Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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

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.

Your institute does not have access to this article

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

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.

Data availability

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

References

  1. Basseri S, Austin RC. Endoplasmic reticulum stress and lipid metabolism: mechanisms and therapeutic potential. Biochem Res Int. 2012;2012:841362.

    Article  Google Scholar 

  2. Sampieri L, Di Giusto P, Alvarez C. CREB3 transcription factors: ER-Golgi stress transducers as hubs for cellular homeostasis. Front Cell Dev Biol. 2019;7:123.

    Article  Google Scholar 

  3. Piperi C, Adamopoulos C, Papavassiliou AG. XBP1: a pivotal transcriptional regulator of glucose and lipid metabolism. Trends Endocrinol Metab. 2016;27:119–22.

    CAS  Article  Google Scholar 

  4. Zhang C, Wang G, Zheng Z, Maddipati KR, Zhang X, Dyson G, et al. ER-tethered transcription factor CREBH regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress. Hepatology. 2012;55:1070–82.

    CAS  Article  Google Scholar 

  5. Yoshida H, Okada T, Haze K, Yanagi H, Yura T, Negishi, et al. ATF6 activated by proteolysis binds in the presence of NF-Y (CBF) directly to the cis-acting element responsible for the mammalian unfolded protein response. Mol Cell Biol. 2000;18:6755–67.

    Article  Google Scholar 

  6. Chen X, Zhang F, Gong Q, Cui A, Zhuo S, Hu Z, et al. Hepatic ATF6 increases fatty acid oxidation to attenuate hepatic steatosis in mice through peroxisome proliferator–activated receptor α. Diabetes. 2016;65:1904–15.

    CAS  Article  Google Scholar 

  7. Usui M, Yamaguchi S, Tanji Y, Tominaga R, Ishigaki Y, Fukumoto M, et al. Atf6α-null mice are glucose intolerant due to pancreatic β-cell failure on a high-fat diet but partially resistant to diet-induced insulin resistance. Metabolism. 2012;61:1118–28.

    CAS  Article  Google Scholar 

  8. Lowe CE, Dennis RJ, Obi U, O’Rahilly S, Rochford JJ. Investigating the involvement of the ATF6α pathway of the unfolded protein response in adipogenesis. Int J Obes. 2012;36:1248–51.

    CAS  Article  Google Scholar 

  9. Lu R, Yang P, O’Hare P, Misra V. Luman, a new member of the CREB/ATF family, binds to herpes simplex virus VP16-associated host cellular factor. Mol Cell Biol. 1997;9:5117–26.

    Article  Google Scholar 

  10. Raggo C, Rapin N, Stirling J, Gobeil P, Smith-Windsor E, O’Hare P, et al. Luman, the cellular counterpart of herpes simplex virus VP16, is processed by regulated intramembrane proteolysis. Mol Cell Biol. 2002;16:5639–49.

    Article  Google Scholar 

  11. Liang G, Audas TE, Li Y, Cockram GP, Dean JD, Martyn, et al. Luman/CREB3 induces transcription of the endoplasmic reticulum (ER) stress response protein Herp through an ER stress response element. Mol Cell Biol. 2006;21:7999–8010.

    Article  Google Scholar 

  12. DenBoer LM, Hardy-Smith PW, Hogan MR, Cockram GP, Audas TE, Lu R. Luman is capable of binding and activating transcription from the unfolded protein response element. Biochem Biophys Res Commun. 2005;331:113–9.

    CAS  Article  Google Scholar 

  13. Audas TE, Li Y, Liang G, Lu R. A novel protein, Luman/CREB3 recruitment factor, inhibits Luman activation of the unfolded protein response. Mol Cell Biol. 2008;12:3952–66.

    Article  Google Scholar 

  14. Minster RL, Hawley NL, Su CT, Sun G, Kershaw EE, Cheng H, et al. A thrifty variant in CREBRF strongly influences body mass index in Samoans. Nat Genet. 2016;48:1049–54.

    CAS  Article  Google Scholar 

  15. Chan C, Kok K, Jin D. CREB3 subfamily transcription factors are not created equal: recent insights from global analyses and animal models. Cell Biosci. 2011;1:6.

    Article  Google Scholar 

  16. Ying Z, Zhang R, Verge VM, Misra V. Cloning and characterization of rat Luman/CREB3, a transcription factor highly expressed in nervous system tissue. J Mol Neurosci. 2015;55:347–54.

    CAS  Article  Google Scholar 

  17. Satoh A, Han S, Araki M, Nakagawa Y, Ohno H, Mizunoe Y, et al. CREBH improves diet-induced obesity, insulin resistance, and metabolic disturbances by FGF21-dependent and FGF21-independent mechanisms. iScience. 2020;23:100930.

    CAS  Article  Google Scholar 

  18. Nakagawa Y, Satoh A, Tezuka H, Han S, Takei K, Iwasaki H, et al. CREB3L3 controls fatty acid oxidation and ketogenesis in synergy with PPARα. Sci Rep. 2016;6:39182.

    CAS  Article  Google Scholar 

  19. Nakagawa Y, Shimano H. CREBH regulates systemic glucose and lipid metabolism. Int J Mol Sci. 2018;19:1396.

    Article  Google Scholar 

  20. Nakagawa Y, Satoh A, Yabe S, Furusawa M, Tokushige N, Tezuka H, et al. Hepatic CREB3L3 controls whole-body energy homeostasis and improves obesity and diabetes. Endocrinology. 2014;155:4706–19.

    Article  Google Scholar 

  21. Kim TH, Jo SH, Choi H, Park JM, Kim MY, Nojima H, et al. Identification of Creb3l4 as an essential negative regulator of adipogenesis. Cell Death Dis. 2014;5:e1527.

    CAS  Article  Google Scholar 

  22. Penney J, Mendell A, Zeng M, Tran K, Lymer J, Turner, et al. LUMAN/CREB3 is a key regulator of glucocorticoid-mediated stress responses. Mol Cell Endocrinol. 2017;439:95–104.

    CAS  Article  Google Scholar 

  23. Babicki S, Arndt D, Marcu A, Liang Y, Grant JR, Maciejewski A, et al. Heatmapper: web-enabled heat mapping for all. Nucleic Acids Res. 2016;44:W147–53.

    CAS  Article  Google Scholar 

  24. Sanyal AJ, Pacana T. A lipidomic readout of disease progression in a diet-induced mouse model of nonalcoholic fatty liver disease. Trans Am Clin Climatol Assoc. 2015;126:271–88.

    PubMed  PubMed Central  Google Scholar 

  25. Miller KK, Parulekar MS, Schoenfeld E, Anderson E, Hubbard J, Klibanski A, et al. Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. J Clin Endocrinol Metab. 1998;83:2309–12.

    CAS  PubMed  Google Scholar 

  26. Baldwin KM, Joanisse DR, Haddad F, Goldsmith RL, Gallagher D, Pavlovich KH, et al. Effects of weight loss and leptin on skeletal muscle in human subjects. Am J Physiol Regul Integr Comp Physiol. 2011;301:R1259–66.

    CAS  Article  Google Scholar 

  27. Sha H, He Y, Chen H, Wang C, Zenno A, Shi H, et al. The IRE1α-XBP1 pathway of the unfolded protein response is required for adipogenesis. Cell Metab. 2009;9:556–4.

    CAS  Article  Google Scholar 

  28. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell. 2001;107:881–91.

    CAS  Article  Google Scholar 

  29. Brown MS, Goldstein JL. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell. 1997;89:331–40.

    CAS  Article  Google Scholar 

  30. Yamamoto K, Yoshida H, Kokame K, Kaufman RJ, Mori K. Differential contributions of ATF6 and XBP1 to the activation of endoplasmic reticulum stress-responsive cis-acting elements ERSE, UPRE and ERSE-II. J Biochem. 2004;136:343–50.

    CAS  Article  Google Scholar 

  31. Kim H, Mendez R, Zheng Z, Chang L, Cai J, Zhang R, et al. Liver-enriched transcription factor CREBH interacts with peroxisome proliferator-activated receptor α to regulate metabolic hormone FGF21. Endocrinology. 2014;155:769–82.

    CAS  Article  Google Scholar 

  32. Ruan HB, Han X, Li MD, Singh JP, Qian K, Azarhoush S. O-GlcNAc transferase/host cell factor C1 complex regulates gluconeogenesis by modulating PGC-1α stability. Cell Metab. 2012;16:226–37.

    CAS  Article  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

Authors

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.

Corresponding authors

Correspondence to Marica Bakovic or Ray Lu.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41366-022-01128-w

Search

Quick links