Methylation of <i>Tcf712</i> promoter by high‐fat diet impairs β‐cell function in mouse pancreatic islets

Hu, Yun; Shi, Peng; He, Ke; Zhu, Yunqing; Yang, Fan; Yang, Min; He, Bangshun; Mao, Xiao‐Ming

doi:10.1002/dmrr.2980

Cited by 6 publications

(5 citation statements)

References 39 publications

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“…High fat diet was found to epigenetically impact TCF7L2, a transcription factor required for pancreatic β-cell survival ( 84). An experimental study demonstrated that mice treated with high fat diet showed an aberrant methylation at the promoter region of the TCF7L2 in β-cells compared to mice fed with a normal diet (84). Although defects in TCF7L2 were commonly detected in T2DM patients, a subset of non-obese T1DM patients were also found to have the same defect (104).…”

Section: Diet and Epigenetic Interplay In T1dm Pathogenesismentioning

confidence: 99%

The Interplay Between Diet and the Epigenome in the Pathogenesis of Type-1 Diabetes

et al. 2021

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The autoimmune disease, Type 1 Diabetes Mellitus (T1DM), results in the destruction of pancreatic β-cells, and the International Diabetes Federation reports that its incidence is increasing worldwide. T1DM is a complex disease due to the interaction between genetic and environmental factors. Certain dietary patterns and nutrients are known to cause epigenetic modifications in physiological conditions and diseases. However, the interplay between diet and epigenetics is not yet well-understood in the context of T1DM. Several studies have described epigenetic mechanisms involved in the autoimmune reactions that destroy the β-cells, but few explored diet components as potential triggers for epigenetic modifications. Clarifying the link between diet and epigenome can provide new insights into the pathogenesis of T1DM, potentially leading to new diagnostic and therapeutic approaches. In this mini review, we shed light on the influence of the diet-epigenome axis on the pathophysiology of T1DM.

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Section: Diet and Epigenetic Interplay In T1dm Pathogenesismentioning

confidence: 99%

The Interplay Between Diet and the Epigenome in the Pathogenesis of Type-1 Diabetes

et al. 2021

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“…Increased DNA Methylation in E-Boxes in Promoter/ Enhancer Areas of Cell Cycle Genes in 1-Year-Old Mice Fed Short-term HFD An HFD has been reported to induce methylation changes in gene regulatory regions in multiple tissues, including pancreatic b-cells (45,46). Therefore, we used a targeted DNA methylation analysis (47) to investigate the DNA methylation pattern of the 21 Myc-targeting cell cycle genes identified in Fig.…”

Section: Myc Recruitment To Cell Cycle Promoters Is Enhanced In Isletmentioning

confidence: 99%

Myc Is Required for Adaptive β-Cell Replication in Young Mice but Is Not Sufficient in One-Year-Old Mice Fed With a High-Fat Diet

et al. 2019

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Failure to expand pancreatic β-cells in response to metabolic stress leads to excessive workload resulting in β-cell dysfunction, dedifferentiation, death, and development of type 2 diabetes. In this study, we demonstrate that induction of Myc is required for increased pancreatic β-cell replication and expansion during metabolic stress–induced insulin resistance with short-term high-fat diet (HFD) in young mice. β-Cell–specific Myc knockout mice fail to expand adaptively and show impaired glucose tolerance and β-cell dysfunction. Mechanistically, PKCζ, ERK1/2, mTOR, and PP2A are key regulators of the Myc response in this setting. DNA methylation analysis shows hypomethylation of cell cycle genes that are Myc targets in islets from young mice fed with a short-term HFD. Importantly, DNA hypomethylation of Myc response elements does not occur in islets from 1-year-old mice fed with a short-term HFD, impairing both Myc recruitment to cell cycle regulatory genes and β-cell replication. We conclude that Myc is required for metabolic stress–mediated β-cell expansion in young mice, but with aging, Myc upregulation is not sufficient to induce β-cell replication by, at least partially, an epigenetically mediated resistance to Myc action.

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“…We also measured the expression of transcription factors that regulate Gipr and/or Glp-1r expression, namely E2f1, MafA, Nkx6.1, Pax6, Pparγ, and Tcf7l2, and found a significant reduction in the expression of all except MafA when comparing Prlr-/to Prlr+/+ mice (Figure 5f). It is interesting to note that all of these transcription factors have been associated with β-cell adaptation during HFD 43,[57][58][59] , but only E2f1 and Pparγ are known to be downstream of PRLR signaling 60,61 .…”

Section: Discussionmentioning

confidence: 99%

Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling

Lee,

Kahlon,

Kola-Ilesanmi

et al. 2024

Preprint

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The role of prolactin receptor (PrlR) signaling in beta-cell adaptation to maternal insulin resistance of pregnancy has been well demonstrated. Using transgenic mice with an inducible beta-cell-specific PrlR deletion bPrlR-/-), we found that intact PrlR, as found in bPrlR+/+ mice, were protected from developing glucose intolerance during pregnancy, and the main mechanism responsible for this PrlR-mediated effect is the up regulation of beta-cell proliferation and insulin synthesis. Interestingly, studies in male mice and humans have found a link between diminished PrlR signaling and abnormal beta-cell function. We aimed to determine whether PrlR has a role in regulating beta-cell function outside of pregnancy, protecting beta-cell against exposure to metabolic stressors. In this study, we found that beta-cell-specific PrlR reduction resulted in impaired glucose tolerance in multiparous female mice challenged with a 12-week course of high-fat diet (HFD). Unlike in pregnancy, where PrlR signaling up regulates beta-cell proliferation resulting in a greater beta-cell mass, we observed no difference in beta-cell mass between the wild type (bPrlR+/+) and mutant (bPrlR-/-) mice. In vitro glucose-stimulated insulin secretion using isolated islets from wild type (bPrlR+/+) and mutant (bPrlR-/-) mice showed comparable insulin response, but bPrlR-/- mice showed blunted first-phase insulin release in vivo, although only when challenged with glucose orally and not intraperitoneally, suggesting an impairment of the incretin effect. In support of the observed defect in incretin action, we found a reduction in expression of both incretin hormone receptors, Gipr and Glp-1r, and several of their upstream regulators, such as E2f1, Nkx6.1, Pax6, Pparg, and Tcf7l2. Together, these results suggested that PrlR signaling plays an important role in preserving beta-cell function in mice exposed to metabolic stress by maintaining incretin receptor expression in beta-cells.

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Methylation of Tcf712 promoter by high‐fat diet impairs β‐cell function in mouse pancreatic islets

Abstract: An HFD was shown to induce aberrant methylation of the Tcf7l2 promoter in mouse islets, which resulted in diminished gene expression. This study provides an evidence of the association between nutrient consumption and gene expression.

Cited by 6 publications

References 39 publications

The Interplay Between Diet and the Epigenome in the Pathogenesis of Type-1 Diabetes

The Interplay Between Diet and the Epigenome in the Pathogenesis of Type-1 Diabetes

Myc Is Required for Adaptive β-Cell Replication in Young Mice but Is Not Sufficient in One-Year-Old Mice Fed With a High-Fat Diet

Beta-cell adaptation to metabolic stresses requires prolactin receptor signaling

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