Dataset Information

MTORC1 to AMPK switching underlies ?-cell metabolic plasticity during maturation and diabetes.

ABSTRACT: Pancreatic beta cells (?-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of ?-cell function, we found that the control of cellular signaling in ?-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this was critical for functional maturation. Moreover, AMPK was activated by the dietary transition taking place during weaning, and this in turn inhibited mTORC1 activity to drive the adult ?-cell phenotype. While forcing constitutive mTORC1 signaling in adult ?-cells relegated them to a functionally immature phenotype with characteristic transcriptional and metabolic profiles, engineering the switch from mTORC1 to AMPK signaling was sufficient to promote ?-cell mitochondrial biogenesis, a shift to oxidative metabolism, and functional maturation. We also found that type 2 diabetes, a condition marked by both mitochondrial degeneration and dysregulated GSIS, was associated with a remarkable reversion of the normal AMPK-dependent adult ?-cell signature to a more neonatal one characterized by mTORC1 activation. Manipulating the way in which cellular nutrient signaling pathways regulate ?-cell metabolism may thus offer new targets to improve ?-cell function in diabetes.

SUBMITTER: Jaafar R

PROVIDER: S-EPMC6763225 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes.

Jaafar Rami R Tran Stella S Shah Ajit N AN Sun Gao G Valdearcos Martin M Marchetti Piero P Masini Matilde M Swisa Avital A Giacometti Simone S Bernal-Mizrachi Ernesto E Matveyenko Aleksey A Hebrok Matthias M Dor Yuval Y Rutter Guy A GA Koliwad Suneil K SK Bhushan Anil A

The Journal of clinical investigation 20190702 10

Pancreatic beta cells (β-cells) differentiate during fetal life, but only postnatally acquire the capacity for glucose-stimulated insulin secretion (GSIS). How this happens is not clear. In exploring what molecular mechanisms drive the maturation of β-cell function, we found that the control of cellular signaling in β-cells fundamentally switched from the nutrient sensor target of rapamycin (mTORC1) to the energy sensor 5'-adenosine monophosphate-activated protein kinase (AMPK), and that this wa ...[more]

PMID: 31265435

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Project description:BackgroundKinases mTORC1 and AMPK act as energy sensors, controlling nutrient responses and cellular growth. Changes in nutrient levels affect diverse transcriptional networks, making it challenging to identify downstream paths that regulate cellular growth or a switch to development via nutrient variation. The life cycle of Dictyostelium presents an excellent model to study the mTORC1 signaling function for growth and development. Dictyostelium grow as single cells in nutrient-rich media, but, upon nutrient withdrawal, growth ceases and cells enter a program for multi-cell development. While nearly half the genome shows gene expression changes upon nutrient removal, we hypothesized that not all of these genes are required for the switch to program development. Through manipulation of mTORC1 activity alone, without nutrient removal, we focused on a core network of genes that are required for switching between growth and development for regulation of cell fate decisions.ResultsTo identify developmentally essential genes, we sought ways to promote development in the absence of nutrient loss. We first examined the activities of mTORC1 and AMPK in Dictyostelium during phases of rapid growth and starvation-induced development and showed they exhibited reciprocal patterns of regulation under various conditions. Using these as initial readouts, we identified rich media conditions that promoted rapid cell growth but, upon mTORC1 inactivation by rapamycin, led to a growth/development switch. Examination of gene expression during cell fate switching showed that changes in expression of most starvation-regulated genes were not required for developmental induction. Approximately 1000 genes which become downregulated upon rapamycin treatment comprise a cellular growth network involving ribosome biogenesis, protein synthesis, and cell cycle processes. Conversely, the upregulation of ~ 500 genes by rapamycin treatment defines essential signaling pathways for developmental induction, and ~ 135 of their protein products intersect through the well-defined cAMP/PKA network. Many of the rapamycin-induced genes we found are currently unclassified, and mutation analyses of 5 such genes suggest a novel gene class essential for developmental regulation.ConclusionsWe show that manipulating activities of mTORC1/AMPK in the absence of nutrient withdrawal is sufficient for a growth-to-developmental fate switch in Dictyostelium, providing a means to identify transcriptional networks and signaling pathways essential for early development.

Dataset Information

MTORC1 to AMPK switching underlies ?-cell metabolic plasticity during maturation and diabetes.

Publications

mTORC1 to AMPK switching underlies β-cell metabolic plasticity during maturation and diabetes.

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