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TAZ promotes PDX1-mediated insulinogenesis

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Abstract

Transcriptional co-activator with PDZ-binding motif (TAZ) is a key mediator of the Hippo signaling pathway and regulates structural and functional homeostasis in various tissues. TAZ activation is associated with the development of pancreatic cancer in humans, but it is unclear whether TAZ directly affects the structure and function of the pancreas. So we sought to identify the TAZ function in the normal pancreas. TAZ defect caused structural changes in the pancreas, particularly islet cell shrinkage and decreased insulin production and β-cell markers expression, leading to hyperglycemia. Interestingly, TAZ physically interacted with the pancreatic and duodenal homeobox 1 (PDX1), a key insulin transcription factor, through the N-terminal domain of TAZ and the homeodomain of PDX1. TAZ deficiency decreased the DNA-binding and transcriptional activity of PDX1, whereas TAZ overexpression promoted PDX1 activity and increased insulin production even in a low glucose environment. Indeed, high glucose increased insulin production by turning off the Hippo pathway and inducing TAZ activation in pancreatic β-cells. Ectopic TAZ overexpression along with PDX1 activation was sufficient to produce insulin in non-β-cells. TAZ deficiency impaired the mesenchymal stem cell differentiation into insulin-producing cells (IPCs), whereas TAZ recovery restored normal IPCs differentiation. Compared to WT control, body weight increased in TAZ-deficient mice with age and even more with a high-fat diet (HFD). TAZ deficiency significantly exacerbated HFD-induced glucose intolerance and insulin resistance. Therefore, TAZ deficiency impaired pancreatic insulin production, causing hyperglycemia and exacerbating HFD-induced insulin resistance, indicating that TAZ may have a beneficial effect in treating insulin deficiency in diabetes.

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Data availability

No datasets were generated during the current study, and all data are provided in full in the results section of this paper.

Abbreviations

ChIP:

Chromatin immunoprecipitation

FoxA2:

Forkhead box A2

GCG:

Glucagon

Glut:

Glucose transporter

GSIS:

Glucose-stimulated insulin secretion

GTT:

Glucose tolerance test

HFD:

High-fat diet

INS:

Insulin

ITT:

Insulin tolerance test

IPCs:

Insulin-producing cells

KO:

Knockout

LATS:

Large tumor suppressor

MSC:

Mesenchymal stem cell

MST:

Mammalian sterile 20-like

NCD:

Normal chow diet

NFAT:

Nuclear factor of activated T cells

NR4A1:

Nuclear receptor 4A1

PAX6:

Paired box protein 6

PDX1:

Pancreatic duodenal homeobox 1

P-KO:

Pancreas-specific KO

PPARγ:

Peroxisome proliferator-activated receptor γ

RUNX:

Runt-related transcription factor

SI:

Stimulation index

TAZ:

Transcriptional co-activator with PDZ-binding motif

TEAD:

TEA domain transcription factor

WT:

Wild type

YAP:

Yes-associated protein

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Acknowledgements

We thank Drs. Jeong-Ho Hong, Hun-Joo Ha, Soo-Young Lee, and Kong-Joo Lee for providing TAZ expression vectors, human insulin, Plat-E, and INS-1 cells, respectively. This work was supported by grants from the National Research Foundation of South Korea (2018R1A5A2025286 and 2020R1A2C2004679) and Korea Basic Science Institute (2021R1A6C101A442).

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  1. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, C206 Science Building, 52 Ewhayeodae-Gil, Seodaemun-Gu, Seoul, 03760, South Korea

    Mi Gyeong Jeong, Hyo Kyeong Kim, Gibbeum Lee, Hee Yeon Won, Da Hye Yoon & Eun Sook Hwang

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Contributions

MGJ performed most in vitro and in vivo experiments, and HKK performed immunohistochemistry. GL conducted the in vivo experiments, and HYW performed the retroviral transduction and established stable cell lines. DHY contributed to the immunoprecipitation and immunoblot analysis. ESH designed all the experiments and prepared the manuscript for publication.

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Correspondence to Eun Sook Hwang.

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All animal care and experiments were approved by the International Animal Care and Use Committee (IACUC; 2010-13-3, 2015-01-020, 17-013, and 19-031) at Ewha Womans University and were conducted according to the IACUC guidelines. The study was performed in accordance with the Declaration of Helsinki.

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Jeong, M.G., Kim, H.K., Lee, G. et al. TAZ promotes PDX1-mediated insulinogenesis. Cell. Mol. Life Sci. 79, 186 (2022). https://doi.org/10.1007/s00018-022-04216-2

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