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Transcription factor CREB3 is a potent regulator of high-fat diet-induced obesity and energy metabolism

International Journal of Obesity volume 46, pages 1446–1455 (2022)Cite this article

Subjects

Abstract

Background

The endoplasmic reticulum senses alterations to cellular homeostasis that activates the unfolded protein response (UPR). UPR proteins are known to aid in regulating glucose and lipid metabolism. CREB3 is a UPR-associated transcription factor whose potential role in regulating energy metabolism remains unclear.

Methods

Eight-week-old wild-type (WT) and Creb3+/− mice were placed on control and high-fat diets (HFD) for 8 weeks, and metabolic phenotypes characterized by weekly weighing, indirect calorimetry, body composition scans, glucose tolerance tests, plasma analysis, tissue lipid quantifications and gene/protein expression analysis.

Results

HFD weight gain in Creb3+/− males was reduced by 34% (p < 0.0001) and females by 39.5% (p = 0.014) from their WT counterparts. No differences were found in HFD food intake or total fecal lipids between genotypes. Creb3+/− mice had increased energy expenditure and respiratory exchange ratios (p = 0.002) relative to WT. Creb3+/− mice had significant reductions in absolute fat and lean tissue, while Creb3+/− females had significant reductions in body fat% and increased lean% composition (p < 0.0001) compared to WT females. Creb3+/− mice were protected from HFD-induced basal hyperglycemia (males p < 0.0001; females p = 0.0181). Creb3+/− males resisted HFD-induced hepatic lipid accumulation (p = 0.025) and glucose intolerance compared to WT (p < 0.0001) while Creb3+/− females were protected from lipid accumulation in skeletal muscle (p = 0.001). Despite the metabolic differences of Creb3+/− mice on HFD, lipid plasma profiles did not significantly differ from WT. Fasted Creb3+/− mice additionally revealed upregulation of hepatic energy expenditure and gluconeogenic genes such as Pgc-1a and Gr (glucocorticoid receptor) (p < 0.05), respectively.

Conclusions

Reduced expression of CREB3 increased energy expenditure and the respiratory exchange ratio, and protected mice from HFD-induced weight gain, basal hyperglycemia, and sex-specific tissue lipid accumulation. We postulate that CREB3 is a novel key regulator of diet-induced obesity and energy metabolism that warrants further investigation as a potential therapeutic target in metabolic disorders.

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Fig. 1: Creb3-deficient mice are resistant to high-fat diet-induced obesity and hepatic steatosis.
Fig. 2: WT and Creb3+/− fasted plasma lipid analysis on CD or HFD.
Fig. 3: Creb3-deficient mice have increased energy expenditure and respiratory exchange ratio on HFD.
Fig. 4: Creb3-deficient mice preserve glucose tolerance on a high-fat diet.
Fig. 5: Creb3-deficient mice have altered hepatic metabolic gene expression.
Fig. 6: Creb3-deficient mice have altered hepatic lipid profiles on HFD.

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Data availability

The data supporting the findings of this study are available from the corresponding author, RL, upon reasonable request.

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Acknowledgements

Special thanks to Tiegh Taylor and Dr. Jenna Penney for assistance with experimental procedures. Thank you to the Central Animal Facility at the University of Guelph for mouse colony care and maintenance. Thanks to Dr. Adronie Verbrugghe of the Ontario Veterinary College at the University of Guelph for use of their DXA machine. Thank you to the Analytical Facility for Bioactive Molecules at SickKids Hospital for the TOF-MS Lipids Analysis.

Funding

Funded by Ontario Ministry of Agriculture, Food and Rural Affairs (OMAFRA), NSERC Collaborative Research & Development and MITACS.

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Author notes

  1. These authors contributed equally: Marica Bakovic, Ray Lu.

Authors and Affiliations

  1. Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON, Canada

    Brandon S. Smith & Ray Lu

  2. Department of Kinesiology & Health Sciences, University of Waterloo, Waterloo, ON, Canada

    Kalsha H. Diaguarachchige De Silva, Ashkan Hashemi & Robin E. Duncan

  3. Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada

    Sophie Grapentine & Marica Bakovic

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  1. Brandon S. Smith
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Contributions

BSS devised the study, carried out experiments, analyzed data, and wrote the paper. KHDD, AH, and SG performed experiments and analyzed data. RED, MB, and RL contributed to experimental design and paper writing.

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Correspondence to Marica Bakovic or Ray Lu.

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Smith, B.S., Diaguarachchige De Silva, K.H., Hashemi, A. et al. Transcription factor CREB3 is a potent regulator of high-fat diet-induced obesity and energy metabolism. Int J Obes 46, 1446–1455 (2022). https://doi.org/10.1038/s41366-022-01128-w

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