activation of growth factor signaling upstream of mTORC1. In summary, RagA signaling dictates dynamic responses to feeding-fasting cycles to tune metabolism so as to match the nutritional state.

2021-05-11 | MTBLS2397 | MetaboLights

Real-time quantitative PCR analysis of microRNAS in islets of mice exposed to low-protein diet during gestation

Project description:Maternal low-protein diet increases the susceptibility of offspring to type 2 diabetes. An insult to the pancreas during development can have long-term consequences on β-cell mass and function. Because nutrients and growth factors signaling converge on mTOR, we hypothesized that mTOR plays a central role in β-cell programming during fetal development. In this study, we revealed that newborns of dams exposed to low-protein diet (LP0.5) throughout pregnancy exhibited decreased insulin levels, β-cell fraction, and mTOR signaling. Adult LP0.5 offspring demonstrated enhanced insulin sensitivity but remained glucose intolerant due to an insulin secretory defect and not reduced β-cell mass. The insulin secretory defect was distal to Ca2+ influx, at the level of proinsulin biosynthesis and insulin content. LP0.5 islets exhibited reduced mTOR protein and increased expression of specific microRNAs. The reductions in mTOR protein and insulin secretion in LP0.5 islets were restored to normal by blockade of microRNAs 199a-3p and 342. Finally, transient activation of mTORC1 signaling in β-cells during the last week of pregnancy rescued the neonatal β-cell fraction defect and metabolic abnormalities in LP0.5 mice. These findings identify a major role of microRNAs and mTOR in β-cell programing by maternal low-protein diet. To investigate which microRNAs are altered in islets isolated from 2-3 months old male offspring of dams fed low-protein diet (LP0.5) or control diet throughout pregnancy

2014-07-11 | GSE59279 | GEO

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