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The daily caloric restriction and alternate-day fasting ameliorated lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1

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Abstract

Purpose

A possible link between pescadillo 1 (PES1) and lipid metabolism has been reported. However, whether PES1 is involved in the effects of daily caloric restriction (CR) and alternate-day fasting (ADF) interventions on diabetes-related lipid dysregulation is not elucidated. The current study aims are to explore the role of PES1 in effects of CR and ADF on diabetic mice and related mechanism.

Methods

Eight-week-old male db/db mice with type 2 diabetes mellitus (T2DM) were randomly divided into untreated T2DM, CR and ADF groups. McArdle hepatocytes were treated with 48 h high glucose (HG), 48 h normal glucose (NG) and 24 h HG plus 24 h NG, respectively. Pes1 siRNA and overexpression plasmid were, respectively, transfected into liver cells, and AAV9-Pes1-shRNA was injected into db/db mice.

Results

After 12-week interventions, the peroxisome proliferator-activated receptor alpha (PPAR-α) and carnitine palmitoyltransferase 1A (CPT1A) levels in livers of T2DM mice were enhanced by CR and ADF interventions with reductions of hepatic and plasma triglycerides. Unexpectedly, hepatic PES1 levels were downregulated by two interventions, consistent with the results of 48 h NG and 24 h HG plus 24 h NG-treated cells. Moreover, CPT1A level was upregulated in Pes1-siRNA-treated cells and AAV9-Pes1-shRNA injected murine livers, in contrast to Pes1 overexpression in cultured cells. Mechanistically, 48 h NG or 24 h HG plus 24 h NG treatment increased PPAR-α binding to Pes1 promoter, suppressing the PES1 expression, thereby lowering the PES1-mediated ubiquitination of CPT1A.

Conclusion

The present study suggests that CR and ADF may improve lipid dysregulation in diabetic mice by downregulating hepatic PES1.

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Data Availability Statement

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We thank all the participants in the present study.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC, 81570786 to K.C and 82070986 to Z.J), Wanjiang scholar grants from Anhui Province of China (9101041203 to Z.J).

Author information

Author notes

  1. Jielin Zhou and Zhengxuan Jiang contributed equally to this work.

Authors and Affiliations

  1. Department of Nutrition and Food Hygiene, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China

    Jielin Zhou, Chengcheng Li, Mengjun Tian & Keyang Chen

  2. Department of Ophthalmology, The Second Affiliated Hospital, Anhui Medical University, Hefei, 230021, Anhui, China

    Zhengxuan Jiang

  3. Department of Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, 230032, Anhui, China

    Yan Lin, Juan Liu & Keyang Chen

  4. AIER Hefei Eye Hospital Affiliated To Anhui Medical University, Hefei, 230031, Anhui, China

    Yong Liu

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  1. Jielin Zhou
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  3. Yan Lin
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  5. Juan Liu
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Contributions

JZ prepared the manuscript. JZ, ZJ, and YL performed the experimental work. JZ, MT, CL, and JL performed the statistical analysis. YL*, KC designed the research, edited/revised manuscript and ZJ and KC provided the finical supports. All authors approved the manuscript for publication.

Corresponding authors

Correspondence to Yong Liu or Keyang Chen.

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The authors declare no conflict of interest.

Ethics approval

This study was approved by the Institutional Animal Care and Use Committee of Anhui Medical University, in accordance with the International Guidance principles for Biomedical Research Involving Animals of CIOMS; Protocol license number: LLSC 20180152.

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Zhou, J., Jiang, Z., Lin, Y. et al. The daily caloric restriction and alternate-day fasting ameliorated lipid dysregulation in type 2 diabetic mice by downregulating hepatic pescadillo 1. Eur J Nutr 61, 2775–2797 (2022). https://doi.org/10.1007/s00394-022-02850-x

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  • DOI: https://doi.org/10.1007/s00394-022-02850-x

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