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The transcription factor CREB has no non-redundant functions in hepatic glucose metabolism in mice

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Abstract

Aims/hypothesis

Excessive hepatic glucose production is a hallmark of insulin resistance in type 2 diabetes. The cAMP responsive transcription factor cAMP responsive element binding protein (CREB), thought to be a key activator of the hepatic gluconeogenic gene regulation programme, has been suggested as a therapeutic target to reduce glucose output by the liver. Here, we test directly the requirement for hepatocytic CREB for the maintenance of glucose homeostasis.

Methods

We derived mice with a Creb (also known as Creb1) loxP allele for conditional, cell-type specific gene ablation. Hepatocyte-specific deletion of Creb was induced by injecting Creb loxP/loxP mice with Cre recombinase expression adeno-associated virus.

Results

Strikingly, we found no difference in fed and fasted glucose levels, or in glucose, insulin and glucagon tolerance in mice fed a normal chow or a high-fat diet. In addition, mRNA levels of liver-specific genes, including several CREB target genes involved in gluconeogenesis, were not affected by CREB deficiency in the liver.

Conclusion/interpretation

Our data show that CREB has no non-redundant functions in hepatic glucose metabolism, and is therefore not likely to be a useful target for the development of glucose-lowering drugs.

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Abbreviations

AAV:

Adeno-associated virus

ACREB:

Acidic cAMP responsive element binding protein

ASO:

Antisense oligonucleotide

CRE:

cAMP responsive element

CREB:

cAMP responsive element binding protein

ES:

Embryonic stem

GFP:

Green fluorescent protein

HNF4α:

Hepatocyte nuclear factor 4α

PPARγ:

Peroxisome proliferator-activated receptor γ

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Acknowledgements

The authors would like to thank J. Richa (Transgenic Chimeric Mouse Facility of the University of Pennsylvania, Philadelphia, PA, USA) for blastocyst injection, A. Sandhu (Penn Vector Core, University of Pennsylvania, Philadelphia, PA, USA) for production of AAV, J. Schug and L. Everett (University of Pennsylvania, Philadelphia, PA, USA) for helpful comments on the design and analysis of mRNA expression profiling, and D. Martinez, N. Panackal and S. Agrio (Pathology Core of the Joseph Stokes Jr Research Institute, Children’s Hospital of Philadelphia, Philadelphia, PA, USA) for histological services.

Funding

This research was supported by the National Institutes of Health (NIH) grant no. P01-DK049210. The Transgenic Chimeric Mouse Facility of the University of Pennsylvania was supported by NIH grant no. P30-DK19525.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

JL performed experiment and data interpretation and derived the Creb conditional gene ablation model. DL performed experiments, acquired data, and performed data analysis and interpretation for characterising the mouse. KHK designed the study and participated in interpretation and discussion of the data. DL wrote the manuscript. JL and KHK carried out critical revisions of the manuscript. DL and KHK are responsible for the integrity of the work as a whole. All authors approved the final versions of the manuscript.

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Authors and Affiliations

  1. Department of Genetics and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, 12-126 Translational Research Center, 3400 Civic Center Boulevard, Philadelphia, PA, 19104-6145, USA

    Dolim Lee, John Le Lay & Klaus H. Kaestner

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  1. Dolim Lee
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  2. John Le Lay
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  3. Klaus H. Kaestner
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Correspondence to Klaus H. Kaestner.

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Lee, D., Le Lay, J. & Kaestner, K.H. The transcription factor CREB has no non-redundant functions in hepatic glucose metabolism in mice. Diabetologia 57, 1242–1248 (2014). https://doi.org/10.1007/s00125-014-3203-2

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  • DOI: https://doi.org/10.1007/s00125-014-3203-2

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