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Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model.

ABSTRACT: Elucidating the mechanisms of regulation of β-cell proliferation is key to understanding the pathogenesis of diabetes mellitus. Txnip is a tumor suppressor that is upregulated in diabetes and plays an important role in the regulation of insulin sensitivity; however, its potential effect on pancreatic β-cell proliferation remains unclear. Here, we evaluated the role of Txnip in pancreatic β-cell compensatory proliferation by subjecting WT and Txnip knockout (KO) mice to a high-fat diet (HFD). Our results demonstrate that Txnip deficiency improves glucose tolerance and increases insulin sensitivity in HFD-induced obesity. The antidiabetogenic effect of Txnip deficiency was accompanied by increased β-cell proliferation and enhanced β-cell mass expansion. Furthermore, Txnip deficiency modulated the expression of a set of transcription factors with key roles in β-cell proliferation and cell cycle regulation. Txnip KO in HFD mice also led to activated levels of p-PI3K, p-AKT, p-mTOR and p-GSK3β, suggesting that Txnip may act via PI3K/AKT signaling to suppress β-cell proliferation. Thus, our work provides a theoretical basis for Txnip as a new therapeutic target for the treatment of diabetes mellitus.

SUBMITTER: Lei Z

PROVIDER: S-EPMC9066588 | biostudies-literature | 2022 Apr

REPOSITORIES: biostudies-literature

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Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model.

Lei Zhandong Z Chen Yunfei Y Wang Jin J Zhang Yan Y Shi Wenjuan W Wang Xuejiao X Xing Dehai D Li Dongxue D Jiao Xiangying X

Endocrine connections 20220429 4

Elucidating the mechanisms of regulation of β-cell proliferation is key to understanding the pathogenesis of diabetes mellitus. Txnip is a tumor suppressor that is upregulated in diabetes and plays an important role in the regulation of insulin sensitivity; however, its potential effect on pancreatic β-cell proliferation remains unclear. Here, we evaluated the role of Txnip in pancreatic β-cell compensatory proliferation by subjecting WT and Txnip knockout (KO) mice to a high-fat diet (HFD). Our ...[more]

PMID: 35294398

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Project description:ᅟ: Astrocytosis is a reactive process involving cellular, molecular, and functional changes to facilitate neuronal survival, myelin preservation, blood brain barrier function and protective glial scar formation upon brain insult. The overall pro- or anti-inflammatory impact of reactive astrocytes appears to be driven in a context- and disease-driven manner by modulation of astrocytic Ca2+ homeostasis and activation of Ca2+/calmodulin-activated serine/threonine phosphatase calcineurin. Here, we aimed to assess whether calcineurin is dispensable for astrocytosis in the hypothalamus driven by prolonged high fat diet (HFD) feeding. Global deletion of calcineurin A beta (gene name: Ppp3cb) led to a decrease of glial fibrillary acidic protein (GFAP)-positive cells in the ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), and arcuate nucleus (ARC) of mice exposed chronically to HFD. The concomitant decrease in Iba1-positive microglia in the VMH further suggests a modest impact of Ppp3cb deletion on microgliosis. Pharmacological inhibition of calcineurin activity by Fk506 had no impact on IBA1-positive microglia in hypothalami of mice acutely exposed to HFD for 1 week. However, Fk506-treated mice displayed a decrease in GFAP levels in the ARC. In vivo effects could not be replicated in cell culture, where calcineurin inhibition by Fk506 had no effect on astrocytic morphology, astrocytic cell death, GFAP, and vimentin protein levels or microglia numbers in primary hypothalamic astrocytes and microglia co-cultures. Further, adenoviral overexpression of calcineurin subunit Ppp3r1 in primary glia culture did not lead to an increase in GFAP fluorescence intensity. Overall, our results point to a prominent role of calcineurin in mediating hypothalamic astrocytosis as response to acute and chronic HFD exposure. Moreover, discrepant findings in vivo and in cell culture indicate the necessity of studying astrocytes in their "natural" environment, i.e., preserving an intact hypothalamic microenvironment with neurons and non-neuronal cells in close proximity.

Dataset Information

Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model.

Publications

Txnip deficiency promotes β-cell proliferation in the HFD-induced obesity mouse model.

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