Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic β Cell Function

Wortham, Matthew; Benthuysen, Jacqueline R.; Wallace, Martina; Savas, Jeffrey N.; Mulas, Francesca; Divakaruni, Ajit S.; Liu, Fen-Fen; Albert, Verena; Taylor, Brandon; Sui, Yinghui; Sáez, Enrique; Murphy, Anne N.; Yates, John R.; Metallo, Christian M.; Sander, Maike

doi:10.1016/j.celrep.2018.11.031

Cited by 45 publications

(56 citation statements)

References 63 publications

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“…Lsd1 Δβ islets exhibited increased isotopic labelling and accumulation of citrate and malate ( Fig. 3g, h), which have been shown to increase during glucose stimulation 45,46 . Lsd1 Δβ islets also exhibited increased 13 C labelling of glycine, aspartate, and glutamate (Extended Data Fig.…”

mentioning

confidence: 82%

“…Mouse islets were isolated and cultured as previously described 45 . Mouse islets were cultured in complete media (RPMI 1640 with 8 mM glucose, 10% FBS, 2 mM Lglutamine, 100 U/mL Pen/Strep, 1 mM sodium pyruvate, 10 mM HEPES, and 0.25 mg/mL amphoterecin B) at 37°C with 5% CO 2 for a maximum of 48 hours.…”

Section: Cell Line and Islet Culturementioning

confidence: 99%

“…Static insulin secretion assays were performed as previously described 45 . Unless otherwise noted, all insulin secretion measurements were performed after islets were allowed to recover overnight from isolation (mouse islets) or shipment (human islets) in complete islet media (formulations described above).…”

Section: Insulin Secretion Measurementsmentioning

confidence: 99%

“…Respirometry was performed as previously described 45 . Briefly, following islet isolations, islets were pooled within each experimental group and transferred to complete islet media, then shipped overnight at room temperature to Boston University.…”

Section: Islet Respirometrymentioning

confidence: 99%

“…The day of nutrient tracing, islets were briefly washed in KRBH containing 2.8 mM unlabeled glucose and were then transferred to KRBH containing 2.8 mM U-13 C glucose in low-adherence 12-well plates in groups of 220 islets per well (each well being considered a replicate). Plates were then incubated at 37°C and 5% CO 2 for two hours to allow for 13 C incorporation into downstream metabolites, which is not expected to result in steady state labelling based previous islet tracing experiments 45 . After tracing, islets were transferred to pre-chilled Eppendorf tubes, washed once in 0.9% NaCl, and snap frozen.…”

Section: Targeted Metabolomicsmentioning

confidence: 99%

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Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Wortham¹,

F²,

Jy³

et al. 2019

Preprint

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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-stimulated histone acetylation plays a key role in adapting insulin secretion through regulation of genes involved in β-cell nutrient sensing and metabolism. Nutrient regulation of the epigenome occurs 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. Islets from mice adapted to chronically increased insulin demand exhibited similar epigenetic and transcriptional changes. Moreover, genetic variants associated with fasting glucose and type 2 diabetes are enriched at LSD1-bound sites in human islets, suggesting that interpretation of nutrient signals is genetically determined. Our findings reveal that adaptive insulin secretion involves Lsd1-mediated coupling of nutrient state to regulation of the islet epigenome. MainThe ability to regulate nutrient metabolism in response to feeding and fasting is necessary for metabolic homeostasis. Nutrient utilization is acutely regulated by hormones and metabolites that change in response to feeding state 1 . If an energy state persists, adaptive control mechanisms increasingly influence nutrient metabolism. This is exemplified by adaptation of liver metabolism to fasting, wherein a network of nutrient-and hormoneresponsive transcriptional complexes act in tandem with epigenetic changes to drive metabolic rewiring coupled to changes in fuel availability 2-6 . Understanding how feeding

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mentioning

confidence: 82%

Section: Cell Line and Islet Culturementioning

confidence: 99%

Section: Insulin Secretion Measurementsmentioning

confidence: 99%

Section: Islet Respirometrymentioning

confidence: 99%

Section: Targeted Metabolomicsmentioning

confidence: 99%

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Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Wortham¹,

F²,

Jy³

et al. 2019

Preprint

Self Cite

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Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

et al. 2020

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Aging is a physiological decline in both structural homeostasis and functional integrity, progressively affecting organismal health. A major hallmark of aging is the accumulation of senescent cells, which have entered a state of irreversible cell cycle arrest after experiencing inherent or environmental stresses. Although cellular senescence is essential in several physiological events, it plays a detrimental role in a large array of age-related pathologies. Recent biomedical advances in specifically targeting senescent cells to improve healthy aging, or alternatively, postpone natural aging and age-related diseases, a strategy termed senotherapy, have attracted substantial interest in both scientific and medical communities. Challenges for aging research are highlighted and potential avenues that can be leveraged for therapeutic interventions to control aging and age-related disorders in the current era of precision medicine.

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Lipid-associated metabolic signalling networks in pancreatic beta cell function

Prentki

Corkey

2019

Diabetologia

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Significant advances have been made in deciphering the mechanisms underlying fuel-stimulated insulin secretion by pancreatic beta cells. The contribution of the triggering/ATP-sensitive potassium (K ATP)-dependent Ca 2+ signalling and K ATP-independent amplification pathways, that include anaplerosis and lipid signalling of glucose-stimulated insulin secretion (GSIS), are well established. A proposed model included a key role for a metabolic partitioning 'switch', the acetyl-CoA carboxylase (ACC)/malonyl-CoA/carnitine palmitoyltransferase-1 (CPT-1) axis, in beta cell glucose and fatty acid signalling for insulin secretion. This model has gained overwhelming support from a number of studies in recent years and is now refined through its link to the glycerolipid/NEFA cycle that provides lipid signals through its lipolysis arm. Furthermore, acetyl-CoA carboxylase may also control beta cell growth. Here we review the evidence supporting a role for the ACC/malonyl-CoA/CPT-1 axis in the control of GSIS and its particular importance under conditions of elevated fatty acids (e.g. fasting, excess nutrients, hyperlipidaemia and diabetes). We also document how it is linked to a more global lipid signalling system that includes the glycerolipid/NEFA cycle.

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Integrated In Vivo Quantitative Proteomics and Nutrient Tracing Reveals Age-Related Metabolic Rewiring of Pancreatic β Cell Function

Cited by 45 publications

References 63 publications

Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Nutrient regulation of the islet epigenome controls adaptive insulin secretion

Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

Lipid-associated metabolic signalling networks in pancreatic beta cell function

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