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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.

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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.

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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.

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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.

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